Colorectal Cancer Patients Research Articles

Comprehensive Analysis and Experimental Validation of HEPACAM2 as a Potential Prognosis Biomarker and Immunotherapy Target in Colorectal Cancer.

The role of HEPACAM family member 2 (HEPACAM2) is unclear in colorectal cancer (CRC). The objective of this study was to perform an extensive examination of HEPACAM2 and validate it experimentally in CRC. This study investigated the significance of HEPACAM2 in CRC and its potential diagnostic utility utilizing data from the Cancer Genome Atlas (TCGA) database. Additionally, the study examined potential regulatory networks involving HEPACAM2, including its associations with immune infiltration, immune checkpoint genes, tumor mutational burden (TMB), microsatellite instability (MSI), mRNA expression-based stemness index (mRNAsi), and drug sensitivity in CRC. The expression of HEPACAM2 was further validated using the GSE89076 dataset, and quantitative reverse transcription PCR (qRT-PCR) was employed to confirm HEPACAM2 expression levels in six pairs of CRC tissue samples. HEPACAM2 exhibited abnormal expression patterns in various types of cancer, including CRC. A decrease in HEPACAM2 expression levels in CRC was found to be significantly correlated with the T stage (p < 0.001). Reduced HEPACAM2 expression in CRC patients was also linked to poorer overall survival (OS) (p = 0.007). The expression levels of HEPACAM2 in CRC patients were identified as an independent prognostic factor (p = 0.016). Furthermore, HEPACAM2 was associated with TCF-dependent signaling in response to WNT, G2/M checkpoints, and other pathways. The expression of HEPACAM2 in CRC was found to be associated with immune infiltration, immune checkpoint genes, TMB / MSI, and mRNAsi. Additionally, the expression of HEPACAM2 in CRC was significantly and inversely correlated with the drug sensitivities to gw772405x and 6-phenyl-6h-indeno[1,2-c]isoquinoline-5,11-dione. qRT-PCR confirmed that the expression level of HEPACAM2 was found to be lowly expressed in CRC tissues. These findings suggest that HEPACAM2 may serve as a potential prognostic biomarker and immunotherapeutic target for CRC patients.

A novel colorimetric assay for the detection of urinary N1, N12-diacetylspermine, a known biomarker for colorectal cancer

Urinary N1, N12-diacetylspermine (DAS) is a known biomarker for colorectal cancer (CRC). However, DAS levels in both healthy and CRC patients’ urine samples are extremely low and often challenging to quantify. Complex and expensive methods do exist to detect DAS in urine, but simpler, less expensive methods to detect DAS are needed, especially in low resource settings. Here we describe a highly efficient, fast, precise, and inexpensive colorimetric assay to detect low levels of DAS in human urine samples. We used recombinant diacetylspermine oxidase (rDAS Ox), expressed and extracted from E. coli, to oxidize DAS, producing three products including hydrogen peroxide (H2O2). The level of DAS present, which correlates with H2O2 levels, was measured using horseradish peroxidase (HRP), which together with H2O2, oxidized Amplex™ Red to produce the pink-colored resorufin. The concentration of resorufin is directly proportional to H2O2 (and DAS) levels. As urine contains metabolites which interfere with these oxidation reactions, we developed a simple two column-based protocol using ion exchange resins to remove these compounds and concentrate the DAS. With this novel cleaning and concentrating method, DAS was concentrated 15 times (confirmed by nuclear magnetic resonance (NMR) spectroscopy) and <1 μM DAS could be detected. Correlation graphs of urine samples spiked with known DAS concentrations versus assay-determined DAS concentrations had high coefficients of determination (R2) for 0-10 μM DAS (0.94) and for 0-1 μM DAS (0.91), clearly demonstrating the excellent performance of the two-column protocol with the rDAS Ox reaction mixture. To the best of our knowledge, this is first reported colorimetric enzymatic assay that quantitates DAS in urine.

Clinical Significance of HHLA2 as a Novel Therapeutic Target for Colorectal Cancer.

