Search

BACKGROUND: The present study aimed to validate the accuracy of a tumor-specific antibody to target liver metastases of colorectal cancer. METHODS: A humanized anti-CEA antibody conjugated to a fluorescent dye (M5A-IR800) was tested for targeting human colorectal cancer liver metastases (CRLMs) expressing luciferase in an orthotopic mouse model. Orthotopic mouse models of CRLMs were established by implanting fragments of a luciferase-expressing human colorectal cancer cell line, LS174T, in the liver of nude mice. Mice received 50 µg M5A-IR800 72 h prior to imaging. To test co-localization, bioluminescence imaging was performed using D-luciferin, which was given via intraperitoneal injection just prior to imaging. RESULTS: Tumors were able to be visualized non-invasively through the skin with the luciferase-luciferin signal. Intra-abdominal imaging showed accurate labeling of CRLMs with M5A-IR800, which co-localized with the luciferase-luciferin signal. CONCLUSIONS: The present results validate the accuracy of a tumor-specific anti-CEA antibody in targeting liver metastases of colorectal cancer.

Objective biomarkers are crucial for early diagnosis to promote treatment and raise survival rates for diseases. With the smallest non-coding RNAs-piwi-RNAs (piRNAs)-and their transcripts, we sought to identify if these piRNAs could be used as biomarkers for colorectal cancer (CRC). Using previously published data from serum samples of patients with CRC, 13 differently expressed piRNAs were selected as potential biomarkers. With this data, we developed a machine learning (ML) algorithm and created 1020 different piRNA sequence descriptors. With the Naïve Bayes Multinomial classifier, we were able to isolate the 27 most influential sequence descriptors and achieve an accuracy of 96.4%. To test the validity of our model, we used data from piRBase with known associations with CRC that we did not use to train the ML model. We were able to achieve an accuracy of 85.7% with these new independent data. To further validate our model, we also tested data from unrelated diseases, including piRNAs with a correlation to breast cancer and no proven correlation to CRC. The model scored 44.4% on these piRNAs, showing that it can identify a difference between biomarkers of CRC and biomarkers of other diseases. The final results show that our model is an effective tool for diagnosing colorectal cancer. We believe that in the future, this model will prove useful for colorectal cancer and other diseases diagnostics.

Despite ethical and historical arguments for removing race from clinical algorithms, the consequences of removal remain unclear. Here, we highlight a largely undiscussed consideration in this debate: varying data quality of input features across race groups. For example, family history of cancer is an essential predictor in cancer risk prediction algorithms but is less reliably documented for Black participants and may therefore be less predictive of cancer outcomes. Using data from the Southern Community Cohort Study, we assessed whether race adjustments could allow risk prediction models to capture varying data quality by race, focusing on colorectal cancer risk prediction. We analyzed 77,836 adults with no history of colorectal cancer at baseline. The predictive value of self-reported family history was greater for White participants than for Black participants. We compared two cancer risk prediction algorithms-a race-blind algorithm which included standard colorectal cancer risk factors but not race, and a race-adjusted algorithm which additionally included race. Relative to the race-blind algorithm, the race-adjusted algorithm improved predictive performance, as measured by goodness of fit in a likelihood ratio test (P-value:

BackgroundThe Affordable Care Act expanded Medicaid coverage for people with low income in the United States. Expanded insurance coverage could promote more timely access to cancer treatment, which could improve overall survival (OS), yet the long-term effects of Medicaid expansion (ME) remain unknown. We evaluated whether ME was associated with improved timely treatment initiation (TTI) and 3-year OS among patients with breast, cervical, colon, and lung cancers who were affected by the policy.MethodsMedicaid-insured or uninsured patients aged 40-64 with stage I-III breast, cervical, colon, or non-small cell lung cancer within the National Cancer Database (NCDB). A difference-in-differences (DID) approach was used to compare changes in TTI (within 60 days) and 3-year OS between patients in ME states versus nonexpansion (NE) states before (2010-2013) and after (2015-2018) ME. Adjusted DID estimates for TTI and 3-year OS were calculated using multivariable linear regression and Cox proportional hazards regression models, respectively.ResultsME was associated with a relative increase in TTI within 60 days for breast (DID = 4.6; p

PURPOSE: To examine the association of a traditional Mexican diet score with risk of total, breast, and colorectal cancer among women of Mexican ethnic descent in the Womens Health Initiative (WHI). METHODS: Participants were WHI enrollees who self-identified as being of Mexican descent. Data from food frequency questionnaires self-administered at study baseline were used to calculate the MexD score, with higher scores indicating greater adherence to an a priori-defined traditional Mexican diet (high in dietary fiber, vegetables, and legumes). Incident cancers were self-reported by participants from 1993 to 2020 and adjudicated by trained physicians. We used multivariable-adjusted Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 2,343 Mexican descent women (median baseline age: 59 years), a total of 270 cancers (88 breast, 37 colorectal) occurred during a mean follow-up of 14.4 years. The highest tertile of MexD score was associated with a lower risk of all-cancer incidence (HR: 0.67; 95% CI 0.49-0.91; p-trend: 0.01) and colorectal cancer (HR: 0.38; 95% CI 0.14-0.998; p-trend

BACKGROUND: Both defects in mismatch repair (dMMR) and high microsatellite instability (MSI-H) have been recognised as crucial biomarkers that guide treatment strategies and disease management in colorectal cancer (CRC). As MMR and MSI tests are being widely conducted, an increasing number of MSI-H tumours have been identified in CRCs with mismatch repair proficiency (pMMR). The objective of this study was to assess the clinical features of patients with pMMR/MSI-H CRC and elucidate the underlying molecular mechanism in these cases. METHODS: From January 2015 to December 2018, 1684 cases of pMMR and 401 dMMR CRCs were enrolled. Of those patients, 93 pMMR/MSI-H were identified. The clinical phenotypes and prognosis were analysed. Frozen and paraffin-embedded tissue were available in 35 patients with pMMR/MSI-H, for which comprehensive genomic and transcriptomic analyses were performed. FINDINGS: In comparison to pMMR/MSS CRCs, pMMR/MSI-H CRCs exhibited significantly less tumour progression and better long-term prognosis. The pMMR/MSI-H cohorts displayed a higher presence of CD8+ T cells and NK cells when compared to the pMMR/MSS group. Mutational signature analysis revealed that nearly all samples exhibited deficiencies in MMR genes, and we also identified deleterious mutations in MSH3-K383fs. INTERPRETATION: This study revealed pMMR/MSI-H CRC as a distinct subgroup within CRC, which manifests diverse clinicopathological features and long-term prognostic outcomes. Distinct features in the tumour immune-microenvironment were observed in pMMR/MSI-H CRCs. Pathogenic deleterious mutations in MSH3-K383fs were frequently detected, suggesting another potential biomarker for identifying MSI-H. FUNDING: This work was supported by the Science and Technology Commission of Shanghai Municipality (20DZ1100101).

Today, colorectal cancer (CRC) diagnosis is performed using colonoscopy, which is the current, most effective screening method. However, colonoscopy poses risks of harm to the patient and is an invasive process. Recent research has proven metabolomics as a potential, non-invasive detection method, which can use identified biomarkers to detect potential cancer in a patients body. The aim of this study is to develop a machine-learning (ML) model based on chemical descriptors that will recognize CRC-associated metabolites. We selected a set of metabolites found as the biomarkers of CRC, confirmed that they participate in cancer-related pathways, and used them for training a machine-learning model for the diagnostics of CRC. Using a set of selective metabolites and random compounds, we developed a range of ML models. The best performing ML model trained on Stage 0-2 CRC metabolite data predicted a metabolite class with 89.55% accuracy. The best performing ML model trained on Stage 3-4 CRC metabolite data predicted a metabolite class with 95.21% accuracy. Lastly, the best-performing ML model trained on Stage 0-4 CRC metabolite data predicted a metabolite class with 93.04% accuracy. These models were then tested on independent datasets, including random and unrelated-disease metabolites. In addition, six pathways related to these CRC metabolites were also distinguished: aminoacyl-tRNA biosynthesis; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis; arginine biosynthesis; and alanine, aspartate, and glutamate metabolism. Thus, in this research study, we created machine-learning models based on metabolite-related descriptors that may be helpful in developing a non-invasive diagnosis method for CRC.

