Search Results (520)

Background: Colorectal cancer (CRC) is a prevalent gastrointestinal malignancy, ranking third in incidence and second in cancer-related mortality. Despite therapeutic advances, challenges such as chemotherapy toxicity and drug resistance persist. Thus, there is an urgent need for novel CRC treatments. However, developing new drugs is time-consuming and resource-intensive. As a more efficient approach, drug repurposing offers a promising alternative for discovering new therapies. Methods: In this study, we screened 1068 small molecular compounds from an FDA-approved drug library in CRC cells. Menadione was selected for further study based on its activity profile. Mechanistic analysis included a cell death pathway PCR array, differential gene expression, enrichment, and network analysis. Gene expressions were validated by RT-qPCR. Results: We identified menadione as a potent anti-tumor drug. Menadione induced three programmed cell death (PCD) signaling pathways: necroptosis, apoptosis, and autophagy. Furthermore, we found that the anti-tumor effect induced by menadione in CRC cells was mediated through a key gene: MAPK8. Conclusions: By employing methods of cell biology, molecular biology, and bioinformatics, we conclude that menadione can induce multiple forms of PCD in CRC cells by activating MAPK8, providing a foundation for repurposing the “new use” of the “old drug” menadione in CRC treatment. Full article

Background: Bulgaria carries a high burden of colorectal cancer (CRC) but, at the start of this study, lacked a nationwide organized screening program. Understanding specialist views (particularly on mail-based fecal testing) is essential for effective policy development. Objective: The objective is to assess the attitudes towards, practices of, and perceived barriers to CRC screening among Bulgarian gastroenterologists, with a focus on the feasibility of mail-based fecal occult blood testing (FOBT). Methods: A cross-sectional survey of 38 gastroenterologists examined clinical use of FOBT, screening method preferences, and perceived systemic and patient-level barriers to CRC screening. Results: Among respondents, 57.89% reported using FOBT in clinical practice, and 71.05% indicated they would undergo the test themselves and recommend it to relatives. Colonoscopy was the preferred diagnostic tool for 84.21% of participants; however, the existing literature raises concerns about its feasibility for large-scale population screening. Key systemic barriers, rated on a 5-point Likert scale, included financial constraints (mean = 3.08), inadequate infrastructure (2.89), and healthcare workforce shortages (2.71). Patient-level barriers were led by low health literacy (4.13), lack of motivation (3.95), and procedural fears (3.26). A majority (84.38%) believed that mail-based FOBT would increase screening uptake, and 57.89% supported annual distribution of test kits. Nearly all respondents (97.37%) favored initiating screening at age 50. Conclusions: This study highlights strong support among Bulgarian gastroenterologists for a national CRC screening program, with particular endorsement of mail-based FOBT. Despite acknowledged systemic and population-level barriers, the findings suggest that such an approach could increase screening coverage, promote early detection, and support the strategic rollout of Bulgaria’s emerging cancer control initiatives. Full article

