Colorectal Cancer Research Articles

Risk of recurrence in early-onset versus late-onset non-metastatic colorectal cancer, 2004–2019: a nationwide cohort study

The incidence of colorectal cancer (CRC) in individuals younger than 50 years of age (early-onset CRC) is increasing. Early-onset CRC often present at advanced stage, suggesting a more aggressive cancer course compared to late-onset CRC (age 50-79). This nationwide cohort study estimates the incidence of recurrence following early-onset CRC and late-onset CRC. The study included all Danish patients <80 years old operated for first-time Union for International Cancer Control (UICC) stage I-III CRC between January 2004 and December 2019. Recurrence status was determined by applying a validated algorithm to individual-level data from nationwide health registries. The 5-year cumulative incidence functions (CIF) of recurrence were reported for early-onset versus late-onset CRC. The difference in time to recurrence was estimated as a time ratio (TR) using an accelerated failure time model. Among 25,729 CRC patients, 1441 (5.6%) had early-onset CRC. Compared to late-onset CRC, early-onset was associated with advanced disease stages and higher treatment intensity. The 5-year CIF of recurrence was 29% (95% CI: 26%-31%) in early-onset versus 21% (95% CI: 21%-22%) in late-onset CRC. The higher CIF of recurrence for early-onset patients persisted in stage-stratified analysis. Time to recurrence was shorter in early-onset versus late-onset patients with TR=0.76 (95% CI: 0.67-0.85). The 5-year CIF of recurrence decreased from 2004 to 2019 for both early- and late-onset patients-most prominent for early-onset patients. Early-onset CRC was associated with higher incidence of recurrence at all disease stages. Indicating that the increased risk is not explained by delayed diagnosis. The excess risk diminished from 2004 to 2019, suggesting that early-onset CRC may achieve a similar recurrence risk as late-onset CRC in a contemporary setting. Aarhus University, Novo Nordisk Foundation, Innovation Fund Denmark, and the Danish Cancer Society.

Pre-diagnostic plasma advanced glycation end-products and soluble receptor for advanced glycation end-products and mortality in colorectal cancer patients.

Advanced glycation end-products (AGEs), formed endogenously or obtained exogenously from diet, may contribute to chronic inflammation, intracellular signaling alterations, and pathogenesis of several chronic diseases including colorectal cancer (CRC). However, the role of AGEs in CRC survival is less known. The associations of pre-diagnostic circulating AGEs and their soluble receptor (sRAGE) with CRC-specific and overall mortality were estimated using multivariable-adjusted Cox proportional hazards regression among 1369 CRC cases in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Concentrations of major plasma AGEs, Nε-[carboxy-methyl]lysine (CML), Nε-[carboxy-ethyl]lysine (CEL) and Nδ-[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1), were measured using ultra-performance liquid chromatography mass-spectrometry. sRAGE was assessed by enzyme-linked immunosorbent assay. Over a mean follow-up period of 96 months, 693 deaths occurred of which 541 were due to CRC. Individual and combined AGEs were not statistically significantly associated with CRC-specific or overall mortality. However, there was a possible interaction by sex for CEL (Pinteraction = .05). Participants with higher sRAGE had a higher risk of dying from CRC (HRQ5vs.Q1 = 1.67, 95% CI: 1.21-2.30, Ptrend = .02) or any cause (HRQ5vs.Q1 = 1.38, 95% CI: 1.05-1.83, Ptrend = .09). These associations tended to be stronger among cases with diabetes (Pinteraction = .03) and pre-diabetes (Pinteraction <.01) before CRC diagnosis. Pre-diagnostic AGEs were not associated with CRC-specific and overall mortality in individuals with CRC. However, a positive association was observed for sRAGE. Our findings may stimulate further research on the role of AGEs and sRAGE in survival among cancer patients with special emphasis on potential effect modifications by sex and diabetes.