BACKGROUND: Rural residents have a higher prevalence of colorectal cancer (CRC) mortality compared to urban individuals. Policies have been aimed at improving access to CRC screening to reduce these outcomes. However, little attention has been paid to other determinants of CRC-related outcomes, such as stage at diagnosis, treatment, or survivorship care. The main objective of this analysis was to evaluate literature describing differences in CRC screening, stage at diagnosis, treatment, and survivorship care between rural and urban individuals. MATERIALS AND METHODS: We conducted a systematic review of electronic databases using a combination of MeSH and free-text search terms related to CRC screening, stage at diagnosis, treatment, survivorship care, and rurality. We identified 921 studies, of which 39 were included. We assessed methodological quality using the ROBINS-E tool and summarized findings descriptively. A meta-analysis was performed of studies evaluating CRC screening using a random-effects model. RESULTS: Seventeen studies reported disparities between urban and rural populations in CRC screening, 12 on treatment disparities, and 8 on staging disparities. We found that rural individuals were significantly less likely to report any type of screening at any time period (pooled odds ratio = 0.81, 95% CI, 0.76-0.86). Results were inconclusive for disparities in staging at diagnosis and treatment. One study reported a lower likelihood of use of CRC survivorship care for rural individuals compared to urban individuals. CONCLUSION: There remains an urgent need to evaluate and address CRC disparities in rural areas. Investigators should focus future work on assessing the quality of staging at diagnosis, treatment, and survivorship care in rural areas.

Previous research has found that milk is associated with a decreased risk of colorectal cancer (CRC). However, it is unclear whether the milk digestion by the enzyme lactase-phlorizin hydrolase (LPH) plays a role in CRC susceptibility. Our study aims to investigate the direct causal relationship of CRC risk with LPH levels by applying a two-sample Mendelian Randomization (MR) strategy. Genetic instruments for LPH were derived from the Fenland Study, and CRC-associated summary statistics for these instruments were extracted from the FinnGen Study, PLCO Atlas Project, and Pan-UK Biobank. Primary MR analyses focused on a cis-variant (rs4988235) for LPH levels, with results integrated via meta-analysis. MR analyses using all variants were also undertaken. This analytical approach was further extended to assess CRC subtypes (colon and rectal). Meta-analysis across the three datasets illustrated an inverse association between genetically predicted LPH levels and CRC risk (OR: 0.92 [95% CI, 0.89-0.95]). Subtype analyses revealed associations of elevated LPH levels with reduced risks for both colon (OR: 0.92 [95% CI, 0.89-0.96]) and rectal cancer (OR: 0.92 [95% CI, 0.87, 0.98]). Consistency was observed across varied analytical methods and datasets. Further exploration is warranted to unveil the underlying mechanisms and validate LPHs potential role in CRC prevention.

Claudins (CLDN1-CLDN24) are a family of tight junction proteins whose dysregulation has been implicated in tumorigeneses of many cancer types. In colorectal cancer (CRC), CLDN1, CLDN2, CLDN4, and CLDN18 have been shown to either be upregulated or aberrantly expressed. In the normal colon, CLDN1 and CLDN3-7 are expressed. Although a few claudins, such as CLDN6 and CLDN7, are expressed in CRC their levels are reduced compared to the normal colon. The present review outlines the expression profiles of claudin proteins in CRC and those that are potential biomarkers for prognostication.

Bile acids (BAs) affect the intestinal environment by ensuring barrier integrity, maintaining microbiota balance, regulating epithelium turnover, and modulating the immune system. As a master regulator of BA homeostasis, farnesoid X receptor (FXR) is severely compromised in patients with inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). At the front line, gut macrophages react to the microbiota and metabolites that breach the epithelium. We aim to study the role of the BA/FXR axis in macrophages. This study demonstrates that inflammation-induced epithelial abnormalities compromised FXR signaling and altered BAs' profile in a mouse CAC model. Further, gut macrophage-intrinsic FXR sensed aberrant BAs, leading to pro-inflammatory cytokines' secretion, which promoted intestinal stem cell proliferation. Mechanistically, activation of FXR ameliorated intestinal inflammation and inhibited colitis-associated tumor growth, by regulating gut macrophages' recruitment, polarization, and crosstalk with Th17 cells. However, deletion of FXR in bone marrow or gut macrophages escalated the intestinal inflammation. In summary, our study reveals a distinctive regulatory role of FXR in gut macrophages, suggesting its potential as a therapeutic target for addressing IBD and CAC.

As the Editor-in-Chief of World Journal of Gastroenterology, every week prior to a new issues online publication, I perform a careful review of all encompassed articles, including the title, clinical and/or research importance, originality, novelty, and ratings by the peer reviewers. Based on this review, I select the papers of choice and suggest pertinent changes (e.g., in the title) to the Company Editors responsible for publication. This process, while time-consuming, is very important for assuring the quality of publications and highlighting important articles that Readers may revisit.

INTRODUCTION: Non-Hispanic Black (NHB) Americans have a higher incidence of colorectal cancer (CRC) and worse survival than non-Hispanic white (NHW) Americans, but the relative contributions of biological versus access to care remain poorly characterized. This study used two nationwide cohorts in different healthcare contexts to study health system effects on this disparity. METHODS: We used data from the Surveillance, Epidemiology, and End Results (SEER) registry as well as the United States Veterans Health Administration (VA) to identify adults diagnosed with colorectal cancer between 2010 and 2020 who identified as non-Hispanic Black (NHB) or non-Hispanic white (NHW). Stratified survival analyses were performed using a primary endpoint of overall survival, and sensitivity analyses were performed using cancer-specific survival. RESULTS: We identified 263,893 CRC patients in the SEER registry (36,662 (14%) NHB; 226,271 (86%) NHW) and 24,375 VA patients (4,860 (20%) NHB; 19,515 (80%) NHW). In the SEER registry, NHB patients had worse OS than NHW patients: median OS of 57 months (95% confidence interval (CI) 55-58) versus 72 months (95% CI 71-73) (hazard ratio (HR) 1.14, 95% CI 1.12-1.15, p = 0.001). In contrast, VA NHB median OS was 65 months (95% CI 62-69) versus NHW 69 months (95% CI 97-71) (HR 1.02, 95% CI 0.98-1.07, p = 0.375). There was significant interaction in the SEER registry between race and Medicare age eligibility (p

BACKGROUND: Primary care physicians (PCP) play a key role in offering colorectal cancer (CRC) screenings, particularly amongst underserved populations. Given potential delays in or omission of CRC screening in the absence of a PCP, we aimed to determine stage of CRC at diagnosis in an underserved population. METHODS: A retrospective chart review was conducted at two Los Angeles County safety-net hospitals. Inclusion criteria were a CRC diagnosis between 2018 and 2021 and age between 50 and 75 years at diagnosis time. The primary outcome was the cancer stage at diagnosis. RESULTS: A total of 373 patients were included, of those, 52.5 % had a PCP. Compared to others, PCP was similar in age, racial composition, and primary spoken language (Table 1). Of patients with a PCP, 52.0% were diagnosed by screening. After screening, the most common indication for colonoscopy were blood per rectum (24.9 %) and imaging findings (18.0 %). Patients with a PCP had a significantly lower rate of late stage CRC than those without a PCP (42.4 % vs. 68.0 %, p