Colorectal cancer (CRC) is a high-indence malignance of the digestive system with a high mortality rate in the world. The results are desired to provide an important theoretical basis for discovering new therapeutic targets for CRC. The expression of human endogenous retrovirus-H-long terminal repeat association protein 2 (HHLA2) in human CRC was detected to explore its correlationship with clinicopathological features and prognosis of patients and its potential in treating CRC. Western blot was employed to detect HHLA2 expression in fresh tissues obtained from 6 CRC patients' excisions, including cancer, paracancer, and normal issues. Immunohistochemical staining was employed to determine HHLA2 expression in paraffin-embedded specimens of 139 patients with colorectal cancer, and its relationship with the clinicopathological profiles and survival was analyzed. Small interfering RNA (siRNA) targeting HHLA2 was used to transfect CRC cells to silent HHLA2. MTT, plate colony formation, cell scratch, and Transwell assay were conducted to observe the proliferation, migration, and invasion of CRC cells. HHLA2 protein was expressed in human colorectal cancer tissues, paracancer tissues and normal tissues, which was significantly upregulated in cancer tissues (P<0.01). HHLA2 expression level in CRC tissues showed a close correlationship with the invasion depth of the tumor (P=0.000), metastasis of regional lymph nodes (P=0.018), clinical stage (P=0.010), and patient survival (P=0.011). Correlation with gender (P=0.873), age (P=0.864), location of the tumor (P=0.768), degree of tumor differentiation (P=0.569) and distant metastasis (P=0.494) exhibited no significance. The survival time of CRC patients with high and low HHLA2 expression groups was 43.231 months and 55.649 months, respectively, with a statistical difference between the two groups (P=0.001). Silencing HHLA2 inhibited proliferation, migration and invasion of CRC cells significantly. HHLA2 is overexpressed in CRC tissues which is associated with poor prognosis of patients. HHLA2 might be recognized as a new candidate for adjuvant diagnosis and prognosis of CRC, as well as a promised new target for immunotherapy of CRC.

Establishment and Validation of a Prognostic Nomogram for Predicting Postoperative Overall Survival in Advanced Stage III-IV Colorectal Cancer Patients.

Most colorectal cancer (CRC) patients are at an advanced stage when they are first diagnosed. Risk factors for predicting overall survival (OS) in advanced stage CRC patients are crucial, and constructing a prognostic nomogram model is a scientific method for survival analysis. A total of 2956 advanced stage CRC patients were randomised into training and validation groups at a 7:3 ratio. Univariate and multivariate Cox proportional hazards regression analyses were used to screen risk factors for OS and subsequently construct a prognostic nomogram model for predicting 1-, 3-, 5-, 8- and 10-year OS of advanced stage CRC patients. The performance of the model was demonstrated by the area under the curve (AUC) values, calibration curves and decision curve analysis (DCA). Kaplan-Meier curves were used to plot the survival probabilities for different strata of each risk factor. There was no statistically significant difference (p > 0.05) in the 32 clinical variables between patients in the training and validation groups. Univariate and multivariate Cox proportional hazards regression analyses demonstrated that age, location, TNM, chemotherapy, liver metastasis, lung metastasis, MSH6, CEA, CA199, CA125 and CA724 were risk factors for OS. We estimated the AUC values for the nomogram model to predict 1-, 3-, 5-, 8- and 10-year OS, which in the training group were 0.826 (95% CI: 0.807-0.845), 0.836 (0.819-0.853), 0.839 (0.820-0.859), 0.835 (0.809-0.862) and 0.825 (0.779-0.870) respectively; in the validation group, the corresponding AUC values were 0.819 (0.786-0.852), 0.831 (0.804-0.858), 0.830 (0.799-0.861), 0.815 (0.774-0.857) and 0.802 (0.723-0.882) respectively. Finally, the 1-, 3-, 5-, 8- and 10-year OS rates for advanced stage CRC patients were 73.4 (71.8-75.0), 49.5 (47.8-51.4), 43.3 (41.5-45.2), 40.1 (38.1-41.9) and 38.6 (36.6-40.8) respectively. We constructed and validated an original nomogram for predicting the postoperative OS of advanced stage CRC patients, which can help facilitates physicians to accurately assess the individual survival of postoperative patients and identify high-risk patients.

New Treatment Modalities for Colorectal Cancer Through Simultaneous Suppression of FSP1 and GPX4.

