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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

Background: Some colorectal cancers (CRCs) are clinically diagnosed as cT4a with serosal invasion (SI). However, the cT4a is most often underdiagnosed pathologically as pT3 without SI by hematoxylin–eosin (H&E) staining alone. Using Elastica van Gieson (EVG) staining, some pT3 tumors invade the elastic lamina (EL), which extends just below the serosal layer. Recently, EL invasion (ELI) has been described as a poor prognostic factor for disease-free survival (DFS) and overall survival (OS) in patients with pStage II CRC. However, its clinicopathological significance remains unclear due to the limited number of studies and poor understanding of ELI. Objective: This study investigated the association between the ELI and patient prognosis. Methods: After 1982, pathological diagnosis was routinely performed using H&E and EVG staining methods, and long-term follow up was performed until 2016. All clinicopathological features including ELI were prospectively registered into our computer and 569 patients with pStage II CRC were collected from the database. Based on the ELI status, pT3 was divided into three pathological categories: pT3ELI − was defined as pT3a, pT3ELI + as pT3b and unidentified EL (pT3EL −) as pT3u. Results: Using H&E staining alone, gross cT4a was most often pathologically underdiagnosed as pT3 (93.8%) and very rarely as pT4a, resulting in a large diagnostic discrepancy. Using EVG staining, 60.7% of the cT4a tumors were diagnosed as pT3b. The 10-year DFS and OS rates were similar for pT3a and pT3u patients. However, the 10-year DFS and OS rates of pT3b patients were significantly lower than those of pT3a patients (75.6% vs. 95.6%, p < 0.0001 and 58.4% vs. 70.6%, p = 0.0024, respectively) but did not differ from those of pT4a patients (70.6%, p = 0.5799 and 52.0%, p = 0.1116, respectively). Multivariate analysis revealed that the ELI was the strongest independent risk factor for recurrence and CRC-specific death (p < 0.0001). Conclusions: A better understanding of the ELI allows us to reconsider the diagnostic discrepancy of serosal invasion, i.e., pT3b should be considered pT4a. The ELI-based subclassification of pT3 is expected to be incorporated into the TNM staging system in the future. The ELI is a notable prognostic indicator in patients with pStage II CRC. [ABSTRACT FROM AUTHOR]

Microsatellite stable (MSS) colorectal cancers (CRCs) are often resistant to anti-programmed death-1 (PD-1) therapy. Here, we show that a CRC pathogen, Fusobacterium nucleatum (Fn), paradoxically sensitizes MSS CRC to anti-PD-1. Fecal microbiota transplantation (FMT) from patients with Fn -high MSS CRC to germ-free mice bearing MSS CRC confers sensitivity to anti-PD-1 compared to FMT from Fn -low counterparts. Single Fn administration also potentiates anti-PD-1 efficacy in murine allografts and CD34+-humanized mice bearing MSS CRC. Mechanistically, we demonstrate that intratumoral Fn generates abundant butyric acid, which inhibits histone deacetylase (HDAC) 3/8 in CD8+ T cells, inducing Tbx21 promoter H3K27 acetylation and expression. TBX21 transcriptionally represses PD-1, alleviating CD8+ T cell exhaustion and promoting effector function. Supporting this notion, knockout of a butyric acid-producing gene in Fn abolishes its anti-PD-1 boosting effect. In patients with MSS CRC, high intratumoral Fn predicts favorable response to anti-PD-1 therapy, indicating Fn as a potential biomarker of immunotherapy response in MSS CRC. [Display omitted] • Fn boosts anti-PD-1 efficacy in microsatellite stable colorectal cancer (MSS CRC) • Fn represses PD-1 expression on CD8+ TILs and reactivates their effector functions • Fn -derived butyric acid down-regulates PD-1 on CD8+ TILs via a HDAC3/8-TBX21 axis • High intratumoral Fn abundance correlates with favorable response in MSS CRC Wang et al. report that colorectal cancer (CRC)-promoting gut pathogen Fusobacterium nucleatum paradoxically sensitizes microsatellite stable colorectal cancer (MSS CRC) to anti-PD-1 in experimental models and predicts favorable response to anti-PD-1 in patients with MSS CRC. Mechanistically, F. nucleatum- derived butyric acid relieves CD8+ TIL exhaustion by repressing PD-1 via a HDAC3/8-TBX21 axis. [ABSTRACT FROM AUTHOR]

Background and Purpose: Wnt binding to Frizzleds (FZD) is a crucial step that leads to the initiation of signalling cascades governing multiple processes during embryonic development, stem cell regulation and adult tissue homeostasis. Recent efforts have enabled us to shed light on Wnt–FZD pharmacology using overexpressed HEK293 cells. However, assessing ligand binding at endogenous receptor expression levels is important due to differential binding behaviour in a native environment. Here, we study FZD paralogue, FZD7, and analyse its interactions with Wnt‐3a in live CRISPR‐Cas9‐edited SW480 cells typifying colorectal cancer. Experimental Approach: SW480 cells were CRISPR‐Cas9‐edited to insert a HiBiT tag on the N‐terminus of FZD7, preserving the native signal peptide. These cells were used to study eGFP‐Wnt‐3a association with endogenous and overexpressed HiBiT‐FZD7 using NanoBiT/bioluminescence resonance energy transfer (BRET) and NanoBiT to measure ligand binding and receptor internalization. Key Results: With this new assay the binding of eGFP‐Wnt‐3a to endogenous HiBiT‐FZD7 was compared with overexpressed receptors. Receptor overexpression results in increased membrane dynamics, leading to an apparent decrease in binding on‐rate and consequently in higher, up to 10 times, calculated Kd. Thus, measurements of binding affinities to FZD7 obtained in overexpressed cells are suboptimal compared with the measurements from endogenously expressing cells. Conclusions and Implications: Binding affinity measurements in the overexpressing cells fail to replicate ligand binding affinities assessed in a (patho)physiologically relevant context where receptor expression is lower. Therefore, future studies on Wnt–FZD7 binding should be performed using receptors expressed under endogenous promotion. [ABSTRACT FROM AUTHOR]