Herein, we describe the synthesis and characterization of a series of thiosemicarbazone platinacycles. Their activity towards HCT116 and A2780 cancer cell lines as well as normal fibroblasts was explored and conclusions about the influence of their structures were drawn based on the results. Ligands L1–3, tetranuclear compounds [Pt(L1–3)]4, [Pt(L1–3)(PPh3)], and [Pt(L1–L3)2{Ph2P(CH2)4PPh2}], and phosphine derivatives, were deemed unpromising owing to their lack of activity. However, mono-coordinated diphosphine complexes [Pt(L1–L3)(Ph2PCH2PPh2 -P)] showed high selectivity and low IC50 values, and their antiproliferative activity was further studied. The three studied derivatives 3a, 3b and 3c showed a fast internalization of HCT116 colorectal cancer cells with similar IC50 values, which induced a depolarization of mitochondrial membrane potential, with the subsequent triggering of apoptosis and autophagy in the case of 3c. In the case of compounds 3a and 3b, cell death mechanisms (extrinsic and intrinsic apoptosis, respectively) were triggered via the induction of reactive oxygen species (ROS). The three compounds were not toxic to a chicken embryo in vivo (after 48 h), and, importantly, showed an anti-angiogenic potential after exposure to the IC50 of compounds 3a, 3b and 3c. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) using photosensitizer (PS)‐embedded silicone membrane‐covered self‐expandable metallic stents (SEMSs) can function in palliative therapeutic option for malignant gastrointestinal tract obstruction. However, stent‐related complications should be considered, and accurate delivery of light sources is technically difficult. Here, a Chlorin e6 (Ce6)‐an embedded stent‐based catheter is developed to improve its therapeutic efficacy and safety. PDT using Ce6‐embedded stent successfully induced cell death of colorectal cancer cell line. PDT‐treated liver tissues showed an increase in ablation depth in proportion to irradiation energy, and 600 J/cm2 demonstrates an even and sufficient ablation depth. Endoluminal PDT using the Ce6‐embedded stent‐based catheter was technically successful in a rat colon model without procedure‐related complications such as colonic perforation or stricture formation. The results in colonoscopy, colonography, and histological examination, along with statistical analysis, suggest that a novel PDT modality using a Ce6‐embedded stent‐based catheter was safely conducted and demonstrated apoptotic cell death at 12 h after PDT, and it gradually recovered from 2 to 4 weeks. Thus, the PDT using the Ce6‐embedded stent‐based catheter may represent a promising new approach for the treatment of malignant colorectal obstruction. [ABSTRACT FROM AUTHOR]

Resistance to chemotherapy remains the main challenge for cancer treatment. One of the mechanisms of tumor escape from cytotoxic agents could be the formation of cell-in-cell (CIC) structures, in which the outer cell protects the inner cell from unfavorable environment. Such structures have been found in many tumor types, however, their link to chemosensitivity is elusive. Here, we tested whether the CIC structures can promote resistance of colorectal cancer cells to chemotherapy. To identify CIC structures in cell cultures and in tumor xenografts, both transmission electron microscopy and confocal fluorescence microscopy of live and fixed cells as well as tissue slices and histopathology were used. Cytogenetic analysis was performed to detect chromosome instability associated with the drug resistance. It was found that in the five colorectal cancer cell lines intrinsic chemoresistance positively correlated with the ability of cells to spontaneously form CIC structures. Cultured cells treated with oxaliplatin and Irinotecan and tumor xenografts treated with FOLFOX or FOLFIRI regimens displayed an increased number of CICs after the treatment. The release of the inner cell from CIC structure was observed after removal of the drug. The number of CICs in the cell lines and tumors with acquired resistance to oxaliplatin was higher than in the drug-naive counterparts. The development of chemoresistance was also accompanied by the changes in the cell's ploidy. These preliminary data clearly demonstrate the associations of CIC structures with chemoresistance of colorectal cancer in cultured cells and tumor xenografts and show the prospect of further clinical validation of CICs as a potential prognostic marker for treatment efficiency. [ABSTRACT FROM AUTHOR]

Endocrine fibroblast growth factors (eFGFs) play essential roles in cellular signaling processes, including development and differentiation, and are implicated in various cancers. However, their precise involvement in colon neoplasia and colon adenocarcinoma (COAD) remains incompletely understood. Here, we conducted a comprehensive investigation utilizing multiple databases to explore the multifaceted characteristics of eFGFs. Through integrated analyses of diverse databases, including TIMER2.0, UALCAN, OncoDB, cBioPortal, LinkedOmics, STRING, htfTarget, mirTarBase, circBank, and DGIdb, we explored eFGFs' gene expression, DNA methylation, prognostic significance, genetic alterations, gene regulatory networks, functional analysis, and drug interactions in COAD patients. Our findings revealed elevated expression levels of eFGFs in COAD, with aberrant gene expression potentially linked to promoter methylation. Importantly, hypermethylation of FGF21 and FGF23 and downregulation of FGF23 correlated with poor survival outcomes in COAD patients. Functional analyses highlighted the involvement of eFGF genes in Ras signaling, PI3K-Akt signaling, and cancer pathways. Furthermore, we validated our findings through a cross-sectional study by quantitative real-time polymerase chain reaction (qRT-PCR), confirming significant overexpression of FGF21 in colon polyps compared to normal mucosa. Additionally, we observed elevated RNA expression of FGF21 and FGF23 in adenomatous polyps compared to hyperplastic polyps. This study sheds new light on the critical roles of eFGFs in COAD tumorigenesis and underscores their potential as promising prognostic markers for COAD, as well as discriminative markers for distinguishing high-risk from low-risk polyps. These findings provide valuable insights into the complex molecular mechanisms underlying colorectal neoplasia and offer potential avenues for targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims Design Methods Results Conclusion Implications for the Profession and/or Patient Care Impact Reporting Method Patient or Public Contribution To identify the longitudinal trajectories of psychological distress and to explore the predictive factors of different trajectories among young and middle‐aged colorectal cancer patients from diagnosis to 6 months postoperation.A longitudinal study was conducted, guided by the STROBE checklist.A total of 214 patients were recruited from July 2021 to May 2022 at a cancer hospital in Guangzhou, China. Data were collected from diagnosis to 6 months post‐surgery, using the Brief Symptom Inventory‐18, Distress Disclosure Index, Connor–Davidson Resilience Scale and Social Support Rating Scale. We also collected socio‐demographic and clinical characteristics at baseline. General estimation equation (GEE) was used to analyse the overall trend of psychological distress. To identify distinct distress trajectories, growth mixture modelling (GMM) and latent class growth modelling (LCGM) were both used.Longitudinal trajectories of psychological distress: the average score of psychological distress at different time points were 12.02 ± 9.87, 17.40 ± 9.73, 15.91 ± 10.05, 16.28 ± 11.24 and 16.31 ± 11.66. GEE showed four unique trajectories of psychological distress: chronic distress, no distress, steady increase and significantly increased. With reference to resilient group, multinomial logistic regression showed that education level, monthly income, minor offspring, stoma, residence, self‐disclosure and psychological resilience were predictive factors of chronic distress class or increase‐distress class.From diagnosis to 6 months post‐surgery, psychological distress increased at discharge, gradually stabilising thereafter. Meanwhile, results revealed heterogeneity in this population. To effectively alleviate distress, it is crucial to identify high‐risk individuals through predictive factors and implement tailored interventions.This study offers the trajectory and predictors of psychological distress in the process of diagnosis and treatment, and can be used in the clinical identification and monitoring of high‐risk patients.The findings suggest that healthcare providers should regularly monitored and identified the psychological distress of patients, and took individualised intervention measures.This study is reported using the STROBE guidelines.No patient or public engagement. [ABSTRACT FROM AUTHOR]

Trivariate joint modeling for longitudinal count data, recurrent events, and a terminal event for family data has increased interest in medical studies. For example, families with Lynch syndrome (LS) are at high risk of developing colorectal cancer (CRC), where the number of polyps and the frequency of colonoscopy screening visits are highly associated with the risk of CRC among individuals and families. To assess how screening visits influence polyp detection, which in turn influences time to CRC, we propose a clustered trivariate joint model. The proposed model facilitates longitudinal count data that are zero‐inflated and over‐dispersed and invokes individual‐specific and family‐specific random effects to account for dependence among individuals and families. We formulate our proposed model as a latent Gaussian model to use the Bayesian estimation approach with the integrated nested Laplace approximation algorithm and evaluate its performance using simulation studies. Our trivariate joint model is applied to a series of 18 families from Newfoundland, with the occurrence of CRC taken as the terminal event, the colonoscopy screening visits as recurrent events, and the number of polyps detected at each visit as zero‐inflated count data with overdispersion. We showed that our trivariate model fits better than alternative bivariate models and that the cluster effects should not be ignored when analyzing family data. Finally, the proposed model enables us to quantify heterogeneity across families and individuals in polyp detection and CRC risk, thus helping to identify individuals and families who would benefit from more intensive screening visits. [ABSTRACT FROM AUTHOR]