Ferroptosis is a nonapoptotic type of cell death that is dependent on iron and involves the accumulation of reactive oxygen species. Ferroptosis suppressor protein 1 (FSP1) and glutathione peroxidase 4 (GPX4) are ferroptosis regulators that inhibit ferroptosis through independent pathways. This study assessed the prognostic value of GPX4 and FSP1 expression in colorectal cancer (CRC). We also examined the effects of FSP1 and GPX4 inhibition on cell survival of CRC cells. This study included 206 surgical specimens from Stage II or III CRC patients. FSP1 and GPX4 expression was analyzed immunohistochemically, and the association of their expression levels with clinical outcome was evaluated. We also examined the effects of FSP1 and GPX4 inhibitors on the cell proliferative capacity of CRC cell lines. Overall survival and recurrence-free survival were reduced in patients with high expression of FSP1 or GPX4, and those with both GPX4 and FSP1 expression showed worse prognosis. Positivity of both FSP1 and GPX4 was an independent poor prognostic factor for CRC patients. In CRC cells, the combination of GPX4 and FSP1 inhibitors led to more effective cell death than either inhibitor alone. High expression of both GPX4 and FSP1 is a significant poor prognostic factor for CRC. Simultaneous inhibition of GPX4 and FSP1 to induce ferroptosis may be a novel therapeutic strategy in CRC.

Noncoding RNA Linc00475 promotes the proliferation of colorectal cancer cells by targeting miR-107/CDK6 axis.

Colorectal cancer (CRC) represents a substantial challenge to public health. Despite extensive research, the pathogenesis of CRC is not yet fully elucidated, hindering the development of effective therapeutic strategies. Recent advancements have underscored the importance of Non-coding RNAs in tumor biology. Our research identified a significant upregulation of Linc00475 in CRC, which correlated with reduced survival rates among CRC patients. Consequently, this study aimed to elucidate the mechanisms by which Linc00475 contributed to CRC progression. Employing a comprehensive array of experimental techniques-including CCK-8 assays, colony formation assays, flow cytometry, quantitative PCR (qPCR), western blot analysis, and in vivo tumorigenesis assays-we have demonstrated that Linc00475 enhances CRC cell proliferation. Further analysis revealed that Linc00475 directly interacted with miR-107, leading to its downregulation. Moreover, our findings confirmed that miR-107 directly targeted CDK6, which was markedly downregulated following Linc00475 silencing. In vivo experiments further indicated that the silencing of Linc00475 markedly inhibited the proliferation of CRC cells. Collectively, our findings suggested that Linc00475 facilitated CRC cell proliferation through the regulation of the miR-107/CDK6 axis, thereby providing a novel perspective for understanding the molecular mechanisms underlying CRC development.

The ketogenic diet modulates tumor-associated neutrophil polarization via the AMOT-YAP/TAZ axis to inhibit colorectal cancer progression

Despite significant advances in the diagnosis and treatment of colorectal cancer (CRC), the prognosis for late-stage patients remains poor, highlighting the urgent need for new preventive and therapeutic strategies. Recent studies have focused on the ketogenic diet (KD) and its metabolite, β-hydroxybutyrate (BHB), for their tumor-suppressive effects and modulation of inflammatory responses. Using the azoxymethane (AOM) / dextran sulfate sodium (DSS)-induced mouse CRC model, we found that the ketogenic diet and BHB inhibit pro-tumor N2-type tumor-associated neutrophils (TANs) while promoting the polarization of TANs towards the anti-tumor N1 type. This shift in TANs polarization affects tumor growth and metastasis. The underlying mechanism involves BHB acting on the intracellular receptor histone deacetylases 3 (HDAC3), which modulates the activation of the AMOT-YAP/TAZ axis, leading to the inhibition of pro-carcinogenic factor transcription and release. Moreover, clinical cohort data corroborate these findings, showing that CRC patients with elevated BHB levels have significantly lower rates of lymph node involvement, which is associated with a higher infiltration ratio of anti-carcinogenic N1-type TANs in the tumor microenvironment (TME). These results suggest that BHB levels could serve as a prognostic biomarker for CRC. In conclusion, our findings indicate that BHB derived from KD regulates TANs polarization in CRC via the HDAC3-AMOT-YAP/TAZ axis, effectively inhibiting tumor growth and metastasis. These insights establish a novel theoretical basis for employing the KD in the treatment of CRC and for developing cancer adjuvant immunotherapy strategy based on the polarization of neutrophils.