Aims: Traditionally, mismatch repair (MMR) status is determined by a panel of four antibodies (MLH1, PMS2, MSH2, MSH6). If all proteins are retained, cases are MMR proficient (pMMR), while loss of one or more proteins is indicative of MMR deficiency (dMMR). This approach has been challenged in favour of a two‐antibody approach, using PMS2 and MSH6 as a first screening. Their retainment is deemed sufficient to declare cases pMMR. In this study we aim to verify the validity of the two‐antibody approach. Methods and Results: We performed a nationwide study in colorectal cancer (CRC) and endometrial cancer (EC) diagnosed between 2016 and 2023, including 47,657 patients to evaluate the two‐antibody approach. In 0.17% and 0.4% of cases of CRC and EC, respectively, dMMR cases would be missed with the two‐antibody approach. Subgroup analyses pointed towards slightly increased miss rates in younger patients (under the age of 50 years) in both groups and identified special subtypes (signet ring cell carcinoma, medullary carcinoma, and mucinous carcinoma in CRC and clear cell carcinoma in EC) with increased miss rates. For these specific subgroups, a low threshold should be used for further testing. In case of ambiguous or heterogeneous staining patterns, four antibodies should be used. Conclusion: In general, the application of a two‐antibody MMR testing strategy does not lead to considerable failure of dMMR identification and saves costs. [ABSTRACT FROM AUTHOR]

Aim: Recommendations for surveillance after colonoscopy are based on risk factors for metachronous advanced colorectal neoplasia (AN) and colorectal cancer (CRC). The value of these risk factors remains unclear in populations enriched by individuals with a positive faecal immunochemical test and were investigated in a modern setting. Methods and Results: This population‐based cohort study included all individuals in the Netherlands of ≥55 years old with a first adenoma diagnosis in 2015. A total of 22,471 patients were included. Data were retrieved from the Dutch Nationwide Pathology Databank (Palga). Primary outcomes were metachronous AN and CRC. Patient and polyp characteristics were evaluated by multivariable Cox regression analyses. During follow‐up, 2416 (10.8%) patients were diagnosed with AN, of which 557 (2.5% from the total population) were CRC. Adenomas with high‐grade dysplasia (hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.40–1.83), villous histology (HR 1.91, 95% CI 1.59–2.28), size ≥10 mm (HR 1.12, 95% CI 1.02–1.23), proximal location (HR 1.12, 95% CI 1.02–1.23), two or more adenomas (HR 1.28, 95% CI 1.16–1.41), and serrated polyps ≥10 mm (HR 1.67, 95% CI 1.42–1.97) were independent risk factors for metachronous AN. In contrast, only adenomas with high‐grade dysplasia (HR 2.49, 95% CI 1.92–3.24) were an independent risk factor for metachronous CRC. Conclusions: Risk factors for metachronous AN and CRC were identified for populations with access to a faecal immunochemical test (FIT)‐based screening programme. If only risk factors for metachronous CRC are considered, a reduction in criteria for surveillance seems reasonable. [ABSTRACT FROM AUTHOR]

Summary: Background: Elevated allostatic load (AL) has been associated with the risk and poor prognosis of many chronic diseases. The association between AL and inflammatory bowel disease (IBD) is unknown. Aims: The aim of this study is to investigate the associations between AL and the risk and prognosis of IBD. Methods: We included 326,345 adults and 3767 patients with IBD from the UK Biobank. AL served as the exposure, estimated using the AL biomarker panel, with the primary outcomes including the risk and prognosis of IBD. We used Cox regression models to examine the associations. Results: High AL biomarker panel was associated with a greater risk of IBD (hazard ratio: 1.19, 95% CI: 1.08–1.31), ulcerative colitis (1.17, 95%CI: 1.04–1.32), and Crohn's disease (1.25, 95%CI: 1.05–1.49). Risk of developing IBD increased by 12% in quartile 2, 20% in quartile 3, and 37% in quartile 4 as AL biomarker panel increased. The all‐cause mortality risk in IBD compared with quartile 1 rose by 54% for quartile 2, 72% for quartile 3, and 82% for quartile 4, as AL biomarker panel increased. Similar effects were also observed for ulcerative colitis and Crohn's disease. An increase in AL biomarker panel count was associated with an elevated risk of intestinal resection and colorectal cancer in IBD. Conclusions: Increased AL is associated with IBD risk, as well as the risks of intestinal resection, colorectal cancer and mortality. [ABSTRACT FROM AUTHOR]

PIWI proteins, traditionally associated with germline development, have recently gained attention for their expression in various cancers, including colorectal cancer. However, the molecular mechanisms underlying their reactivation and impact on cancer initiation and progression remain elusive. Here, we found that PIWIL1 is expressed at relatively high levels in CRC-derived samples and cell lines, where it undergoes a dynamic relocalization to the centrosome during mitosis. Knockdown of PIWIL1 induces G2/M arrest associated with disruption of the mitotic spindle and aberrant metaphase events, highlighting its role in cell cycle progression. We also found that the expression of PIWIL1 is lost during the differentiation of Caco-2 cells into enterocytes and that PIWIL1 is expressed in cells at the base of the intestinal crypts in normal human colon tissue, where intestinal stem cells are known to reside. Thus, it is possible that the presence of PIWIL1 in cancer cells reflects a physiological role of this protein in stem cell maintenance, which would argue in favor of the proposed stem cell origin of CRC. Supporting this view, dedifferentiation of human fibroblasts into induced pluripotent stem cells (iPSCs) involves the reactivation of PIWIL2 expression, another member of the PIWI protein family. Overall, our findings suggest a role of PIWIL1 in mediating cell cycle dynamics, both in colorectal cancer cells and possibly also in intestinal stem cells. In a broader aspect, we provide evidence supporting an involvement of PIWI proteins in somatic stem cell maintenance, thus expanding the known non-gonadal functions of this protein family. [ABSTRACT FROM AUTHOR]

The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies on sex hormones and from the Trøndelag Health Study (HUNT) and large consortia on cancers. There was suggestive evidence of 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio 0.60, 95% confidence interval 0.37–0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Colorectal cancer is the third most common cancer worldwide. Micropapillary carcinoma (MPC) is increasingly identified as a poor prognostic marker in various cancers, including breast, bladder and lung. It remains an under recognized subtype in colorectal cancer. The aim of this study is to evaluate the prevalence, implications and impact on survival of MPC in colorectal cancer in an Australian cohort.A retrospective review of all colorectal cancer resections in two tertiary centres in Sydney Australia was performed, between 2019 and 2024. MPC was identified on histolopathology as per standard guidelines of the resected specimens. Variables collected included age, sex, TNM, site, lymphovascular invasion (LVI), and lymph node involvement.Of 597 colorectal cancer resections during the study period, 21 cases of MPC were identified (3.5%). Mean age was 60 years (SD 15 years). Twenty patients (95%) had T3–T4 tumours, 19 (90%) had positive lymph node involvement, 18 (86%) had confirmed or suspected LVI, and 4 (19%) had distant metastatic disease. Overall 1‐year survival was 90% and 3‐year survival was 76%.MPC is associated with high risk features in colorectal adenocarcinoma. Accurate histopathological diagnosis of these more aggressive cancers should guide prognostication, individualized adjuvant treatment and close surveillance. [ABSTRACT FROM AUTHOR]