Background: Autophagy is a crucial mechanism for maintaining cellular homeostasis and responding to environmental stress, and it is closely linked to tumor drug resistance. Through multi-omics analysis, this study explores the expression patterns, functions, and potential role of the autophagy-related gene Angiotensinogen (AGT) in colorectal cancer (CRC), particularly in relation to chemotherapy resistance. Methods: This study first compared AGT expression between CRC and normal tissues using the GTEx and TCGA databases. Differences in expression were assessed using Wilcoxon Rank Sum Tests, and the prognostic impact of AGT was evaluated through univariate Cox survival analysis and meta-analysis. Functional enrichment was performed using the limma and fgsea packages. Drug sensitivity analysis was conducted based on the CTRP database, while immune infiltration was assessed using the CIBERSORT and ESTIMATE methods. Spatial transcriptomic characteristics were explored through 10x Visium technology and deconvolution analysis to investigate the correlation between AGT expression levels and tumor cell content.scRNA-seq data from CRC tissues were sourced from Tumor Immune Single Cell Hub (TISCH).Functional annotation was performed with Single-sample gene set enrichment analysis (SSGSEA), and pseudotime analysis using Monocle 2 mapped their developmental trajectories. The potential of AGT inhibitors in the treatment of CRC was analyzed using drug-target Mendelian randomization.Finally, Phenome-Wide Association Study (PheWAS) was conducted to evaluate genetic associations and potential side effects of AGT inhibitors. Results: AGT expression was significantly higher in CRC tissues compared to normal tissues and was associated with shorter recurrence-free survival (RFS). Autophagy signaling pathways were markedly enriched in the high AGT expression group. AGT expression was positively correlated with resistance to chemotherapeutic agents such as gemcitabine, cisplatin, paclitaxel, and 5-fluorouracil. Spatial transcriptomic analysis revealed that AGT was predominantly expressed in malignant tumor regions. Single-cell analysis identified 21 distinct cell subpopulations across 13 major types. AGT expression was significantly higher in tumor samples, especially in the fibroblast C6 subpopulation. Tumor-related pathways were enriched in C1, C5, C6, and C8 subpopulations. Pseudotime analysis revealed that these subpopulations, particularly C6, were in terminal developmental stages.Drug-target Mendelian randomization analysis indicated a negative causal relationship between AGT inhibitors and the risk of both heart failure(ORdrug = 0.950, 95% CI, 0.912–0.990; P = 0.014) and CRC(ORdrug = 0.874, 95% CI: 0.792–0.964; P = 0.007).PheWAS analysis showed no genetic associations between AGT inhibitors and other traits, indicating its specificity and low risk of side effects. Conclusion: Elevated AGT expression in CRC is associated with resistance to chemotherapy, and its inhibition may offer a therapeutic avenue for the treatment of colorectal cancer. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to analyze factors associated with recent complications after colorectal cancer surgery, constructing a nomogram to aid gastrointestinal surgeons in preoperative decision-making for patients at risk of such complications. Methods: In this retrospective study, clinical data were collected from patients undergoing radical colorectal cancer surgery at the Department of Gastrointestinal Surgery of the Affiliated Cancer Hospital of Guizhou Medical University and the Second People's Hospital of Chengdu from November 1, 2021, to January 26, 2024. Univariable and multivariable logistic regression analyses were conducted to assess risk factors for recent postoperative complications and develop a prediction model. External validation was performed using data from 48 postoperative colorectal cancer patients in the Second People's Hospital of Chengdu City from January 1, 2023, to May 30, 2023. Evaluation included receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis using R4.2.2 statistical software. Results: A total of 324 patients who underwent radical colorectal cancer surgery were enrolled. The training cohort (n=176) identified four independent risk factors for recent complications: PNI ≥45 (OR=4.17, P<0.001), Albumin <40 g/L (OR=3.9, P<0.001), ASA score III-IV (OR=6.29, P<0.001), and Tumor diameter ≥5 cm (OR=4.24, P<0.001). A nomogram was constructed incorporating these factors. The AUC of the nomogram model in the training cohort was 0.835, with subsequent internal and external validation cohort AUCs of 0.815 and 0.819, respectively, indicating strong discriminatory ability. The calibration curve demonstrated good consistency, and decision curve analysis indicated high clinical utility. Conclusion: PNI ≥45, Albumin <40 g/L, ASA score III-IV, and Tumor diameter ≥5 cm emerged as independent risk factors for recent complications following colorectal cancer surgery. We developed a nomogram model for these complications, potentially aiding gastrointestinal surgeons in preoperative patient evaluation and treatment planning for colorectal cancer surgery. [ABSTRACT FROM AUTHOR]

Background: The incidence and mortality of colorectal cancer (CRC) have been rising steadily. Early diagnosis and precise treatment are essential for improving patient survival outcomes. Over the past decade, the integration of artificial intelligence (AI) and medical imaging technologies has positioned radiomics as a critical area of research in the diagnosis, treatment, and prognosis of CRC. Methods: We conducted a comprehensive review of CRC-related radiomics literature published between 1 January 2013 and 31 December 2023 using the Web of Science Core Collection database. Bibliometric tools such as Bibliometrix, VOSviewer, and CiteSpace were employed to perform an in-depth bibliometric analysis. Results: Our search yielded 1,226 publications, revealing a consistent annual growth in CRC radiomics research, with a significant rise after 2019. China led in publication volume (406 papers), followed by the United States (263 papers), whereas the United States dominated in citation numbers. Notable institutions included General Electric, Harvard University, University of London, Maastricht University, and the Chinese Academy of Sciences. Prominent researchers in this field are Tian J from the Chinese Academy of Sciences, with the highest publication count, and Ganeshan B from the University of London, with the most citations. Journals leading in publication and citation counts are Frontiers in Oncology and Radiology. Keyword and citation analysis identified deep learning, texture analysis, rectal cancer, image analysis, and management as prevailing research themes. Additionally, recent trends indicate the growing importance of AI and multi-omics integration, with a focus on improving precision medicine applications in CRC. Emerging keywords such as deep learning and AI have shown rapid growth in citation bursts over the past 3 years, reflecting a shift toward more advanced technological applications. Conclusions: Radiomics plays a crucial role in the clinical management of CRC, providing valuable insights for precision medicine. It significantly contributes to predicting molecular biomarkers, assessing tumor aggressiveness, and monitoring treatment efficacy. Future research should prioritize advancing AI algorithms, enhancing multi-omics data integration, and further expanding radiomics applications in CRC precision medicine. [ABSTRACT FROM AUTHOR]

Background: Hepatic metastasis is the primary cause of colorectal cancer (CRC)-induced death. Our previous results showed the anti-metastatic effects of Coptidis rhizoma using in vitro model. Aim: The present study aimed to investigate whether berberine, the main active compound of C. rhizoma, inhibits colon–liver metastasis in an animal model, and to elucidate the underlying mechanisms. Methods: Murine colon carcinoma (CT26) tumor tissue was implanted into the cecum of balb/c mice with/without oral administration of berberine (100 mg/kg) for 21 days, after which liver metastasis was evaluated. In addition, the pharmacological actions of berberine were explored using 5-fluorouracil-resistant human colon cancer cells (HCT116/R). Result: The administration of berberine significantly decreased the number of tumor nodules in the liver, while significant activation of E-cadherin (an epithelial marker), and suppression of vimentin, Snail and TGF-β (mesenchymal markers) were observed in primary colon tumor tissues. Berberine treatment also notably lowered the levels of inflammatory cytokines (TGF-β, TNF- α, IL-6 and IL-1β) in the blood. In HCT116/R cells, berberine significantly inhibited migration and invasion and modulated the expression of TGF-β and representative molecules related to its pathway. The results obtained with a TGF-β inhibitor (SB431542) and a TGF-β siRNA, strongly suggest that the mechanism of action of berberine is linked to TGF-β signaling. Conclusion: In conclusion, berberine evidently possess an anti-colon–liver metastatic effect, and its underlying mechanisms involve the inhibition of epithelial–mesenchymal transition (EMT) through the TGF-β signaling pathway. Thus, we cautiously propose the pharmacological potential of berberine in drug research studies targeting hepatic metastasis from CRC. [ABSTRACT FROM AUTHOR]