Perception and Coping with Self-Perceived Burden among Colorectal Cancer Patients and their Caregivers: A Qualitative Study

Perception and Coping with Self-Perceived Burden among Colorectal Cancer Patients and their Caregivers: A Qualitative Study

Effects of a couple-based self-efficacy intervention on health outcomes among colorectal cancer patients and spousal caregivers: A randomized controlled trial

Effects of a couple-based self-efficacy intervention on health outcomes among colorectal cancer patients and spousal caregivers: A randomized controlled trial

Emodin disrupts the KITENIN oncogenic complex by binding ErbB4 and suppresses colorectal cancer progression in dual blockade with KSRP-binding compound

BackgroundThe KITENIN/ErbB4 complex has been reported to participate in metastasis, which is the principal reason of death in most colorectal cancer patients. PurposeNew therapeutics need to be developed to suppress the malignant effects of the KITENIN/ErbB4 complex, which is related to drug resistance. The present study aimed to evaluate changes in cancer cell invasion capacity, transcriptional regulators, and cellular bioenergetics after targeting the KITENIN/ErbB4 complex with emodin. Moreover, we aimed to reveal the mechanistic effects of emodin and observe the dual blockade effects of ErbB4-targeted therapy with KH-type splicing regulatory protein (KSRP) and search for new alternative blockade pathways. MethodsUsing in vitro, in vivo, molecular-docking, and metabolomics studies, we evaluated the anticancer effect of emodin alone or in combination with DKC-C14S. ResultsEmodin treatment decreased KITENIN and ErbB4 protein levels. The dysfunctional KITENIN/ErbB4 complex suppressed KITENIN-mediated cell invasion and downregulated AP-1 activity, aerobic glycolysis, and the levels of transcriptional regulators associated with cell metabolism. We conclude that emodin targets the KITENIN/ErbB4 complex and offering a novel mechanism by which it disrupts KITENIN-mediated signaling. Furthermore, we were demonstrated that the dual blocking effect of emodin and DKC-14S on the KITENIN complex showed synergistic effects in suppressing colorectal cancer progression under in cell-based and animal assay. ConclusionThe results suggest that co-treatment with ErbB4 and KSRP-binding compounds could constitute a potential strategy for the control colorectal cancer progression by disrupting the KITENIN complex.

ASO Author Reflections: Stage II/III Colorectal Cancer Patients with Mismatch Repair Deficiency Need More Personalized Adjuvant Chemotherapy.

ASO Author Reflections: Stage II/III Colorectal Cancer Patients with Mismatch Repair Deficiency Need More Personalized Adjuvant Chemotherapy.

Oncogenic KRAS mutations modulate BAX-mediated cell death

Kirsten rat sarcoma viral oncogene homolog (KRAS) belongs to the GTPase RAS superfamily, which regulates several cell-signaling pathways involved in the control of important cellular functions, including apoptosis. Oncogenic mutations in KRAS are considered the most common gain-of-function mutations, affecting 30–50 % of colorectal cancer (CRC) patients. While RAS proteins usually play an anti-apoptotic role, little is known about the involvement of KRAS mutations in apoptosis regulation. Here, we aimed to elucidate the role of mutated human KRAS in the regulation of BAX, a key pro-apoptotic member of the Bcl-2 family. For this purpose, we took advantage of the simpler yeast model Saccharomyces cerevisiae, using cells deficient in the main yeast RAS isoform (ras2Δ) co-expressing wild-type KRAS (KRASWT) or the most frequent KRAS mutations found in CRC - KRASG12D, KRASG12V or KRASG13D, along with human BAX. We show that, in comparison with KRASWT, KRAS mutants confer resistance to BAX-induced death and cytochrome c (cyt c) release. The modulation of BAX by KRAS isoforms seems to result from a direct interaction between these proteins, as they co-localize at the mitochondria and there is evidence they may physically interact. We further show that acetic acid significantly increased cell death in cells expressing BAX and co-expressing oncogenic KRAS mutants, but not KRASWT. This suggests a potential mechanism explaining the increased sensitivity of CRC cells harboring a KRAS-activated pathway to acetate. These findings contribute to a clearer understanding of how KRAS regulate BAX function, a relevant aspect in tumor progression.