BackgroundMaterials and methodsResultsConclusionColorectal cancer (CRC) is the most common malignancy of the digestive system in the world. Immune cells and molecules in tumor microenvironment are crucial.Identifying immune system components in cancer aids in biomarker discovery. This study investigated the serum IgE levels and expression of IL-4 and IL-13 in the tissue and serum of CRC patients and explored their possible association with pathological and clinical factors.Thirty-six patients with CRC and 36 healthy individuals were involved in the study. Tissues and blood samples were collected. Serum levels of IgE and IL-4 and IL-13 were analyzed using the ELISA method. The quantitative Real-Time PCR (qRT-PCR) technique was used to assess the expression levels of the cytokines in CRC tissue samples in comparison with the adjacent control tissue.Our results revealed that the serum level of IL-4 and IL-13 and also their gene expression levels were significantly decreased in CRC patients compared to the controls. The results of this study revealed that there is no significant difference in the serum levels of IgE between CRC patients and the control group.All in all, the results of the current research suggest that the expression levels of IL-13, IL-4, and IgE vary between CRC tissue. [ABSTRACT FROM AUTHOR]

Colorectal polyps are structural abnormalities of the gastrointestinal tract that can potentially become cancerous in some cases. The study introduces a novel framework for colorectal polyp segmentation named the Multi-Scale and Multi-Path Cascaded Convolution Network (MMCC-Net), aimed at addressing the limitations of existing models, such as inadequate spatial dependence representation and the absence of multi-level feature integration during the decoding stage by integrating multi-scale and multi-path cascaded convolutional techniques and enhances feature aggregation through dual attention modules, skip connections, and a feature enhancer. MMCC-Net achieves superior performance in identifying polyp areas at the pixel level. The Proposed MMCC-Net was tested across six public datasets and compared against eight SOTA models to demonstrate its efficiency in polyp segmentation. The MMCC-Net's performance shows Dice scores with confidence interval ranging between 77.43 ± 0.12, (77.08, 77.56) and 94.45 ± 0.12, (94.19, 94.71) and Mean Intersection over Union (MIoU) scores with confidence interval ranging from 72.71 ± 0.19, (72.20, 73.00) to 90.16 ± 0.16, (89.69, 90.53) on the six databases. These results highlight the model's potential as a powerful tool for accurate and efficient polyp segmentation, contributing to early detection and prevention strategies in colorectal cancer. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most common cancer and causes high mortality worldwide. Although CRC has been studied widely, the molecular mechanism is not completely known. Eukaryotic translation elongation factor 1 delta (EEF1D) participates in the progression of various tumors, however, the effect of EEF1D on CRC remains unclear. Here, we aimed to identify the potential mechanism of EEF1D in CRC. The expression levels of EEF1D were assessed in CRC samples. Functional analysis of EEF1D in CRC was detected in vitro and in vivo. The regulatory mechanism of EEF1D was identified with RNA immunoprecipitation, RNA pull‐down assay, and proteomics analysis. Our findings confirmed that EEF1D was upregulated in human CRC tissues. Functionally, EEF1D overexpression accelerated cell proliferation and metastasis, whereas EEF1D knockdown inhibited cell proliferation and metastasis both in vitro and in vivo CRC models. Furthermore, we showed that EEF1D was upregulated by SRSF9 via binding to 3′UTR of EEF1D mRNA. EEF1D knockdown reversed the malignant phenotype induced by SRSF9 overexpression. These findings demonstrated that EEF1D promotes CRC progression, and EEF1D may be a molecular target against CRC. [ABSTRACT FROM AUTHOR]

Background: Mutations in the TP53 tumor suppressor gene are well-established drivers of colorectal cancer (CRC) development. However, data on the prevalence of TP53 variants and their association with consensus molecular subtype (CMS) classification in patients with CRC from Rwanda are currently lacking. This study addressed this knowledge gap by investigating TP53 mutation status concerning CMS classification in a CRC cohort from Rwanda. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue blocks were obtained from 51 patients with CRC at the University Teaching Hospital of Kigali, Rwanda. Exons 4 to 11 and their flanking intron-exon boundaries in the TP53 gene were sequenced using Sanger sequencing to identify potential variants. The recently established immunohistochemistry-based classifier was employed to determine the CMS of each tumor. Results: Sequencing analysis of cancerous tissue DNA revealed TP53 pathogenic variants in 23 of 51 (45.1%) patients from Rwanda. These variants were predominantly missense types (18/23, 78.3%). The most frequent were c.455dup (p.P153Afs*28), c.524G > A (p.R175H), and c.733G > A (p.G245S), each identified in three tumors. Trinucleotide sequence context analysis of the 23 mutations (20 of which were single-base substitutions) revealed a predominance of the [C > N] pattern among single-base substitutions (SBSs) (18/20; 90.0%), with C[C > T]G being the most frequent mutation (5/18, 27.8%). Furthermore, pyrimidine bases (C and T) were preferentially found at the 5ʹ flanking position of the mutated cytosine (13/18; 72.2%). Analysis of CMS subtypes revealed the following distribution: CMS1 (microsatellite instability-immune) (6/51, 11.8%), CMS2 (canonical) (28/51, 54.9%), CMS3 (metabolic) (9/51, 17.6%), and CMS4 (mesenchymal) (8/51, 15.7%). Interestingly, the majority of TP53 variants were in the CMS2 subgroup (14/23; 60.1%). Conclusion: Our findings indicate a high frequency of TP53 variants in CRC patients from Rwanda. Importantly, these variants are enriched in the CMS2 subtype. This study, representing the second investigation into molecular alterations in patients with CRC from Rwanda and the first to explore TP53 mutations and CMS classification, provides valuable insights into the molecular landscape of CRC in this understudied population. [ABSTRACT FROM AUTHOR]