Background: Colonoscopy as a common screening practice to prevent colorectal cancer lacks strong evidence. NordICC, the first randomized trial of colonoscopy screening, reported no clear clinical benefit for colonoscopy in the intention-to-screen population with suggested benefit in the risk of colorectal incidence and cancer-specific mortality in the per-protocol analyses. However, although the study was designed to perform survival analysis, no survival outcomes were reported since the underlying assumption for hazard ratio was not valid. We aimed to assess whether colonoscopy screening is associated with improved survival outcomes compared with usual care. Methods: We reconstructed patient-level data from the Kaplan-Meier estimator of the primary endpoints reported in NordICC for the intention-to-screen and adjusted per-protocol populations. The restricted-mean survival time difference (RMST-D) and restricted-mean time loss ratio (RMTL-R), which are robust alternatives to the hazard ratio without specific model assumptions, were calculated for colorectal cancer incidence and death. Results: In this study, no significant difference in colorectal cancer incidence over 10 years was found in the intention-to-screen population (RMST-D: -0.68 days, 95% CI -3.9–2.6; RMTL-R: 1.04, 95% CI 0.88–1.22) or in the per-protocol analysis population (RMST-D: -2.9 days, 95% CI -6.5–0.67; RMTL-R: 1.15, 95% CI 0.97–1.35). In the intention-to-screen population, inviting individuals to colonoscopy did not improve colorectal-cancer death (RMST-D: -0.29 days, 95% CI -1.6–1.0; RMTL-R: 1.07, 95% CI 0.78–1.48). Over 10 years, in the per-protocol analysis, individuals who underwent colonoscopy survived an average of 1.1 more days free of colorectal cancer, but this difference was not statistically significant (RMST-D: 95% CI -0.13–2.3; RMTL-R: 0.72, 95% CI 0.49–1.07). Conclusions: In this reanalysis of the NordICC data, no evidence of improvement in survival outcomes for participants invited to undergo colonoscopy compared to usual care was identified, even when assuming that all invited participants did undergo colonoscopy. Thus, our results do not support the use of colonoscopy as a population-wide screening test as a mean to decrease colorectal cancer incidence or death. Registry: Not applicable. [ABSTRACT FROM AUTHOR]

AbstractThe current study aimed to determine the roles of pivotal and novel lncRNAs associated with the cell cycle in the occurrence and development of Colorectal cancer (CRC). To achieve this, the TCGA-COAD project related to CRC was downloaded, and differential expression analysis was performed to identify differentially expressed lncRNAs, miRNAs, and mRNAs. A cell cycle-associated lncRNA-miRNA-mRNA regulatory network was constructed, and two novel lncRNAs were selected. Two subnetworks were constructed for selected lncRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were illustrated for the genes in each sub-network. qPCR analysis was used to validate the expression levels of the selected lncRNAs in CRC tissues compared with in those adjacent normal tissues. The differential expression analysis identified 416 lncRNAs, 317 miRNAs, and 117 mRNAs. The ceRNA subnetwork genes were associated with different pathways, including cellular senescence, DNA replication, human T-cell leukemia virus 1 infection, and oocyte meiosis. The bioinformatic results based on TCGA project indicated the dysregulation of two novel lncRNAs, MIR29B2CHG and HELLPAR, in CRC tissues compared to adjacent normal tissues. Moreover, qPCR confirmed the dysregulation of lncRNAs in the CRC tissues. ROCs curves revealed that both selected lncRNAs had acceptable specificity and sensitivity as biomarkers. In conclusion, novel cell cycle-associated lncRNAs have the potential to be understood as the underlying molecular mechanisms that influence CRC. Therefore, these lncRNAs can be considered as promising biomarkers for the diagnosis and treatment of CRC. [ABSTRACT FROM AUTHOR]

Polyphenols are natural biomolecules known for circumventing several diseases including cancer with little adverse effects. This study aimed to investigate the polyphenol enriched fractions from the leaf extract of Asystasia gangetica for their composition, biological activities such as antioxidant activity, haemolytic effects, and in vitro cytotoxicity against cancer cell lines. LC–MS/MS analysis of the enriched fractions identified a total of 35 distinct polyphenols with caffeic acid, luteolin, apigenin, and protocatechuic acid at higher concentrations. Fractions AG-3 and AG-4 exhibited the highest total antioxidant activity with higher concentration of phenolics and flavonoids. The AG-4 fraction had the highest levels of DPPH radical scavenging (IC50 = 32.74 µg mL-1) and ABTS radical scavenging (IC50 = 29.45 µg mL–1) activity, in addition to a modest iron chelating activity and reducing power. The fractions exhibited the least haemolytic activity. The cytotoxic potential of enriched fractions against the HCT-116, HeLa, PC-3, and HDF cell lines was further examined. While the extract showed no inhibitory effect on normal HDF cells, the cytotoxic activity of fractions on cell lines varied, with HCT-116 cells having the strongest anticancer activity with an IC50 of 43.82 µg mL–1. Additionally, fractions induced apoptotic activity in HCT-116 cells, resulting in cell cycle arrest at the G2M phase and an increase in sub-G0/G1 cells, with an IC50 of 13.54 µg mL–1 after 48 h of incubation. The in silico molecular docking of the active compounds against the TNIK receptor protein and ADMET (Absorption–Distribution–Metabolism–Excretion–Toxicity) characteristics are described. Overall, the study highlights the enhanced biological and antiproliferative activities of polyphenols in Asystasia gangetica leaf extract, which could be further utilized as a potential cancer treatment strategy. [ABSTRACT FROM AUTHOR]

Fluorouracil-based chemotherapy responses in colorectal cancer (CRC) patients vary widely, highlighting the role of pharmacogenomics in developing better predictive models. We analyzed 379 CRC patients receiving fluorouracil-based chemotherapy, collecting data on fluorouracil metabolism-related SNPs (TYMS, MTHFR, DPYD, RRM1), blood inflammatory markers, and clinical status. Six machine learning models—K-nearest neighbors, support vector machine, gradient boosting decision trees (GBDT), eXtreme Gradient Boosting (XGBoost), LightGBM, and random forest—were compared against multivariate logistic regression and a deep learning model (i.e., multilayer perceptron, MLP). Feature importance analysis highlighted seven predictors: histological grade, N and M staging, monocyte count, platelet-to-lymphocyte ratio, MTHFR rs1801131, and RRM1 rs11030918. In a five-fold cross-validation, XGBoost and GBDT exhibited superior performance, with Area Under Curve (AUC) of 0.88 ± 0.02. XGBoost excelled in identifying favorable prognosis (recall = 0.939). GBDT demonstrated balance in recognizing both categories, with a recall for favorable prognosis of 0.908 and a precision for unfavorable prognosis of 0.863. MLP had a similar AUC (0.87) with high precision for favorable prognosis (recall = 0.946). In external validation, XGBoost model achieved an accuracy of 0.79. An online prognostic tool based on XGBoost was developed, integrating metabolism-related SNPs and inflammatory markers, enhancing CRC treatment precision and supporting tailored chemotherapy. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common malignant tumors. Identification of new effective drug targets for CRC and exploration of bioactive small‐molecules are clinically urgent. The human dCTP pyrophosphatase 1 (DCTPP1) is a newly identified pyrophosphatase regulating the cellular nucleotide pool but remains unexplored as potential target for CRC treatment. Here, twelve unprecedented chemical architectures terpene‐nonadride heterodimers (1–12) and their monomers (13–20) were isolated from endophyte Bipolaris victoriae S27. Compounds 1–12 represented the first example of terpene‐nonadride heterodimers, in which nonadride monomers of 1 and 2 were also first example of 5/6 bicyclic nonadrides. A series of assays showed that 2 could repress proliferation and induce cell cycle arrest, apoptotic and autophagic CRC cell death in vitro and in vivo. Clinical cancer samples data revealed that DCTPP1 was a novel target associated with poor survival in CRC. DCTPP1 was also identified as a new target protein of 2. Mechanically, compound 2 bound to DCTPP1, inhibited its enzymatic activity, intervened with amino acid metabolic reprogramming, and exerted anti‐CRC activity. Our study demonstrates that DCTPP1 was a novel potential biomarker and therapeutic target for CRC, and 2 was the first natural anti‐CRC drug candidate targeting DCTPP1. [ABSTRACT FROM AUTHOR]