Exploring intratumoral budding in colorectal cancer using computational pathology: a biopsy- based evaluation

Due to insufficient evidence, tumor budding (TB) is not currently evaluated in colorectal cancer (CRC) biopsies. This study investigates TB in CRC by establishing the value of intratumoral budding (ITB) in resection specimens and assessing the feasibility and clinical value of TB in biopsies. TB was assessed using an algorithm in all cases. In a test cohort of 555 primarily surgically treated CRC patients, we assessed the prognostic impact of ITB compared to peritumoral budding (PTB). The distribution of ITB in the uppermost five millimeters of resection specimens was analyzed to validate TB counting in biopsies. We further validated the prognostic and predictive impact of TB in biopsies of 285 rectal cancer patients, focusing on overall survival and response to neoadjuvant therapy. High-grade TB, whether intratumoral or peritumoral and in biopsies or resections, was associated with advanced pathological stage, lymphatic invasion, infiltrative tumor border, and poor overall survival in the test cohort. Superficial ITBs (0-3 mm from the lumen) accurately predicted the final TB grade based on PTB in 87% of tumors, with 87% of tumors having at least one superficial ITB hotspot. ITB (hazard ratio 3.5, 95% CI 1.1-10.8) was an independent predictor of overall survival, unlike PTB. In the validation cohort, TB presence in biopsies significantly reduced the likelihood of achieving a pathological complete response (odds ratio 0.3, 95% CI 0.1-0.7, p=0.007). ITB is as prognostic as PTB, and evaluating both can improve risk stratification in CRC. TB assessment in biopsies can identify poor prognosis and predict response to neoadjuvant therapy.

LINC01764 promotes colorectal cancer cells proliferation, metastasis, and 5-fluorouracil resistance by regulating glucose and glutamine metabolism via promoting c-MYC translation.

Few biomarkers are available for predicting chemotherapeutic response and prognosis in colorectal cancer (CRC). Long-noncoding RNAs (lncRNAs) are essential for CRC development and growth. Therefore, studying lncRNAs may reveal potential predictors of chemotherapy response and prognosis in CRC. LINC01764 was analyzed using datasets from Fudan University Shanghai Cancer Center's advanced CRC patients' RNA-seq and The Cancer Genome Atlas datasets. Gene set enrichment analysis was employed to detect related pathways. Cotransfection experiments, RNA pulldown assays, RNA-binding protein immunoprecipitation, protein synthesis activity, and dual-luciferase reporter assays were performed to determine interactions among LINC01764, hnRNPK, and c-MYC. High LINC01764 expression correlates with metastasis, a poor response to FOLFOX/XELOX chemotherapy, and a poor prognosis in CRC. LINC01764 enhance glycolysis and glutamine metabolism to promote CRC cells proliferation, metastasis, and 5-fluorouracil (5-FU) resistance. LINC01764 specifically binds to hnRNPK, facilitating its interaction with c-MYC mRNA and promoting internal ribosome entry site (IRES)-dependent translation of c-MYC, thereby exerting oncogenic effects. LINC01764 induced 5-FU chemoresistance by upregulating the c-MYC, glucose, and glutamine metabolism pathways, which downregulated UPP1, crucial for activating 5-FU. Conclusively, LINC01764 promotes CRC progression and 5-FU resistance through hnRNPK-mediated-c-MYC IRES-dependent translational regulation, which suggests its potential as a predictor of CRC chemotherapy response and prognosis.

Spatial context of immune checkpoints as predictors of overall survival in patients with resectable colorectal cancer independent of standard TNM stages.

While immune checkpoint blockade (ICB) therapy has shown promising results in a small subset of colorectal cancer patients with high microsatellite instability (MSI-H), the majority of patients with colorectal cancer do not respond to ICB therapy. The main obstacle to the success of immunotherapy in cancer treatment is the exhaustion of tumor-infiltrating lymphocytes (TILs). Elucidating the spatial organization of immune checkpoints within the tumor microenvironment could pave the way for the development of novel prognostic tools and therapeutic strategies to enhance antitumor immune responses. To clarify the spatial and functional diversity of tumor-infiltrating lymphocytes (TILs) in the colorectal tumor microenvironment (TME), we performed multiplexed IHC to examine the exhaustion of TILs in the TME (the expression of PD-1 and TIM-3 (T-cell immunoglobulin and mucin-domain-containing protein 3), which are major biomarkers of T-cell exhaustion) and Lasso-Cox analyses of the correlation between CRC prognosis and TME features. For proof of concept, the antitumor efficacy of TIM-3 and PD-1 dual blockade in CRC was further evaluated in a CT26 subcutaneous tumor model of human CRC. We found that the spatial context of PD-1 and TIM-3 successfully predicted the overall survival of CRC patients independent of TNM stage. Dual targeting of PD-1 and TIM-3 in mouse tumor models inhibited tumor progression and reduced T-cell exhaustion, indicating a potential strategy for improving the clinical treatment of CRC.