Purpose: Altered lipid metabolism frequently occurs in patients with solid cancers and dyslipidemia has been associated with poorer outcomes in patients with colorectal cancer. This study sought to investigate whether cholesterol levels are associated with clinical outcomes and can serve as survival predictors. Methods: We conducted a retrospective cohort study with Danish patients diagnosed with colorectal cancer who had surgery with curative intent for UICC stages I to III between 2015 and 2020. Using propensity score adjustment, we matched patients in a 1:1 ratio to examine the impact of total cholesterol (TC) > 4 mmol/L vs. ≤ 4 mmol/L within 365 days prior to surgery on overall survival (OS) and disease-free survival (DFS). Results: A total of 3443 patients were included in the study. Median follow-up time was 3.8 years. Following propensity score matching, 1572 patients were included in the main analysis. There was no statistically significant difference in OS or DFS between patients with TC > 4 mmol/L compared with TC ≤ 4 mmol/L (HR: 0.82, 95% CI, 0.65–1.03, HR: 0.87, 95% CI, 0.68–1.12, respectively.). A subgroup analysis investigating TC > 4 mmol/L as well as low-density lipoprotein (LDL) > 3 mmol/L found a significant correlation with OS (HR: 0.74, 95% CI, 0.54–0.99). Conclusion: TC levels alone were not associated with OS or DFS in patients with colorectal cancer. Interestingly, higher TC and LDL levels were linked to better overall survival, suggesting the need for further exploration of cholesterol's role in colorectal cancer. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Etoposide is a second-line chemotherapy agent widely used for metastatic colorectal cancer. However, we discovered that etoposide treatment induced greater motility potential in four colorectal cancer cell lines. Therefore, we used microarrays to test the mRNA of these cancer cell lines to investigate the mechanisms of etoposide promoting colorectal cancer metastasis. Differentially expressed genes (DEGs) were identified by comparing the gene expression profiles in samples from etoposide-treated cells and untreated cells in all four colorectal cancer cell lines. Next, these genes went through the Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway analysis. Among the top 10 genes including the upregulated and downregulated, eight genes had close interaction according to the STRING database: FAS, HMMR, JUN, LMNB1, MLL3, PLK2, STAG1 and TBL1X. After etoposide treatment, the cell cycle, metabolism-related and senescence signaling pathways in the colorectal cancer cell lines were significantly downregulated, whereas necroptosis and oncogene pathways were significantly upregulated. We suggest that the differentially expressed genes LMNB1 and JUN are potential targets for predicting colorectal cancer metastasis. These results provide clinical guidance in chemotherapy, and offer direction for further research in the mechanism of colorectal cancer metastasis. [ABSTRACT FROM AUTHOR]

Background: Recent studies have highlighted the role of miR-5195-3p in suppressing cell growth in various cancers. However, the specific functional impact of miR-5195-3p in colorectal cancer (CRC) remain to be fully clarified. The importance of miR-5195-3p in CRC was evaluated, aiming to uncover its underlying molecular mechanism and identify it as a potential therapeutic target for CRC. Results: Our research has shown that miR-5195-3p is markedly under-expressed in CRC tissues and cell cultures, with its reduced presence associated with a higher TNM stage, lymphatic invasion, and unfavorable survival outcome. Ectopic miR-5195-3p expression curtailed proliferation, migration, and invasion of SW1116 and HT29 cells. Additionally, we discovered that miR-5195-3p directly targets and negatively influences Toll-like receptor 4 (TLR4) in CRC cells. Moreover, an inverse relationship was noted between miR-5195-3p and TLR4 expression in CRC tissue samples. Notably, restoring TLR4 expression counteracted miR-5195-3p's suppressive impact on cell growth, motility, invasiveness, epithelial-mesenchymal transition (EMT), and the TLR4/MyD88 signaling pathway in SW1116 and HT29 cells. Conclusions: MiR-5195-3p suppresses the CRC cellular functions through the downregulation of TLR4/MyD88 signaling, indicating that targeting miR-5195-3p might offer a viable therapeutic strategy for CRC. [ABSTRACT FROM AUTHOR]

Background: Today, the prognostic tools available at the time of diagnosis in colorectal cancer (CRC) are limited. Better prognostic tools are a prerequisite for personalised treatment. This study aimed to investigate whether circulating tumour DNA (ctDNA) markers found in plasma before clinical diagnosis of CRC could contribute to the prediction of poor prognosis. Methods: This observational cohort study included patients diagnosed with CRC stage I-III within 24 months following participation in the Trøndelag Health Study (n = 85). Known methylated ctDNA biomarkers of CRC were analysed by PCR in plasma. Outcomes were overall survival (OS), recurrence-free survival (RFS) and poor prognosis (PP). Candidate clinical and methylated ctDNA predictors of the outcomes were identified by Cox regression analyses. Results: Methylated GRIA4 (HR 1.96 (1.06–3.63)), RARB (HR 9.48 (3.00–30.00)), SLC8A1 (HR 1.97 (1.03–3.77)), VIM (HR 2.95 (1.22–7.14)) and WNT5A (HR 5.83 (2.33–14.56)) were independent predictors of OS, methylated RARB (HR 9.67 (2.54–36.81)), SDC2 (HR 3.38 (1.07–10.66)), SLC8A1 (HR 2.93 (1.01–8.51)) and WNT5A (HR 6.95 (1.81–26.68)) were independent predictors of RFS and methylated RARB (HR 6.11 (1.69–22.18)), SDC2 (HR 2.79 (1.20–6.49)) and WNT5A (HR 5.57 (3.04–15.26)) were independent predictors of PP (p < 0.05). Conclusions: Prediagnostic ctDNA markers are promising contributors to predicting poor prognosis in CRC, potentially becoming one of the tools guiding more personalised treatment. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims Design Methods Results Conclusions Patient or Public Contribution Relevance to Clinical Practice The aim of this study was to understand the dynamic changes in the needs of patients with enterostomy during the 3 months after discharge and its possible influencing factors.A prospective observational design.This study investigated the supportive care needs of patients who underwent colorectal cancer surgery with colostomy in three Chinese hospitals from May 2023 to October 2023 during the 3 months following discharge from the hospital. The growth mix model was used to describe the needs trajectory and analyse the heterogeneity of the trajectory. Univariate analysis was used to find the factors that might affect the heterogeneity of needs trajectory of patients with enterostomy, and then logistic regression analysis was used to determine the influencing factors of the heterogeneity of needs trajectory of patients with enterostomy. The reporting of this study adhered to the STROBE checklist.A total of 232 patients with enterostomy completed follow‐up. There was heterogeneity in the developmental trajectories of supportive care needs of enterostomy patients and the trajectories of the five dimensions of supportive care needs. The heterogeneity factors affecting the trajectory of supportive care needs included the enterostomy patient's psychosocial adjustment score, type of enterostomy, and educational background and the heterogeneity factors affecting the five dimensions trajectory of supportive care needs include psychosocial adjustment score, tumour staging, type of enterostomy, smoking, chemotherapy and enterostomy self‐care knowledge score.The needs of patients with enterostomy within 3 months after discharge were dynamic. Identifying and meeting the unmet needs of patients with enterostomy was crucial to improving the health‐related quality of life of patients with enterostomy.None.The needs of patients with enterostomy were dynamic, with the needs of most patients with enterostomy decreasing within 3 months of discharge, but some patients with enterostomy continued to have high needs at 3 months after discharge, and clinical nurses were expected to pay special attention to these patients. [ABSTRACT FROM AUTHOR]