Background: Tumor antigen peptide vaccines have shown remarkable efficacy, safety, and reliability in recent studies. However, the screening process for immunopotent antigenic peptides is cumbersome, limiting their widespread application. Identifying neoantigen peptides that can effectively trigger an immune response is crucial for personalized cancer treatment. Methods: Whole exome sequencing was performed on patient-derived colon cancer cells to predict 9-amino-acid (9aa) neoantigen peptides. In vitro simulation of endogenous antigen presentation by antigen-presenting cells (dendritic cells) to CD8+ T cells was conducted, aiming to activate the CD8+ immune response to the predicted antigens. The immunological effects of each neoantigen were assessed using flow cytometry and ELISpot assays, while the relationship between neoantigen immunogenicity and MHC molecular affinity was examined. Results: 1. Next-generation sequencing (NGS) predicted 9-amino acid (9aa) neoantigen peptides for subsequent immunological analysis.2. Higher mDC Levels in Experimental Group: CD11c+CD83+ mature dendritic cells (mDCs) were 96.6% in the experimental group, compared to 0.051% in the control group. CD80 fluorescence intensity was also significantly higher in the experimental group, confirming a greater mDC presence.3. Neoantigen Peptides Promote CD4+, CD8+ T, and NK Cell Proliferation: After 14 days, flow cytometry showed higher percentages of CD4+ T (37.41% vs 7.8%), CD8+ T (16.67% vs 14.63%), and NK cells (33.09% vs 7.81%) in the experimental group, indicating that the neoantigen peptides induced proliferation of CD4+, CD8+ T cells, and NK cells. 4. The results, analyzed using two-way ANOVA, showed that the standardized T-value for HLA molecular affinity variation in the 1-4 range (Group B) was significantly higher than for ≤1 (Group A, p < 0.0001) and >4 (Group C, p < 0.05). Regarding HLA-allele genotypes, HLA-Type 1 had a significantly higher standardized T-value than HLA-Type 2 (p < 0.05) and HLA-Type 3 (p < 0.0001). HLA-Type 1 was identified as the allele associated with the highest T-value. Conclusion: 1. The most immunogenic neoantigens typically exhibit an MHC molecular affinity variation between 1 and 4, indicating that stronger immunogenicity correlates with higher MHC molecular affinity variation. 2. Each patient's HLA molecules were classified into Types 1, 2, and 3, with Type 1 showing the highest binding capacity for neoantigens. Our findings indicate that the most immunogenic neoantigens were associated with HLA Type 1. 3. Neoantigen peptides were shown to activate the proliferation of both CD8+ T-cells and induce proliferation of CD4+ T-cells and NK cells. 4. Variation in MHC molecular affinity and HLA neoantigen genotype are anticipated to serve as valuable variables for screening highly immunogenic neoantigens, facilitating more efficient preparation of effective polypeptide tumor vaccines. [ABSTRACT FROM AUTHOR]

PIK3CA gene encodes the p110α catalytic subunit of PI3K, which regulates the PI3K/AKT/mTOR signaling pathway. PIK3CA gene mutation is one of the most common mutations in colorectal cancer (CRC), affecting about 15%–20% of CRC patients. PIK3CA gene mutation leads to the persistent activation of the PI3K/AKT/mTOR signaling pathway, which promotes the proliferation, invasion, metastasis, and drug resistance of CRC. This article provides a summary of the key detection methods for PIK3CA gene mutation, and provides an introduction to the existing colorectal cancer treatments and their practical applications in the clinic. Besides, this article summarizes the role and mechanism of PIK3CA gene mutation in the occurrence and development of CRC. It also explores the relationship between PIK3CA gene mutation and the clinical features and prognosis of CRC. This article focuses on the influence and mechanism of PIK3CA gene mutation on the targeted therapy and immunotherapy of CRC, and discusses the potential value and future direction of PIK3CA gene mutation in the personalized therapy of CRC. We aim to provide new perspectives and ideas for the precise diagnosis and treatment of CRC. [ABSTRACT FROM AUTHOR]

Background: A complex inheritance has been suggested in families with colorectal-, gastric- and prostate cancer. Therefore, we conducted a genome-wide association study (GWAS) in colorectal cancer patients, who's relatives had prostate-, and/or gastric cancer. Methods: The GWAS analysis consisted of 685 cases of colorectal cancer and 4780 healthy controls from Sweden. A sliding window haplotype analysis was conducted using a logistic regression model. Thereafter, we performed sequencing to find candidate variants, finally to be tested in a nested case–control study. Results: Candidate loci/genes on ten chromosomal regions were suggested with odds ratios between 1.71–3.62 and p-values < 5 × 10–8 in the analysis. The regions suggested were 1q32.2, 3q29, 4q35.1, 4p15.31, 4q26, 8p23.1, 13q33.3, 13q13.3, 16q23.3 and 22q11.21. All regions, except one on 1q32.2, had protein coding genes, many already shown to be involved in cancer, such as ZDHHC19, SYNPO2, PCYT1A, MYO16, TXNRD2, COMT, and CDH13. Sequencing of DNA from 122 colorectal cancer patients with gastric- and/or prostate cancer in their families was performed to search for candidate variants in the haplotype regions. The identified candidate variants were tested in a nested case–control study of similar colorectal cancer cases and controls. There was some support for an increased risk of colorectal-, gastric-, and/or prostate cancer in all the six loci tested. Conclusions: This study demonstrated a proof of principle strategy to identify risk variants found by GWAS, and identified ten candidate loci that could be associated with colorectal, gastric- and prostate cancer. [ABSTRACT FROM AUTHOR]

Colorectal cancer in Brazil is among the main public health concern. The burden of disease can be related to unhealthy lifestyle behavior and inequality in access to health services. The aim of this study was to identify the main factors associated with colorectal cancer mortality in Brazil. This is an ecological study that had the Brazilian Federal Units as the primary units of analysis. Colorectal cancer mortality data (ICD C18-C21) were obtained from Brazilian national mortality system to the year 2020. Prevalence of overweight, food consumption (fiber, whole grains and red meat), physical inactivity, smoke, alcohol consumption, the median of household income, years of study, rates of cancer treatment units and oncologist by Brazilian Federal Units were considered as factor associated to the colorectal cancer mortality. Quasipoisson Generalized Linear Models were used to associate CRC mortality and variables related to dietary intake, risk behavior, and access to health services. In 2020, there were 21,501 deaths by colorectal cancer (51% among women). Prevalence of overweight (men: IRR 1.03; CI: 1.01–1.04; women IRR 1.05; CI 1.02–1.08) and the density of oncologist (men: IRR 1.02; CI: 1.01–1.03; women IRR 1.02; CI 1.01–1.03) were the main factors associated with colorectal cancer mortality. Sociodemographic and food consumption characteristics were not statistically associated with CRC. Prevalence of overweight was the strongest factor associated with mortality from colorectal cancer in Brazil in 2020. Therefore, current public policies to reduce overweight and obesity should be prioritized and strengthened in Brazil. [ABSTRACT FROM AUTHOR]

Background: Tumor Mutational Burden (TMB) have emerged as pivotal predictive biomarkers in determining prognosis and response to immunotherapy in colorectal cancer (CRC) patients. While Whole Exome Sequencing (WES) stands as the gold standard for TMB assessment, carry substantial costs and demand considerable time commitments. Additionally, the heterogeneity among high-TMB patients remains poorly characterized. Methods: We employed eight advanced machine learning algorithms to develop gene-panel-based models for TMB estimation. To rigorously compare and validate these TMB estimation models, four external cohorts, involving 1,956 patients, were used. Furthermore, we computed the Pearson correlation coefficient between the estimated TMB and tumor neoantigen levels to elucidate their association. CD8+ tumor-infiltrating lymphocyte (TIL) density was assessed via immunohistochemistry. Results: The TMB estimation model based on the Lasso algorithm, incorporating 20 genes, exhibiting satisfactory performance across multiple independent cohorts (R2 ≥ 0.859). This 20-gene TMB model proved to be an independent prognostic indicator for the progression-free survival (PFS) of CRC patients (p = 0.001). DNAH5 mutations were associated with a more favorable prognosis in high-TMB CRC patients, and correlated strongly with tumor neoantigen levels and CD8+ TIL density. Conclusions: The 20-gene model offers a cost-efficient approach to precisely estimating TMB, providing prognosis in patients with CRC. Incorporating DNAH5 within this model further refines the categorization of patients with elevated TMB. Utilizing the 20-gene model facilitates the stratification of patients with CRC, enabling more precise treatment planning. [ABSTRACT FROM AUTHOR]