Application of Nanoparticles in the Diagnosis and Treatment of Colorectal Cancer.

Colorectal cancer is a common malignant tumor with high morbidity and mortality rates, imposing a huge burden on both patients and the healthcare system. Traditional treatments such as surgery, chemotherapy and radiotherapy have limitations, so finding more effective diagnostic and therapeutic tools is critical to improving the survival and quality of life of colorectal cancer patients. While current tumor targeting research mainly focuses on exploring the function and mechanism of molecular targets and screening for excellent drug targets, it is crucial to test the efficacy and mechanism of tumor cell therapy that targets these molecular targets. Selecting the appropriate drug carrier is a key step in effectively targeting tumor cells. In recent years, nanoparticles have gained significant interest as gene carriers in the field of colorectal cancer diagnosis and treatment due to their low toxicity and high protective properties. Nanoparticles, synthesized from natural or polymeric materials, are NM-sized particles that offer advantages such as low toxicity, slow release, and protection of target genes during delivery. By modifying nanoparticles, they can be targeted towards specific cells for efficient and safe targeting of tumor cells. Numerous studies have demonstrated the safety, efficiency, and specificity of nanoparticles in targeting tumor cells, making them a promising gene carrier for experimental and clinical studies. This paper aims to review the current application of nanoparticles in colorectal cancer diagnosis and treatment to provide insights for targeted therapy for colorectal cancer while also highlighting future prospects for nanoparticle development.

Characterization of metastasis-specific macrophages in colorectal cancer for prognosis prediction and immunometabolic remodeling

This study develops a prognostic model to predict metastasis and prognosis in colorectal cancer liver metastases by identifying distinct macrophage subsets. Using scRNA-seq data from primary colorectal cancer and liver metastases, we dissected the cellular landscape to find unique macrophage subpopulations, particularly EEF1G + macrophages, which were prevalent in liver metastases. The study leveraged data from GSE231559, TCGA, and GEO databases to construct an 8-gene risk model named EMGS, based on the EEF1G + macrophage gene signature. Patients were divided into high-risk and low-risk groups using the median EMGS score, with the high-risk group showing significantly worse survival. This group also demonstrated upregulated pathways associated with tumor progression, such as epithelial-mesenchymal transition and angiogenesis, and downregulated metabolic pathways. Moreover, the high-risk group presented an immunosuppressive microenvironment, with a higher TIDE score indicating lower effectiveness of immunotherapy. The study identifies potential drugs targeting the high-risk group, suggesting therapeutic avenues to improve survival. Conclusively, the EMGS score identifies colorectal cancer patients at high risk of liver metastases, highlighting the role of specific macrophage subsets in tumor progression and providing a basis for personalized treatment strategies.

Efficacy and Safety of KH903 Plus FOLFIRI as A Second-line Treatment In Unresectable Recurrent or Metastatic Colorectal Cancer: A Randomized Phase 2 Study