Long non-coding RNA AC105118.1 affects glycolysis to facilitate oxaliplatin resistance in colorectal cancer cells by modulating the miR-378a-3p/KIF26B axis

BackgroundOxaliplatin is a first-line chemotherapy drug for colorectal cancer (CRC), but many patients eventually lose treatment efficacy due to acquired resistance. AC105118.1 is a long non-coding RNA with unknown biological function. This research attempts to probe into the molecular regulatory mechanism of AC105118.1 in CRC oxaliplatin resistance. MethodsThe expression level of AC105118.1 in CRC tissues and cells was measured based on The Cancer Genome Atlas (TCGA) data and quantitative reverse transcription polymerase chain reaction (qRT-PCR). We utilized dual-luciferase assay and RNA immunoprecipitation to analyze the interaction between AC105118.1, miR-378a-3p, and their downstream target KIF26B. CCK-8, colony formation assay, and flow cytometry were employed to assess the half inhibitory concentration (IC50), cell proliferation, and apoptosis rate of HCT116/L-OHP cells treated with oxaliplatin. The glycolysis evaluation was completed by measuring the extracellular acidification rate (ECAR), glucose consumption, lactate production, and glycolysis-related proteins (HK2, GLUT1, and LDHA). TUNEL staining was used to detect the level of apoptosis. ResultsAC105118.1 was specifically upregulated in CRC tissues and cells. AC105118.1 indirectly facilitated the expression of miRNA target gene KIF26B by sequestering miR-378a-3p. In HCT116/L-OHP cells, transfection with si-AC105118.1 resulted in a decrease in glycolysis level, a lower maximum IC50 required for oxaliplatin-treated cells, inhibited cell proliferation, and an increase in apoptosis rate. All of these effects were alleviated when simultaneously transfecting miR-378a-3p inhibitor or oe-KIF26B. Knockdown of AC105118.1 significantly inhibited oxaliplatin resistance to CRC in mice. ConclusionAC105118.1 facilitates glycolysis and increases CRC cells’ resistance to oxaliplatin by targeting the miR-378a-3p/KIF26B axis. The present work shed new insights into the function and mechanism of AC105118.1 in molecular function and suggested that the AC105118.1/miR-378a-3p/KIF26B axis is a promising target for intervening CRC oxaliplatin resistance.

13-year colorectal cancer risk after lower-quality, higher-quality and no screening colonoscopy: a cohort study

ObjectiveA lower-quality colonoscopy has been shown to be less effective in reducing colorectal cancer (CRC) incidence than a higher-quality colonoscopy, but the comparison with no screening colonoscopy is lacking. We aimed to compare the 13-year risk of developing CRC between persons with I) a higher-quality screening colonoscopy, II) a lower-quality screening colonoscopy and III) without a screening colonoscopy. Study Design and SettingA healthcare database (∼20% of the German population) was used to emulate a target trial with three arms: Higher-quality screening colonoscopy (higherQualSC) vs. lower-quality screening colonoscopy (lowerQualSC) vs. no screening colonoscopy (noSC) at baseline. The quality of screening colonoscopy was categorized based on the polyp detection rate of the examining physician (cut-off: 21.8%). We included persons aged 55 to 69 years at average CRC risk and CRC screening naïve at baseline. We estimated adjusted cumulative CRC incidence over 13 years of follow-up. ResultsThe higherQualSC arm comprised 142,960 persons, the lowerQualSC arm 62,338 persons and the noSC arm 124,040 persons. The adjusted 13-year CRC risk was 1.77% in the higherQualSC arm, 2.09% in the lowerQualSC arm and 2.74% in the noSC arm. Compared to the noSC arm, the adjusted relative risk was 0.76 (95% CI: 0.70–0.84) in the lowerQualSC arm and 0.65 (95% CI: 0.60–0.69) in the higherQualSC arm. ConclusionOur study shows that a lower-quality screening colonoscopy is also effective in reducing CRC incidence compared to no screening colonoscopy. However, the effect is about one third less than that of a higher-quality screening colonoscopy.

H3K27ac-activated LncRNA NUTM2A-AS1 Facilitated the Progression of Colorectal Cancer Cells via MicroRNA-126-5p/FAM3C Axis.