Background: The number of women veterans has been rising steadily since the Gulf War and many assume the functions of their male counterparts. Women face unique obstacles in their service, and it is imperative that differences in physiology not be overlooked so as to provide better and appropriate care to our women in uniform. Despite this influx and incorporation of female talent, dedicated reports contrasting female and male veterans are rare, outside of specific psychological studies. We therefore attempt to contrast gut constituents, absorption, innate immune system, and nutritional differences to provide a comprehensive account of similarities and differences between female and male veterans, from our single-center perspective, as this has not been carried out previously. Herein, we obtained a detailed roster of commonly used biomedical tests and some novel entities to detect differences between female and male veterans. The objective of this study was to detect differences in the innate immune system and other ancillary test results to seek differences that may impact the health of female and male veterans differently. Methods: To contrast biochemical and sociomedical parameters in female and male veterans, we studied the data collected on 450 female veterans and contrasted them to a group of approximately 1642 males, sequentially from 1995 to 2022, all selected because of above-average risk for CRC. As part of this colorectal cancer (CRC) screening cross-sectional and longitudinal study, we also collected stool, urine, saliva, and serum specimens. We used ELISA testing to detect stool p87 shedding by the Adnab-9 monoclonal and urinary organ-specific antigen using the BAC18.1 monoclonal. We used the FERAD ratio (blood ferritin/fecal p87), a measure of the innate immune system to gauge the activity of the innate immune system (InImS) by dividing the denominator p87 (10% N-linked glycoprotein detected by ELISA) into the ferritin level (the enumerator, a common lab test to assess anemia). FERAD ratios have not been performed elsewhere despite past Adnab-9 commercial availability so we have had to auto-cite our published data where appropriate. Results: Many differences between female and males were detected. The most impressive differences were those of the InImS where males clearly had the higher numbers (54,957 ± 120,095) in contrast to a much lower level in females (28,621 ± 66,869), which was highly significantly different (p < 0.004). Mortality was higher in males than females (49.4% vs. 24.1%; OR 3.08 [2.40–3.94]; p < 0.0001). Stool p87, which is secreted by Paneth cells and may have a protective function, was lower in males (0.044 ± 0.083) but higher in females (0.063 ± 0.116; p < 0.031). Immunohistochemistry of the Paneth cell-fixed p87 antigen was also higher in females (in the descending colon and rectum). In contrast, male ferritin levels were significantly higher (206.3 ± 255.9 vs. 141.1 ± 211.00 ng/mL; p < 0.0006). Females were less likely to be diabetic (29.4 vs. 37.3%; OR 0.7 [0.55–0.90]; p < 0.006). Females were also more likely to use NSAIDs (14.7 vs. 10.7%, OR 1.08 [1.08–2.00]; p < 0.015). Females also had borderline less GI bleeding by fecal immune tests (FITs), with 13.2% as opposed to 18.2% in males (OR 0.68 [0.46–1.01]; p = 0.057), but were less inclined to have available flexible sigmoidoscopy (OR 0.68 [0.53–0.89]; p < 0.004). Females also had more GI symptomatology, a higher rate of smoking, and were significantly younger than their male counterparts. Conclusions: This study shows significant differences with multiple parameters in female and male veterans. Full article

Background: Huang Qin Decoction (HQD) is a well-established Traditional Chinese Medicine (TCM) formulation recognized for its application in the treatment of colorectal cancer (CRC). However, the precise therapeutic mechanisms remain inadequately defined. Methods: This study integrates metabolomics from a mouse model and network pharmacology to screen potential targets and bio-active ingredients of HQD. The pharmacological activity of HQD for CRC was evidenced via single-cell RNA sequencing (scRNA-seq), molecular docking, and molecular dynamics simulations. Atomic force microscopy (AFM) assays and cellular experimental validation were used to confirm the relative mechanisms. Results: The metabolite profile undergoes significant alterations, with metabolic reprogramming evident during the malignant progression of CRC liver metastasis. Network pharmacology analysis identified that HQD regulates several metabolic pathways, including arginine biosynthesis, alanine, aspartate, and glutamate metabolism, nitrogen metabolism, phenylalanine metabolism, and linoleic acid metabolism, by targeting key proteins such as aspartate aminotransferase (GOT1), cytochrome P450 1A2 (CYP1A2), and carbonic anhydrase 2 (CA2). ScRNA-seq analysis indicated that HQD may enhance the functionality of cytotoxic T cells, thereby reversing the immunosuppressive microenvironment. Virtual verification revealed a strong binding affinity between the identified hub targets and active constituents of HQD, a finding subsequently corroborated by AFM assays. Cellular experiments confirmed that naringenin treatment inhibits the proliferation, migration, and invasion of CRC cells by downregulating GOT1 expression and disrupting glutamine metabolism. Conclusions: Computational prediction and in vitro validation reveal the active ingredients, potential targets, and molecular mechanisms of HQD against CRC liver metastasis, thereby providing a scientific foundation for the application of TCM in CRC treatment. Full article

Background/Objectives: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Even though the screening programs have decreased the incidence rates, the prognosis for CRC varies depending on the stage at diagnosis. Thus, early diagnosis is still a big challenge due to screening methods, and subsequent diagnosis is not very sensitive. Methods: In this work, LC-MS-based metabolomics, a powerful and sensitive tool to study complex dynamic changes, was used to analyze 211 human fecal samples from control individuals (CTRL), adenoma (AA), and CRC patients. Results: Multivariate and univariate statistical analysis highlighted cholesteryl esters (CEs) and fecal haemoglobin, quantified by fecal immunochemical test (FIT), as relevant biomarkers that clearly differentiate CRC from AA and CTRL. Predictive models based on random forest and the area under the curve (AUC) of the receiver operating characteristic curve (ROC) demonstrate that CEs, together with FIT measurement, improved the CRC and CTRL classification, but not AA. This study revealed that the AA group is a transitional stage with high heterogeneity. The increased tendency observed in CEs from CTRL to CRC might be related to the imbalance of cholesterol homeostasis due to cancer cells requiring a high cholesterol level for cell development and proliferation. The free cholesterol is probably obtained from CEs, as it is the most cost/effective way to obtain the needed cholesterol. Conclusions: The accumulation of CEs is produced by two possible approaches: (1) dysfunction of cholesterol absorption in the small intestine and/or (2) transported inside exosomes from cell to cell to promote proliferation. Full article