Background: The diagnosis and treatment of colorectal cancer (CRC), especially metastatic colorectal cancer (mCRC), is a major priority and research challenge. We screened for expression differences in the plasma exosomal proteomes of patients with mCRC, those with CRC, and healthy controls (HCs) to discover potential biomarkers for mCRC. Methods: Plasma samples from five patients with mCRC, five patients with CRC, and five HCs were collected and processed to isolate exosomes by ultracentrifugation. Exosomal protein concentrations were determined using the BCA kit, and liquid chromatography-mass spectrometry was utilized to identify and analyze the proteins. Results: From the exosomes isolated from plasma samples, a total of 994 quantifiable proteins were detected, including 287 differentially expressed proteins identified by quantitative proteomics analyses. Totals of 965, 963 and 968 proteins were identified in mCRC patients, CRC patients, and HCs, respectively. The study identified 83 proteins with differential expression in the plasma exosomes of mCRC patients. The top 10 upregulated proteins in the mCRC group and CRC groups were ITGA4, GNAI1, SFTPA2, UGGT1, GRN, LBP, SMIM1, BMP1, HMGN5, and MFAP4, while the top 10 downregulated proteins were PSMB8, LCK, RAB35, PSMB4, CD81, CD63, GLIPR2, RAP1B, RAB30, and CES1. Western Blot validation data confirmed that ITGA4 and GNAI1 were unequivocally enriched in plasma-derived exosomes from mCRC patients. Conclusions: These differential proteins offer potential new candidate molecules for further research on the pathogenesis of mCRC and the identification of therapeutic targets. This study sheds light on the potential significance of plasma exosome proteomics studies in our understanding and treatment of mCRC. [ABSTRACT FROM AUTHOR]

Background: Liquid biopsy based on cell-free DNA (cfDNA) analysis holds significant promise as a minimally invasive approach for the diagnosis, genotyping, and monitoring of solid malignancies. Human tumors release cfDNA in the bloodstream through a combination of events, including cell death, active and passive release. However, the precise mechanisms leading to cfDNA shedding remain to be characterized. Addressing this question in patients is confounded by several factors, such as tumor burden extent, anatomical and vasculature barriers, and release of nucleic acids from normal cells. In this work, we exploited cancer models to dissect basic mechanisms of DNA release. Methods: We measured cell loss ratio, doubling time, and cfDNA release in the supernatant of a colorectal cancer (CRC) cell line collection (N = 76) representative of the molecular subtypes previously identified in cancer patients. Association analyses between quantitative parameters of cfDNA release, cell proliferation, and molecular features were evaluated. Functional experiments were performed to test the impact of modulating DNA methylation on cfDNA release. Results: Higher levels of supernatant cfDNA were significantly associated with slower cell cycling and increased cell death. In addition, a higher cfDNA shedding was found in non-CpG Island Methylator Phenotype (CIMP) models. These results indicate a positive correlation between lower methylation and increased cfDNA levels. To explore this further, we exploited methylation microarrays to identify a subset of probes significantly associated with cfDNA shedding and derive a methylation signature capable of discriminating high from low cfDNA releasers. We applied this signature to an independent set of 176 CRC cell lines and patient derived organoids to select 14 models predicted to be low or high releasers. The methylation profile successfully predicted the amount of cfDNA released in the supernatant. At the functional level, genetic ablation of DNA methyl-transferases increased chromatin accessibility and DNA fragmentation, leading to increased cfDNA release in isogenic CRC cell lines. Furthermore, in vitro treatment of five low releaser CRC cells with a demethylating agent was able to induce a significant increase in cfDNA shedding. Conclusions: Methylation status of cancer cell lines contributes to the variability of cfDNA shedding in vitro. Changes in methylation pattern are associated with cfDNA release levels and might be exploited to increase sensitivity of liquid biopsy assays. [ABSTRACT FROM AUTHOR]

Qualitative faecal immunochemical tests for haemoglobin (FIT), for triaging for colorectal cancer investigations, are available for professional use. The aim was to evaluate these lateral flow tests. No previous analytical evaluations have been published.Analytical sensitivity (AS) was assessed using samples spanning manufacturers’ quoted AS, concurrently with the quantitative OC-SENSOR PLEDIA, using Hb-spiked samples in manufacturers’ buffer (n≥5; ≤9–99 ng Hb/mL buffer), Hb-spiked faeces (n=6; <2–34 µg Hb/g faeces) and natural faeces (n=17; <2–82 μg/g); concentrations for 50 %/100 % Hb-detected were compared with quoted AS. Compatibility with two external quality assessment schemes (EQAS) (n=9; 3–96 μg/g) and prozone compared with manufacturers limits (n=9; 2,500–10,000,000 ng/mL) were tested. Ease-of-use by five healthcare personnel was assessed.Seven products showed lower AS (ng/mL) than manufacturers quoted using Hb-spiked aqueous samples compared with OC-SENSOR, one was equivocal; six manufacturers quoted AS in µg/g, five showed lower AS using Hb-spiked faeces. Results were similar but less consistent for natural faeces. Result lines for low concentrations can be faint and open to interpretation. Results were consistent with manufacturers quoted prozone limits. Results were consistent for seven products for two EQAS. The ease-of-use was 68.5–85.6 %; products with lower scores could be improved with better instructions and sample bottles.AS was lower for seven products (aqueous samples) and five products (aqueous/faecal samples) and prozone consistent with manufacturers expected concentrations, compared with OC-SENSOR. EQAS results were mostly consistent with expected results; products can be used by healthcare professionals, though some manufacturer improvements could be made. [ABSTRACT FROM AUTHOR]

Introduction: Colorectal cancer (CRC) is one of the main causes of deaths worldwide. Early detection and diagnosis of its precursor lesion, the polyp, is key to reduce its mortality and to improve procedure efficiency. During the last two decades, several computational methods have been proposed to assist clinicians in detection, segmentation and classification tasks but the lack of a common public validation framework makes it difficult to determine which of them is ready to be deployed in the exploration room. Methods: This study presents a complete validation framework and we compare several methodologies for each of the polyp characterization tasks. Results: Results show that the majority of the approaches are able to provide good performance for the detection and segmentation task, but that there is room for improvement regarding polyp classification. Discussion: While studied show promising results in the assistance of polyp detection and segmentation tasks, further research should be done in classification task to obtain reliable results to assist the clinicians during the procedure. The presented framework provides a standarized method for evaluating and comparing different approaches, which could facilitate the identification of clinically prepared assisting methods. [ABSTRACT FROM AUTHOR]