Standard-of-care (SoC) imaging for assessing colorectal polyps during colonoscopy, based on white-light colonoscopy (WLC) and narrow-band imaging (NBI), does not have sufficient accuracy to assess the invasion depth of complex polyps non-invasively during colonoscopy. We aimed to evaluate the feasibility of a custom endoscopic optical coherence tomography (OCT) probe for assessing colorectal polyps during routine colonoscopy. Patients referred for endoscopic treatment of large colorectal polyps were enrolled in this pilot clinical study, which used a side-viewing OCT catheter developed for use with an adult colonoscope. OCT images of polyps were captured during colonoscopy immediately before SoC treatment. A deep learning model was trained to differentiate benign from deeply invasive lesions for real-time diagnosis. 35 polyps from 32 patients were included. OCT imaging added on average 3:40 min (range 1:54–8:20) to the total procedure time. No complications due to OCT were observed. OCT revealed distinct subsurface tissue structures that correlated with histological findings, including tubular adenoma (n = 20), tubulovillous adenoma (n = 10), sessile serrated polyps (n = 3), and invasive cancer (n = 2). The deep learning model achieved an area under the receiver operating characteristic curve (AUROC) of 0.984 (95%CI 0.972–0.996) and Cohen's kappa of 0.845 (95%CI 0.774–0.915) when compared to gold standard histopathology. OCT is feasible and safe for polyp assessment during routine colonoscopy. When combined with deep learning, OCT offers clinicians increase confidence in identifying deeply invasive cancers, potentially improving clinical decision-making. Compared to previous studies, ours offers a nuanced comparison between not just benign and malignant lesions, but across multiple histological subtypes of polyps. [ABSTRACT FROM AUTHOR]

There is a growing interest in using fecal mRNA transcripts as biomarkers for non-invasive detection of colorectal cancer (CRC). The following study compares different RNA extraction and reverse transcription PCR (RT-PCR) methods for mRNA detection in stool and identifies a robust and sensitive protocol. A combination of the Stool total RNA purification kit (Norgen) and the Superscript III one-step RT-PCR kit (Invitrogen) provided high RNA purity and sensitive and consistent mRNA detection, making them well-suited candidates for large-scale studies. We tested the protocol by detecting the mRNA of several immune genes (CXCL1, IL8, IL1B, IL6, PTGS2, and SPP1) in 22 CRCs, 24 adenomatous polyps, and 22 control stool samples. All these inflammatory markers, except for CXCL1, showed a strong association with CRC. Cancer stool samples showed increased levels of IL1B, IL8, and PTGS2 transcripts compared to polyp and control groups. Thus, this work supports the potential use of fecal mRNA as biomarkers for CRC detection. [ABSTRACT FROM AUTHOR]

An improved DeepSurv model is proposed for predicting the prognosis of colorectal cancer patients at stage IV. Our model, called as PseudoDeepSurv, is optimized by a novel loss function, which is the combination of the average negative log partial likelihood and the mean-squared error derived from the pseudo-observations approach. The public BioStudies dataset including 999 patients was utilized for performance evaluation. Our PseudoDeepSurv model produced a C-index of 0.684 and 0.633 on the training and testing dataset, respectively. While for the original DeepSurv model, the corresponding values are 0.671 and 0.618, respectively. [ABSTRACT FROM AUTHOR]

Background: Understanding the impact of clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) on solid tumor risk and mortality can shed light on novel cancer pathways. Methods: The authors analyzed whole genome sequencing data from the Trans‐Omics for Precision Medicine Women's Health Initiative study (n = 10,866). They investigated the presence of CHIP and mCA and their association with the development and mortality of breast, lung, and colorectal cancers. Results: CHIP was associated with higher risk of breast (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.03–1.64; p =.02) but not colorectal (p =.77) or lung cancer (p =.32). CHIP carriers who developed colorectal cancer also had a greater risk for advanced‐stage (p =.01), but this was not seen in breast or lung cancer. CHIP was associated with increased colorectal cancer mortality both with (HR, 3.99; 95% CI, 2.41–6.62; p <.001) and without adjustment (HR, 2.50; 95% CI, 1.32–4.72; p =.004) for advanced‐stage and a borderline higher breast cancer mortality (HR, 1.53; 95% CI, 0.98–2.41; p =.06). Conversely, mCA (cell fraction [CF] >3%) did not correlate with cancer risk. With higher CFs (mCA >5%), autosomal mCA was associated with increased breast cancer risk (HR, 1.39; 95% CI, 1.06–1.83; p =.01). There was no association of mCA (>3%) with breast, colorectal, or lung mortality except higher colon cancer mortality (HR, 2.19; 95% CI, 1.11–4.3; p =.02) with mCA >5%. Conclusions: CHIP and mCA (CF >5%) were associated with higher breast cancer risk and colorectal cancer mortality individually. These data could inform on novel pathways that impact cancer risk and lead to better risk stratification. In the Women's Health Initiative Trans‐Omics for Precision Medicine study, participants with clonal hematopoiesis of indeterminate potential (CHIP) had higher breast cancer incidence and a higher colorectal cancer mortality than women without CHIP. The presence of autosomal mosaic chromosomal alterations with >5% cell fraction was associated with higher incidence of breast cancer but no other cancers. [ABSTRACT FROM AUTHOR]

Patients with locally advanced rectal cancer often require neoadjuvant chemoradiation therapy to downstage the disease, but the response is variable with no predictive biomarkers. We have previously revealed through proteomic profiling that myoferlin is associated with response to radiation therapy. The aims of this study were to further validate this finding and explore the potential for myoferlin to act as a prognostic and/or therapeutic target. Immunohistochemical analysis of a tissue microarray (TMA) for 111 patients was used to validate the initial proteomic findings. Manipulation of myoferlin was achieved using small interfering RNA, a small molecular inhibitor (wj460), and a CRISPR-Cas9 knockout cell line. Radiosensitization after treatment was assessed using 2-dimensional clonogenic assays, 3-dimensional spheroid models, and patient-derived organoids. Underlying mechanisms were investigated using electrophoresis, immunofluorescence, and immunoblotting. Analysis of both the diagnostic biopsy and tumor resection samples confirmed that low myoferlin expression correlated with a good response to neoadjuvant long-course chemoradiation therapy. High myoferlin expression was associated with spread to local lymph nodes and worse 5-year survival (P =.01; hazard ratio, 3.5; 95% CI, 1.27-10.04). This was externally validated using the Stratification in Colorectal Cancer database. Quantification of myoferlin using immunoblotting in immortalized colorectal cancer cell lines and organoids demonstrated that high myoferlin expression was associated with increased radioresistance. Biological and pharmacologic manipulation of myoferlin resulted in significantly increased radiosensitivity across all cell lines in 2-dimensional and 3-dimensional models. After irradiation, myoferlin knockdown cells had a significantly impaired ability to repair DNA double-strand breaks. This appeared to be mediated via nonhomologous end-joining. We have confirmed that high expression of myoferlin in rectal cancer is associated with poor response to neoadjuvant therapy and worse long-term survival. Furthermore, the manipulation of myoferlin led to increased radiosensitivity in vitro. This suggests that myoferlin could be targeted to enhance the sensitivity of patients with rectal cancer to radiation therapy, and further work is required. [ABSTRACT FROM AUTHOR]

Background: Many surgeons have begun learning about colorectal surgery using laparoscopy rather than laparotomy. The domains of four-step technique training program (DOF) for laparoscopic colorectal surgery have been designed and implemented by our institute since 2011, and they are expected to provide a safe and effective program for trainees with limited experience in laparoscopic colorectal surgery. Method: The DOF were established with standard surgical procedures, a four-step technique, and learning passports using point credits after the procedure was completed. Patients who underwent minimally invasive colorectal resection at the Chang Gung Memorial Hospital between January 2013 and April 2019 were enrolled. Results: Overall, 2604 and 478 patients were enrolled in the non-training and training groups, respectively. Multivariable logistic regression analysis revealed that the postoperative short-term outcomes were not significantly associated with the training or non-training groups. However, the training group had a significantly longer operative time than the non-training group in the linear regression model. Once the trainee passed the proficiency point (passed 100 points or 30 cases), no significant difference in postoperative short-term outcomes was found between the patients in the non-training and training groups that underwent the entire surgery performed by the trainee. Conclusion: When patients’ safety was evaluated in the training cases under the DOF, no higher rates of postoperative morbidity and mortality were found compared to those in cases performed by experienced surgeons. Additionally, trainees who passed the proficiency point during DOF could safely perform the entire laparoscopic colorectal surgery under supervision without further adverse effects on the patients. [ABSTRACT FROM AUTHOR]