Background/Objectives: 5-Fluorouracil (5-FU) and Irinotecan (IRT) are two of the most used chemotherapeutic agents in CRC treatment. However, achieving treatment goals has been hampered by poor drug delivery to tumor sites and associated toxicity from off-target binding to healthy cells. Though the synergism of 5-FU-IRT has provided incremental improvements in clinical outcomes, the short elimination half-life and off-target binding to healthy cells remain significant challenges. We postulated that nanoencapsulation of a combination of 5-FU and IRT in niosomes would prolong the drugs’ half-lives, while over-encapsulation lyophilized powder in Targit^® oral capsules would passively the CRC microenvironment and avoid extensive systemic distribution. Methods: Ranges of formulation and process variables were input into design of experiment (DOE Fusion One) software, to generate screening experiments. Niosomes were prepared using the thin-film hydration method and characterized by size, the polydispersity index (PDI), morphology and intrastructure, and drug loading. Blank niosomes ranged in size from 215 nm to 257 nm. Results: After loading with the 5-FU-IRT combination, the niosomes averaged 251 ± 2.20 nm with a mean PDI of 0.293 ± 0.01. The surfactant-to-cholesterol ratio significantly influenced the niosome size and the PDI. The hydrophilic 5-FU exhibited superior loading compared to the lipophilic IRT molecules, which probably competed with other lipophilic niosome components in niosomes’ palisade layers. In vitro dissolution in biorelevant media showed delayed release until lower intestinal region (IRT) or colonic region (5-FU). Conclusions: Thus, co-nanoencapsulation of 5-FU/IRT in niosomes, lyophilization, and over-encapsulation of powder in colon-specific capsules could passively target the CRC cells in the colonic microenvironment. Full article

Background: COVID-19 has been linked to prolonged immune dysfunction and long-term health complications. Herpes zoster (HZ), a marker of impaired cell-mediated immunity, may signal increased vulnerability to infections, cardiovascular disease, and potentially cancer. However, its association with colorectal cancer (CRC) after COVID-19 has not been fully explored. Objective: To investigate the long-term risks of cardiovascular events, acute respiratory failure, sepsis, and CRC in COVID-19 survivors who developed HZ compared to those who did not. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Adults diagnosed with COVID-19 between January 2020 and January 2022 were included. Among the full cohort (aged ≥18 years), 27,664 patients with post-COVID HZ were identified. Due to platform limitations, propensity score matching (PSM) was applied to a restricted subgroup of patients aged 55–60 years, yielding a 1:1 matched cohort for controlled comparisons. Outcomes were assessed over a three-year follow-up. Results: In the matched age-restricted cohort, patients with post-COVID HZ had significantly higher risks of cardiovascular events, acute respiratory failure, sepsis, and CRC compared to matched controls. Subgroup analyses identified age ≥ 50, chronic kidney disease, diabetes, and hypertension as strong independent risk factors across outcomes. Despite the low absolute CRC incidence, cancer-free survival significantly favored the non-HZ group. Conclusion: Herpes zoster reactivation after COVID-19 is associated with increased risk of colorectal cancer. Enhanced surveillance and early CRC screening may benefit this high-risk population. Full article

Background: To overcome the limitations of conventional CRC (colorectal cancer) mouse models in replicating metastasis and enabling efficient therapeutic evaluation, we developed a novel implantation method using tissue adhesive to establish reproducible orthotopic and metastatic tumors. Conventional models using injection or suturing techniques often suffer from technical complexity, inconsistent tumor establishment, and limited metastatic reliability. Methods: We developed and validated a novel orthotopic and metastatic CRC model utilizing tissue adhesive for tumor transplantation. Uniform tumor fragments derived from bioluminescent HCT116/Luc xenografts were affixed to the cecum of nude mice. Tumor growth and metastasis were monitored through bioluminescence imaging and confirmed by the results of histological analysis of metastatic lesions. The model’s utility for therapeutic testing was evaluated using MK801, an NMDA receptor antagonist. Results: The biological-based model demonstrated rapid and reproducible tumor implantation (<5 min), consistent primary tumor growth, and robust metastasis to the liver and lungs. The biological-based approach achieved 80% tumor engraftment (4/5), with consistent metastasis to the liver and lungs in all mice, compared with lower and variable metastasis rates in injection (0%, 0/5) and suturing (20%, 1/5) methods. MK801 treatment significantly suppressed both primary tumor growth and metastasis, validating the model’s suitability for preclinical drug evaluation. Conclusions: By enabling rapid, reproducible, and spontaneous formation of metastatic lesions using a minimally invasive tissue adhesive technique, our model represents a significant methodological advancement that supports high-throughput therapeutic screening and bridges the gap between experimental modeling and clinical relevance in colorectal cancer research. Full article