Short-chain fatty acids (SCFAs) are produced by bacterial fermentation in the colon and are thought to be protective against gastrointestinal disease. SCFAs such as acetate, propionate and butyrate are important metabolites in the maintenance of intestinal homeostasis and have been shown to be beneficial in colorectal cancer (CRC). SCFAs are responsible for maintaining a normal intestinal barrier and exhibit numerous immunomodulatory functions. In this review article, we will discuss the metabolism and mechanism of action of SCFAs and their effects on the CRC, with particular emphasis on dietary fiber treatment and the clinical research progress. [ABSTRACT FROM AUTHOR]

ABSTRACT Antimicrobial peptides (AMPs) are renowned for their broad‐spectrum efficacy against viruses, bacteria, and fungi, thereby holding promise for medicinal applications. Nisin, a bacteriocin synthesized by gram‐positive bacteria such as Lactobacillus and Streptococcus, has been used as a food preservative owing to its antimicrobial characteristics for decades. However, recent developments prompt further research on its application as therapeutic interventions, mainly focusing on anticancer activity. In line with this, the present study portrays the effects of nisin on human colorectal cancer cells and the underlying molecular mechanisms. A dose‐dependent decrease in cell viability with increasing concentrations of nisin was determined by the Alamar blue viability assay, which was supported by significant morphological changes in cells. Subsequently, we probed the apoptotic effects of nisin using EtBr/AO staining, confirming the induction of apoptosis upon nisin treatment, which was further confirmed by ELISA analysis. Elevated levels of Caspase 7 indicated increased apoptosis in nisin‐treated cells. As pharmaceutical p53 reactivation is considered as an attractive strategy to combat chemoresistance and adverse effects, the effect of nisin on p53 expression was determined by mRNA analysis. An upregulation in p53 expression in nisin‐treated cells compared to untreated controls suggests that bacterial nisin reactivates mutated p53. To assess cell cycle dynamics, we utilized PI flow cytometry, unveiling a G0/G1 phase arrest in nisin‐treated cells in contrast to untreated controls. In summary, our results strongly advocate the potential of nisin as a compelling candidate for drug development against colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: How to reduce the high incidence rate and mortality of colorectal cancer (CRC) effectively is the focus of current research. Endoscopic treatment of early-stage CRC and colorectal adenomas (CAC) has a high success rate, but although several treatments are available for advanced CRC, such as surgery, radiotherapy, chemotherapy, and immunotherapy, the 5-year survival rate remains low. In view of the high incidence rate and mortality of CRC, early rational drug prevention for high-risk groups and exploration of alternative treatment modalities are particularly warranted. Summary: Gut microbiota is the target of and interacts with probiotics, prebiotics, aspirin, metformin, and various Chinese herbal medicines (CHMs) for the prevention of CRC. In addition, the anti-cancer mechanisms of probiotics differ widely among bacterial strains, and both bacterial strains and their derivatives and metabolites have been found to have anti-cancer effects. Gut microbiota plays a significant role in early drug prevention of CRC and treatment of CRC in its middle and late stages, targeting gut microbiota may be a new strategy for colorectal cancer treatment. Key message: This review covers current progress in the role of gut microbiota and drugs in CRC. [ABSTRACT FROM AUTHOR]

Background: A blood-based diagnostic test is a promising strategy for colorectal cancer (CRC). The MethyDT test (IColohunter), which detects methylation levels of NTMT1 and MAP3K14-AS1, exhibited potential in discriminating CRC, but its clinical performance needs to be validated in large-scale populations. Methods: A multicenter, double-blinded, cross-sectional study that enrolled 1194 participants was performed. Plasma samples were collected to detect methylation levels of NTMT1 and MAP3K14-AS1 using quantitative methylation-specific PCR with the MethyDT test, and the accuracy was further evaluated by Sanger sequencing. Results: The sensitivities of the MethyDT test for detecting CRC, early stages of CRC (I and II), advanced adenoma (AA), and high-grade intraepithelial neoplasia (HGIN) were 91.2% (95% confidence interval [CI], 88.4–94.0), 87.4% (95% CI, 82.5–92.2), 43.5% (95% CI, 35.7–51.4), and 72.7% (95% CI, 57.5–87.9), respectively. The specificities for participants with non-AA, interfering diseases (ID), and no evidence of disease (NED) were 85.0% (95% CI, 78.8–91.3), 93.7% (95% CI, 91.4–95.9) and 97.3% (95% CI, 90.5–99.7), respectively, and its overall specificity for all-controls was 92.4% (95% CI, 90.3–94.4). The consistency of the MethyDT test with pathology for CRC was high with a kappa value of 0.830 (95% CI, 0.795–0.865). Additionally, the MethyDT test was comparable to Sanger sequencing for detecting methylation with kappa values > 0.97. Conclusions: The MethyDT test demonstrates excellent sensitivity and specificity for CRC and high consistency with Sanger sequencing for methylation, suggesting it may serve as a potential noninvasive diagnostic tool for the detection of CRC. Trial registration: This clinical trial has been registered in ClinicalTrials.gov (NCT05508503). [ABSTRACT FROM AUTHOR]

The treatment outcomes of nanomedicines against colorectal cancer are severely restricted by their insufficient accumulation in the tumor tissues, unsatisfactory antitumor effect, and weak immunometabolic modulation. To address these issues, flying‐saucer‐shaped nanoheterojunctions by coating copper oxide (CuxO) onto the surface of PEGylated zinc oxide (ZnO) nanoparticles are constructed. When exposed to ultrasound, the resultant CuxO@ZnO nanoheterojunctions exhibit increased locomotor activities, facilitating colorectal mucus infiltration, deep tumor penetration, and tumor cell internalization. The decoration of CuxO suppresses the rapid recombination of electrons and holes in CuxO@ZnO exposed to ultrasound, promoting the production of singlet oxygen and hydroxyl radical, which are generated by CuxO through a Fenton‐like chemodynamic reaction and CuxO@ZnO through sonodynamic reaction. After rectal administration, the sono‐chemodynamic CuxO@ZnO plus PD‐L1 antibodies effectively inhibit the growth of orthotopic and distant tumors. It elicits immunometabolic responses by inducing immunogenic cell death, activating the interferon genes signaling pathway stimulator, and inhibiting glucose transport and the glycolytic signaling pathways. This combined modality also increases the proportion of beneficial microbes (e.g., Bifidobacterium) and decreases the abundance of harmful microorganisms (e.g., Romboutsia) in the intestine. This treatment modality (CuxO@ZnO plus ultrasound and PD‐L1 antibodies) is a promising strategy for the synergistic treatment of colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: Pelvic floor rehabilitation is common in patients with colorectal cancer, the purpose of this study is to analyze the role of pelvic floor rehabilitation in patients with colorectal cancer and to understand the specific details of pelvic floor rehabilitation intervention in patients with colorectal cancer. Methods: Six databases were searched for this scoping review and reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for scoping reviews. Results: A total of 1014 studies were searched, and 12 studies were finally included for analysis. The study found that pelvic floor rehabilitation for colorectal cancer patients can help improve bowel symptoms, quality of life, and psychological status of colorectal cancer patients after surgery, but details of the interventions for pelvic floor rehabilitation for colorectal cancer patients are not standardized. Conclusions: Pelvic floor rehabilitation has shown positive significance in patients with colorectal cancer, but there is a lack of uniform standards in the process of pelvic floor rehabilitation intervention in patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