The scaffold protein PEAK1 acts downstream of integrin adhesion complexes and the epidermal growth factor receptor, orchestrating signaling events that control cell proliferation and cytoskeletal remodeling. In this study we investigated the role of PEAK1 in colorectal carcinoma (CRC) progression using various in vitro and in vivo models to replicate the stepwise pathogenesis of CRC. While we observed a cell-type specific role for PEAK1 in the proliferation and in human CRC cell lines in vitro, our in vivo experiments using different CRC mouse models driven by loss of Apc, with or without oncogenic Kras or Pten loss suggest that PEAK1 does not significantly contribute to tumor formation in vivo. However, the survival time of Peak1−/− mice in the Apcfl/+ model appeared to be slightly increased. Furthermore, PEAK1 promotes EGF-induced Caco-2 cell proliferation and regulates spheroid polarization and lumenization. Given that the Caco-2 cells harbor mutations in the tumor suppressors APC and β-CATENIN, but not in other tumor suppressors or in proto-oncogenes, we conclude that the PEAK1's impact on colon carcinogenesis is limited, potentially playing a role in the initial stage of the adenoma to carcinoma progression. [ABSTRACT FROM AUTHOR]

Though several anti-PD-1/PD-L1 antibodies approved for monotherapy in microsatellite instability-high or mismatch repair-deficient unresectable/metastatic solid tumors, novel immunotherapy with better anti-tumor activity is needed in clinic. In this single-arm, multicenter, pivotal, phase II study, patients received iparomlimab (a novel humanized anti-PD-1 mAb, 200 mg or 3 mg/kg for patients with body weight < 40 kg, IV, Q3W) until disease progression, intolerable toxicities, withdrawal of consent, death, or up to 2 years. The primary endpoint was objective response rate (ORR) assessed by independent radiological review committee (IRRC). Totally, 120 patients were enrolled, of whom 60 patients failed from prior standard therapy, were enrolled in the full analysis set (FAS). As of Jan 20, 2024, the confirmed ORR per IRRC in FAS were 50.0% (30/60; 95% CI 36.8–63.2%) patients, including 4 (6.7%) complete response (CR) and 26 (43.3%) partial response (PR). In colorectal cancer (CRC) patients in FAS, the ORR reached 57.9% (22/38; 95% CI 40.8–73.7%) per IRRC, with 3 (7.9%) CR and 19 (50.0%) PR. Furtherly, the ORRs in liver metastatic or non-liver metastatic CRC patients were 52.9% (9/17, 95% CI 27.8–77.0%) vs 61.9% (13/21, 95% CI 38.4%–81.9%). The incidence of TRAE was 90.8% (any grade) and 20.8% (grade ≥ 3). Immune-related adverse events occurred in 33.3% (any grade) and 5.0% (grade ≥ 3) of patients. No iparomlimab-related death occurred. Iparomlimab presented encouraging antitumor activity with durable response and tolerable safety profile. Trial registration ClinicalTrials.gov Identifier: NCT04326829. [ABSTRACT FROM AUTHOR]

PD-1/PD-L1 blockade therapies have displayed extraordinary clinical efficacy for melanoma, renal, bladder and lung cancer; however, only a minority of colorectal cancer (CRC) patients benefit from these treatments. The efficacy of PD-1/PD-L1 blockade in CRC is limited by the complexities of tumor microenvironment. PD-1/PD-L1 blockade immunotherapy is based on T cell-centered view of tumor immunity. However, the onset and maintenance of T cell responses and the development of long-lasting memory T cells depend on innate immune responses. Acknowledging the pivotal role of innate immunity in anti-tumor immune response, this review encapsulates the employment of combinational therapies those involve PD-1/PD-L1 blockade alongside the activation of innate immunity and explores the underlying cellular mechanisms, aiming to harnessing innate immune responses to induce long-lasting tumor control for CRC patients who received PD-1/PD-L1 blockade therapy. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a malignant tumor with poor prognosis and adverse therapeutic effect. The study aims to elucidate the contribution of OGT-mediated glycosylation of ADAR to chemoresistance in CRC through its role and regulatory mechanisms. Variations in OGT expression levels and their impact on CRC cell chemoresistance were investigated using gain-of-function and loss-of-function assays. Through a series of molecular biology experiments, we confirmed that ADAR is the downstream target of OGT regulation, emphasizing the role of OGT-mediated glycosylation in stabilizing ADAR. Furthermore, RNA immunoprecipitation (RIP) assays were conducted to examine the effects of ADAR-mediated A-to-I editing on the mRNA stability and translation of genes associated with DNA damage repair. Elevated OGT expression was found to enhance CRC's malignancy and resistance to chemotherapy. OGT's influence leads to the glycosylation of ADAR, thereby increasing its protein levels. ADAR, through its role in A-to-I editing, modulates the mRNA editing of genes implicated in DNA damage repair. This regulation enhances the expression of these genes, improves DNA repair capabilities, and ultimately, fosters chemoresistance in CRC cells. In conclusion, ADAR promotes PARP1 expression under the positive regulation of OGT-mediated O-glycosylation modification to enhance drug resistance in COAD cells. It provides the research basis for overcoming the drug resistance of CRC. [ABSTRACT FROM AUTHOR]

In consideration of the important influence of gut microbiota on colorectal cancer (CRC) development and host immune system, regulating microbiota and intestinal environment can be an assisting approach to CRC treatment. To remodel tumor microenvironment, the anti‐CRC molecular targeting drug regorafenib (REG)‐encapsulating nanoparticle (UIRN) is constructed with the amphiphilic inulin‐ursodeoxycholic acid conjugate. UIRN increases the intra‐tumoral concentration and accumulation time of REG. In the CT26 tumor‐bearing mouse model, the relative abundance of probiotics and short‐chain fatty acid concentrations in colon are upregulated after treatment with UIRN, with decreased proportion of pro‐tumoral bacteria. Combining gut microbiota modulation and the function of REG to induce polarization of tumor‐associated macrophages toward the M1‐type, UIRN conquers immunosuppression and enhances anti‐tumor immunity. UIRN not only efficiently controls tumor progression alone but also exhibits adjuvant effects to chemotherapy and immunotherapy agents. The microbiota‐regulating and tumor‐suppressing functions of UIRN also work in the colitis‐associated CRC model. With good biosafety, UIRN displays hopeful application prospects in CRC therapy. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions The study aimed to describe the incidence of pregnancy‐associated colorectal cancer (PACRC) in New South Wales (NSW), Australia, and to examine the perinatal outcomes of women with PACRC and their babies.A population‐based cohort study was conducted using linked data from NSW. The study group comprised all women diagnosed with colorectal cancer during pregnancy (gestational CRC) or postpartum (postpartum CRC). Women who gave birth without cancer during pregnancy or postpartum formed the comparison group (no‐cancer group).A total of 123 women were diagnosed with PACRC (22 gestational, 101 postpartum), and 1 786 078 women were in the no‐cancer group. The incidence of PACRC was 6.9/100 000 women giving birth. From 1994 to 2013, the incidence significantly increased even when adjusting for maternal age (adjusted increase of 5.8% per year). Women with gestational CRC had significantly higher odds of severe maternal complications (AOR 29.27, 95% CI: 11.18–76.63) and were more likely to give birth by labor induction or no‐labor caesarean section (AOR 4.39, 95% CI: 1.50–12.84) than women in the no‐cancer group. Although babies born to women with gestational CRC did not experience congenital anomalies, they had higher odds of planned preterm birth (AOR 9.91, 95% CI: 1.99–49.21) and severe neonatal adverse outcomes (AOR 8.65, CI: 3.65–20.5) than babies of women without cancer.The study found a significant increase in PACRC incidence in NSW over the study period, independent of maternal age. Increased interventions during gestational CRC births reflect management challenges with higher maternal and neonatal morbidities. [ABSTRACT FROM AUTHOR]