BackgroundPatients with recurrent or metastatic advanced colorectal cancer (mCRC) often face the clinical dilemma as this unresectable disease is continuously progressing and endangering the patients’ lives. In the current study, we explored the clinical feasibility of KH903 in combination with FOLFIRI chemotherapy as a new clinical indication for mCRC. MethodsPatients (N=122) were randomized 1:1 to 4mg/kg q1w KH903 or 5mg/kg q2w KH903, and both groups of patients were treated with the fixed regimen of FOLFIRI (every 2 weeks) along with the KH903 therapy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were Overall Survival (OS), objective response rate (ORR), and disease control rate (DCR). ResultsAs of December 30, 2020, median (m)PFS was 5.68 months (95% CI,4.67-7.13) with 4mg/kg q1w vs. 5.19 months (95% CI, 4.04, 5.78) with 5mg/kg q2w (HR, 0.76; 95% CI, 0.50-1.16),and mOS was 13.14 months (95% CI, 10.61-19.52) vs. 16.03 months (95% CI, 10.28- NE), respectively (HR, 1.11; 95% CI, 0.65-1.89), The ORR was 15.9% and 11.9% for both groups, respectively, and The DCR for both groups was 85.7% and 83.1%, respectively. Grade 3 or higher treatment-related adverse event rates for both groups were 68.3% vs.52.5%, respectively. ConclusionsKH903 in combination with FORFIRI in second-line treatment of patients with mCRC showed prolonged mPFS and mOS, comparing to the similar agents (Avastin®, ZALTRAP®, Cyramza®) and no new safety signals were observed. Micro AbstractIn the current study, we explored the clinical feasibility of KH903 in combination with FOLFIRI chemotherapy as a new clinical indication for mCRC. We demonstrated that KH903 in combination with FORFIRI in second-line treatment of patients with mCRC showed prolonged mPFS and mOS, comparing to the similar agents. It was suggested that KH903 in combination with FOLFIRI has shown further clinical development value, and its efficacy and safety can be further confirmed in later clinical trials, providing more options for second-line treatment of metastatic colorectal cancer patients.

Methanolic Extract of the Nutritional Plant (Diospyros kaki Thunb.) Exhibits Anticancer Activity by Inducing Mitochondrial Dysfunction in Colorectal Cancer Cells.

Background/Objectives:Diospyros kaki, the most widely cultivated species of persimmon, has been long used in traditional medicine since its leaves' extracts contain high amounts of flavonoids and terpenoids, endowed with several beneficial effects. However, its anticancer activity towards colorectal cancer (CRC) has not been investigated in depth. Methods: The effect of a methanolic extract of D. kaki leaves, rich in kaempferol and quercetin derivatives, have been evaluated on an E705 CRC cell line, representative of most CRC patients, and on SW480 cells, carrying a KRAS-activating mutation. Results: This extract is effective in reducing tumor cells' viability without affecting the healthy mucosa cell line CCD 841. In fact, Western blot experiments showed its ability to induce apoptosis in cancer cells by increasing oxidative stress and disrupting mitochondrial functionality, as shown by reactive oxygen species measurement and Seahorse analysis. Conclusions: With the aim of increasing healthspan, as well as the substantial societal and macroeconomic costs associated with cancer, our results could pave the way to a role for D. kaki extract in both CRC treatment and prevention.

Elucidating the Mechanisms of Astragalus Membranaceus in Colorectal Cancer Patients through Bioinformatics Analysis.

Astragalus membranaceus has shown positive clinical efficacy in treating colorectal cancer (CRC). This study aimed to identify the key active components of Astragalus and determine effective targets of these components in CRC patients. We identified active components of Astragalus membranaceus and differentially expressed genes in traditional Chinese medicine systems pharmacology database and The Cancer Genome Atlas. Additionally, the enrichment analysis of differential target genes (DTGs) was performed using the R-package clusterProfiler. Immunocyte correlation analysis and non-coding regulatory network construction were performed for biomarkers using Spearman's method and NetworkAnalyst. Finally, molecular docking of biomarkers and their corresponding molecule drugs was done with Autodock Vina software. We identified 20 active components of Astragalus membranaceus and 1 403 target genes through screening. A total of 2 300 differentially expressed genes, and 3 035 hub genes in CRC were screened. The integration of the target genes with the significantly differentially expressed genes and Hub genes identified resulted in a total of 86 DTGs. Subsequently, the results showed 828 enriched GO biological processes, 184 enriched GO molecular functions, 59 enriched GO cellular components, and 46 enriched KEGG pathways. We also obtained a total of 143 PPI pairs involving 67 nodes. Additionally, we constructed 45 mRNA-TF pairs, 101 miRNA-mRNA pairs, and 200 miRNA- mRNA-TF triplets. Finally, molecular docking was performed for the active component quercetin with F2 and UGT1A1 and formic acid with FGA, AHSG, and KNG1. This study identified the active components of Astragalus membranaceus and their corresponding targets in CRC. These findings provide robust evidence for precision drug therapy in patients with CRC.