While the incidence of colorectal cancer (CRC) in patients above 50 years old has been decreasing over the last several decades, the incidence of CRC among younger patients has been increasing. Early-onset CRC (EO-CRC) is known to exhibit distinct characteristics including specific genetic mutations and modifiable risk factors, which warrants tailored screening and management approaches. This review synthesizes current insights on EO-CRC’s epidemiological, genetic, molecular, and clinical features, as well as a call for action for future research on prevention and clinical management. Full article

Organoids are three-dimensional (3D) structures that mimic the architecture and functionality of human organs, providing a novel approach to study diseases such as colorectal cancer (CRC). This review aims to explore the impact of organoids on understanding CRC and their potential use in exploring therapeutic outcomes. Colorectal cancer, characterized by the transformation of colonic epithelial cells into adenomas and carcinomas, remains one of the top causes of cancer-related morbidity and mortality worldwide. Traditional two-dimensional (2D) cell cultures fail to replicate the tumor microenvironment in an effective manner, which highlights the need for advanced 3D models. Organoids preserve the genetic and phenotypic properties of the original tumors, allowing for improved disease modeling, drug screening, and personalized medicine applications. When using patient-derived organoids (PDOs), researchers can gain insights into CRC initiation, progression, and treatment outcome. Ultimately, organoids represent an encouraging platform for improving therapeutic strategies for CRC, potentially leading to better patient outcomes through tailored treatment approaches. Full article

Background: Colorectal cancer (CRC) remains a significant global health burden, with early detection and intervention crucial for improving patient outcomes. This study aims to develop and evaluate a novel proof-of-concept ensemble framework combining transformer-based language models and decision tree-based models for early-stage CRC screening, diagnosis, and prognosis. Methods: The ensemble framework consists of four key components: (1) GastroGPT, a transformer-based language model for extracting relevant data points from patient histories; (2) a decision tree-based model for assessing CRC risk and recommending colonoscopy; (3) GastroGPT for extracting data points from early CRC patients’ histories; and (4) a suite of decision tree-based models for predicting survival outcomes in early-stage CRC patients. The study employed a retrospective, observational, methodological design using simulated patient cases. Results: GastroGPT demonstrated high accuracy in extracting relevant data points from patient histories. The decision tree-based model for CRC risk assessment achieved an area under the receiver operating characteristic curve (AUC-ROC) of 0.85 (95% CI: 0.78–0.92) in predicting the need for colonoscopy. The decision tree-based models for survival prediction showed strong performance, with C-indices ranging from 0.71 to 0.75 for overall survival and disease-free survival at 24, 36, and 48 months. Conclusions: The novel ensemble framework demonstrates promising performance in early-stage CRC screening, diagnosis, and prognosis. Further research is needed to validate the models using larger, real-world datasets and to assess their clinical utility in prospective studies. Full article

Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide, posing a substantial health and economic burden. Despite advances in screening and treatment, significant socioeconomic and healthcare-related disparities persist across European Union (EU) member states. This study aims to identify trends and inequality in CRC burden over time and to explore the relationship between country-level socioeconomic and healthcare indicators and CRC burden across EU member states. Methods: Age-standardized mortality, years lived with disability (YLD), years of life lost (YLL), and disability-adjusted life years (DALY) rates were extracted from Global Burden of Diseases Study 2021 for 24 EU countries. Socioeconomic and healthcare indicators were extracted from Eurostat between 2005 and 2021. The Gini index was calculated to evaluate CRC-related health inequality, and generalized linear mixed models were used to assess the link between indicators and disease burden. Results: The Gini index for age-standardized YLDs declined from 0.19 to 0.12 between 1990 and 2021, while inequality in YLL (from 0.11 to 0.16), DALY (from 0.11 to 0.15), and mortality rates (from 0.12 to 0.14) increased. The number of practicing physicians (p < 0.05) and higher levels of education (p < 0.001) were related to lower death, DALY, YLD, and YLL rates. Conversely, greater income inequality was linked to higher mortality, DALY, and YLL rates (p < 0.05). Conclusions: Our findings underscore that, in addition to expanding organized screening programs, enhancing physician availability and addressing socioeconomic inequalities are essential for reducing the burden of CRC. Full article