Early cancer diagnosis from bisulfite‐treated cell‐free DNA (cfDNA) fragments requires tedious data analytical procedures. Here, we present a deep‐learning‐based approach for early cancer interception and diagnosis (DECIDIA) that can achieve accurate cancer diagnosis exclusively from bisulfite‐treated cfDNA sequencing fragments. DECIDIA relies on transformer‐based representation learning of DNA fragments and weakly supervised multiple‐instance learning for classification. We systematically evaluate the performance of DECIDIA for cancer diagnosis and cancer type prediction on a curated dataset of 5389 samples that consist of colorectal cancer (CRC; n = 1574), hepatocellular cell carcinoma (HCC; n = 1181), lung cancer (n = 654), and non‐cancer control (n = 1980). DECIDIA achieved an area under the receiver operating curve (AUROC) of 0.980 (95% CI, 0.976–0.984) in 10‐fold cross‐validation settings on the CRC dataset by differentiating cancer patients from cancer‐free controls, outperforming benchmarked methods that are based on methylation intensities. Noticeably, DECIDIA achieved an AUROC of 0.910 (95% CI, 0.896–0.924) on the externally independent HCC testing set in distinguishing HCC patients from cancer‐free controls, although there was no HCC data used in model development. In the settings of cancer‐type classification, we observed that DECIDIA achieved a micro‐average AUROC of 0.963 (95% CI, 0.960–0.966) and an overall accuracy of 82.8% (95% CI, 81.8–83.9). In addition, we distilled four sequence signatures from the raw sequencing reads that exhibited differential patterns in cancer versus control and among different cancer types. Our approach represents a new paradigm towards eliminating the tedious data analytical procedures for liquid biopsy that uses bisulfite‐treated cfDNA methylome. [ABSTRACT FROM AUTHOR]

Background: Arginase is abundantly expressed in colorectal cancer and disrupts arginine metabolism, promoting the formation of an immunosuppressive tumor microenvironment. This significant factor contributes to the insensitivity of colorectal cancer to immunotherapy. Tumor-associated macrophages (TAMs) are major immune cells in this environment, and aberrant arginine metabolism in tumor tissues induces TAM polarization toward M2-like macrophages. The natural compound piceatannol 3ʹ-O-glucoside inhibits arginase activity and activates nitric oxide synthase, thereby reducing M2-like macrophages while promoting M1-like macrophage polarization. Methods: The natural compounds piceatannol 3ʹ-O-glucoside and indocyanine green were encapsulated within microparticles derived from tumor cells, termed PG/ICG@MPs. The enhanced cancer therapeutic effect of PG/ICG@MP was assessed both in vitro and in vivo. Results: PG/ICG@MP precisely targets the tumor site, with piceatannol 3ʹ-O-glucoside concurrently inhibiting arginase activity and activating nitric oxide synthase. This process promotes increased endogenous nitric oxide production through arginine metabolism. The combined actions of nitric oxide and piceatannol 3ʹ-O-glucoside facilitate the repolarization of tumor-associated macrophages toward the M1 phenotype. Furthermore, the increase in endogenous nitric oxide levels, in conjunction with the photodynamic effect induced by indocyanine green, increases the quantity of reactive oxygen species. This dual effect not only enhances tumor immunity but also exerts remarkable inhibitory effects on tumors. Conclusion: Our research results demonstrate the excellent tumor-targeting effect of PG/ICG@MPs. By modulating arginine metabolism to improve the tumor immune microenvironment, we provide an effective approach with clinical translational significance for combined cancer therapy. [ABSTRACT FROM AUTHOR]

Background: The issue of patients returning to work is increasingly garnering attention from countries worldwide. This study aims to investigate the risk factors associated with patients returning to work after undergoing permanent enterostomies. Additionally, it seeks to establish and validate a nomogram prediction model, thereby providing a more effective reference for patients aiming to return to work. Methods: This study was a cross-sectional investigation conducted between September 2022 and September 2023. We conveniently selected 293 postoperative patients with permanent colorectal stomas due to colorectal cancer from three tertiary hospitals in Liaoning Province. Participants were categorized into Returned and Non-Returned groups based on their return to work status. Data were collected using a general information questionnaire, a Stoma Acceptance Questionnaire, and the Ostomy Adjustment Inventory. Binary logistic regression analysis was performed using SPSS 25.0 software to identify independent influencing factors. A predictive model was constructed using R Studio 4.3.0 software. Internal validation was conducted through 1,000 rounds of Bootstrap resampling, and model performance was assessed using Receiver Operating Characteristic (ROC) curves, the Hosmer-Lemeshow (H-L) test, and calibration curves. Results: After surgery, the return-to-work rate for patients with permanent colorectal stomas was 29.69%. Age, education level, postoperative time, stoma complication, adjuvant therapy, stoma acceptance score, and ostomy adjustment inventory score were identified as independent factors influencing the return-to-work status of these patients (P < 0.05). These factors were incorporated into a logistic regression model generated by R software, resulting in a ROC curve with an area under the curve (AUC) of 0.916 (95% CI: 0.884–0.947). The Youden index was 0.731, and the cutoff value was 0.228. Sensitivity and specificity were 0.920 and 0.811, respectively. The H-L test demonstrated good model fit (χ2 = 12.858, P = 0.117, P > 0.05). Calibration curves indicated a close alignment between predicted and actual probabilities. Conclusions: The postoperative return-to-work rate is low in patients with permanent enterostomies. The prediction model developed in this study demonstrates strong performance and offers predictive value, providing a scientific foundation for assessing patients' return to work. Caregivers should prioritize the early identification of various patient types for proactive intervention to enhance the rate of postoperative return to work. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Aims Methods Results Conclusions Trial Registration The positivity thresholds of faecal immunochemical testing (FIT) in colorectal cancer (CRC) screening vary between countries.To explore the trade‐off between colonoscopies performed, adverse events and lesions detected at different FIT thresholds in a Norwegian CRC screening trial.We included first participation in biennial FIT screening for 47,265 individuals aged 50–74 years. Individuals with FIT > 15 μg Hb/g faeces were referred for colonoscopy. We estimated the number of colonoscopies, adverse events, screen‐detected CRCs, advanced adenomas and serrated lesions expected at FIT thresholds currently or recently used in other European countries ranging between 20 and 150 μg/g.At the 15 μg/g threshold (Norway), 3705 participants underwent colonoscopy, of whom 203 had CRC, 1119 advanced adenomas and 256 advanced serrated lesions. Using a 47 μg/g threshold, 1826 (49.3%) individuals would have undergone colonoscopy, and 154 (75.9%) would have been diagnosed with CRC, 702 (62.7%) with advanced adenoma and 128 (50.0%) with advanced serrated lesion compared to the 15 μg/g threshold. At 150 μg/g, the corresponding figures would have been 838 (22.6%) undergoing colonoscopy, 114 (56.2%) with CRC, 345 (30.8%) advanced adenoma and 54 (21.1%) advanced serrated lesions. The detection rate of stage I CRC was 0.22% at 15 μg/g and 0.11% at 150 μg/g. Post‐colonoscopy bleeding rates were 0.8% and 1.7%, respectively.Increasing the FIT threshold reduces colonoscopy demand, but substantially decreases lesion detection and unfavourably changes CRC stage distribution. The risk of adverse events at colonoscopy increased with FIT threshold, requiring country‐specific information on adverse events.Clinicaltrials.gov identifier: NCT01538550 [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a prevalent malignancy with high mortality rates and poor prognosis. Shikonin (SHK) has demonstrated extensive anti-tumor activity across various cancers, yet its clinical application is hindered by poor solubility, limited bioavailability, and high toxicity. This study aims to develop SHK-loaded exosomes (SHK-Exos) and assess their efficacy in CRC progression. Exosomes were isolated using ultracentrifugation and characterized via TEM, NTA, and western blotting. Their cellular internalization was confirmed through confocal microscopy post PKH67 labeling. Effects on cell behaviors were assessed using CCK-8 and Transwell assays. Cell cycle and apoptosis were analyzed via flow cytometry. A xenograft tumor model evaluated in vivo therapeutic potential, and tumor tissues were examined using H&E staining and in vivo imaging. SHK-Exos demonstrated effective cell targeting and internalization in CRC cells. In vitro, SHK-Exos surpassed free SHK in inhibiting aggressive cellular behaviors and promoting apoptosis, while in vivo studies showed substantial efficacy in reducing tumor growth with excellent tumor targeting and minimal toxicity. Employing SHK-Exos effectively impedes CRC progression in vitro and in vivo, offering significant therapeutic potential. This research underscores the advantages of using autologous exosomes as a drug carrier, enhancing efficacy and reducing toxicity. [ABSTRACT FROM AUTHOR]

Aim Method Results Conclusion Colorectal cancer rates are increasing in older populations, who often have comorbidities and face higher surgical risks and mortality rates. Therefore, surgical outcomes, such as 5‐year mortality rates, may not be appropriate, necessitating a focus on postoperative quality of life. However, determining optimal postoperative outcome measures for older colorectal cancer patients poses a challenge. This scoping review aimed to explore currently available data describing postoperative outcomes used to assess older patients undergoing elective colorectal cancer surgery.We conducted a comprehensive literature search of major electronic databases from inception to March 2023. Studies exploring frail or older individuals with colorectal cancer undergoing elective surgical procedures, and which reported postoperative outcomes, were included. Outcomes were categorized as surgery‐specific versus person‐centred and summarized using narrative synthesis. The type and rate of surgery‐specific outcomes were tabulated.Of 1366 identified citations, 16 studies focused on person‐centred outcomes and 66 reported exclusively on surgery‐specific outcomes. Nine ‘person‐centred outcome’ studies reported discharge destination, primarily home discharge. Postoperative delirium ranged from 8.2% to 18.1% in six studies. Four studies explored geriatric syndromes, three analysed activities of daily living, and three studies reported significant quality of life improvement. The 66 ‘surgery‐specific outcome’ studies assessed mortality (N = 61); length of stay (N = 40); postoperative complications (N = 47); readmission (N = 18); reoperation (N = 16); and survival (N = 42).Person‐centred outcomes are underreported, but crucial for guiding patient management. Older patients require adequate information about their postoperative recovery period to enhance wellbeing. Future research must address this gap to improve care for older people undergoing elective colorectal cancer surgery. [ABSTRACT FROM AUTHOR]

The O-GlcNAc transferase (OGT) is an essential enzyme that mediates protein O-Glc-NAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O-GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent mice by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT (Ogt-/-) caused a marked reduction in tumor growth in both syngeneic mice tumor models and a genetic mice colorectal cancer (CRC) model induced by mutation of the Apc gene (Apcmin). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgas or Sting from Ogt-/- cancer cells restored tumor growth, and this correlated with impaired CD8+ T-cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor-cell-intrinsic mechanism to repress antitumor immunity. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a severe gastrointestinal cancer and a leading cause of cancer-related deaths in Ghana. The potential role of gut Enterobacteriaceae in the increasing incidence of CRC in Ghana is yet to be thoroughly investigated. In this study, Enterobacteriaceae from CRC patients and healthy control participants were analyzed by whole genome sequencing to identify genomic features that are associated with CRC. Socio-demographic data showed a significant association between age and alcohol consumption and CRC. Escherichia coli was the most abundant Enterobacteriaceae isolated from the study participants and they were predominantly intestinal commensals. Escherichia coli isolates belonging to phylogroup D encoded the highest number of virulence genes. The agn43 and int genes were widespread in Escherichia coli isolates from the CRC patients. Multilocus sequence types of potentially pathogenic Escherichia coli from the CRC patients also encoded genes involved in aggregation, adherence and biofilm formation. The ampC2 and ampH antimicrobial resistance genes were also widespread in the genome of the Escherichia coli isolates. This study highlights the virulence tendencies of Escherichia coli from CRC patients and their ability to transfer virulence determinants to other Enterobacteriaceae residing in the gut. [ABSTRACT FROM AUTHOR]