Background: Colorectal cancer (CRC) is among the leading causes of cancer-related mortality worldwide, with increasing attention being paid to modifiable dietary factors in its prevention. Hazelnut (Corylus avellana L.) represent a nutrient-dense food rich in unsaturated fats, polyphenols, fiber, and phytosterols, with potential anticarcinogenic properties. This systematic review aimed to evaluate the role of hazelnut consumption in the prevention and modulation of CRC risk, with specific focus on experimental, mechanistic, and preclinical evidence. Methods: Following PRISMA guidelines, a systematic search was conducted in PubMed, Google Scholar, and the Cochrane Library for articles published from 2015 onward. Eligible studies included original in vitro and in vivo models, as well as observational studies, evaluating hazelnut or hazelnut-derived products in relation to CRC-related biological, metabolic, or clinical outcomes. Data extraction focused on bioactive composition, experimental models, molecular pathways, and fecal/metabolic markers of carcinogenesis. Results: A total of 11 studies were included after screening 24 records: 8 in vitro investigations, 2 in vivo animal experiments, and 1 epidemiological study. In vitro studies showed that hazelnut derivatives—including fermented hazelnuts and oil-based extracts—exert antiproliferative effects via BAX/BCL-2 modulation, increased caspase-3 activity, and oxidative stress reduction. In vivo studies confirmed improved lipid metabolism, modulation of bile acid composition (notably reduced lithocholic/deoxycholic acid ratio), and enhanced antioxidant defenses. FIBEROX^®, a hazelnut skin extract enriched in dietary fiber, demonstrated promising effects on gut microbiota and bile acid detoxification. Conclusions: Hazelnut and their bioactive compounds may aid CRC prevention through multiple molecular and metabolic pathways. Further human studies are needed to confirm these effects and support dietary recommendations. Full article

Drug resistance is still one of the main challenges for the treatment of colorectal cancer (CRC). Whilst some resistance mechanisms are well known, from the static therapy success rate, clearly, still much is undiscovered. Intracellular transport mechanisms have attracted attention as having a possible role in drug resistance, and here, the Endosomal Sorting Complex Required for Transport (ESCRT) protein family is studied as a source of drug resistance modulation using human CRC cell lines and clinical material. From an initial screening of ESCRT proteins in a panel of 10 CRC wild-type cell lines using immunoblotting, Vacuolar Protein Sorting-Associated Protein A4 (VPS4A) was identified as being consistently highly expressed, and it was selected for further investigation. Immunohistopathological evaluation in a small panel of CRC patient samples demonstrated high expression in the tumor epithelium compared to normal intestinal epithelium. The knockdown of VPS4A resulted in enhanced sensitivity of cells to oxaliplatin, and it was subsequently seen that oxaliplatin-resistant sublines had significantly higher VPS4A expression than their wild-type variants. In addition, it was demonstrated that a small molecule inhibitor of VPS4A, aloperine, could interact synergistically with oxaliplatin to enhance its sensitivity in an oxaliplatin-resistant cell line. We hypothesize from initial RNA sequencing analysis that the mechanism of action of VPS4A modulation is through depleting levels of the drug efflux transporter MRP2 in the cell, preventing oxaliplatin egress and increasing cell exposure to the drug. The evidence presented here thus indicates that ESCRT machinery, specifically VPS4A, may act as a modulator of oxaliplatin resistance in CRC. Full article

The landscape for the screening of colorectal cancer (CRC) has witnessed multiple triumphs over the past decades from policy-level interventions. In the United States (US), the most prominent intervention of this nature is the Patient Protection and Affordable Care Act (ACA), enacted more than a decade ago. Since its enactment, the ACA has seen multiple legal challenges, and its impact on CRC screening has been relatively well studied. However, a consolidated, concise analysis of the data on this subject is lacking. Herein, we evaluate the impact of the ACA on CRC screening through the lens of a policy analysis, highlighting its strengths and shortcomings, and suggest policy-level interventions to address these shortcomings and improve CRC screening adoption. Full article