Long non-coding RNAs (lncRNAs) are of great importance in the process of colorectal cancer (CRC) tumorigenesis and progression. However, the functions and underlying molecular mechanisms of the majority of lncRNAs in CRC still lack clarity. A Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect lncRNA NUTM2A-AS1 expression in CRC cell lines. Cell counting kit 8 (CCK-8) assay and flow cytometry were used to examine the biological functions of lncRNA NUTM2A-AS1 in the proliferation and apoptosis of CRC cells. RT-qPCR and western blot were implemented for the detection of cell proliferation-, apoptosis-related proteins, and FAM3C. Bioinformatics analysis and dual- luciferase reporter assays were utilized to identify the mutual regulatory mechanism of ceRNAs. lncRNA NUTM2A-AS1 notably elevated in CRC cell lines and the silenced of NUTM2A- AS1 declined proliferation and facilitated apoptosis. Mechanistically, NUTM2A-AS1 was transcriptionally activated by histone H3 on lysine 27 acetylation (H3K27ac) enriched at its promoter region, and NUTM2A-AS1 acted as a sponge for miR-126-5p, leading to the upregulation of FAM3C expression in CRC cell lines. Our research proposed NUTM2A-AS1 as an oncogenic lncRNA that facilitates CRC malignancy by upregulating FAM3C expression, which might provide new insight and a promising therapeutic target for the diagnosis and treatment of CRC.

Exploration of the key active ingredients and mechanisms of Sparganii Rhizoma-Curcumae Rhizoma compatible formulation against human colorectal cancer through network pharmacology and in vitro experiments

IntroductionSparganii Rhizoma-Curcumae Rhizoma (SR-CR) formulation may offer an effective treatment for human colorectal cancer (CRC). However, the active ingredients and underlying mechanisms of this herbal formulation remain unclear. MethodsThis study integrates network pharmacology, molecular docking and experimental verification to identify key active ingredients and elucidate the mechanisms of SR-CR in CRC treatment. ResultsTwenty-three active components of SR-CR were identified using the TCMSP, UniProt and Gene Cards databases. These components were associated with 178 targets, of which 118 are directly related to CRC. Protein-protein interaction (PPI) network analysis identified protein kinase B (AKT) 1, epidermal growth factor receptor (EGFR), SRC, Bcl2 and CASP3 as core anti-CRC targets. Gene Ontology (GO) and KEGG pathway analyses were performed on these 178 intersecting targets, and the results showed that these targets are involved in EGFR tyrosine kinase inhibitor resistance and AGE-RAGE signaling pathway in diabetic complications. At the same time, five compounds, including bisdemethoxycurcumin, formononetin, β-sitosterol, stigmasterol and hederagenin, were selected based on the target number of effective components and tested for cytotoxicity against human CRC cell lines HT-29, HCT-8 and HCT-116 in vitro. The results showed that bisdemethoxycurcumin exhibited significant anti-proliferative activity against HCT-116 cells. Molecular docking results indicated that bisdemethoxycurcumin effectively binds with AKT, EGFR, Bcl-2 and CASP3. Further pharmacological experiments demonstrated that bisdemethoxycurcumin inhibits HCT-116 cell proliferation and migration via inhibiting EGFR-AKT pathway, and induces apoptosis by up-regulating Bcl-2 expression. DiscussionBased on our study, inhibiting the EGFR-AKT pathway and upregulating Bcl2 may be one of the mechanisms by which SR-CR inhibits the growth of CRC. The main active ingredients of SR-CR include bisdemethoxycurcumin, formononetin, β-sitosterol, stigmasterol and hederagenin, which may exert anti-colon cancer activity by targeting the regulation of AKT, EGFR, Bcl-2 and CASP3. However, we need more in vitro and in vivo evidence to confirm this conclusion. This study lays the foundation for further research on the pharmacological mechanism of SR-CR in the treatment of CRC.

A feasibility study of a couple-based illness perception intervention for couples coping with colorectal cancer

PurposeAs a special psychological variable, illness perception significantly affects the cancer adaptions of colorectal cancer couples. No studies focus on facilitating cancer adaption by targeting the illness perception in colorectal cancer couples. This research attempted to explore the feasibility, acceptability, and potential effectiveness of an illness perception intervention program designed for couples with colorectal cancer, guided by a self-regulation common sense model. MethodsA single-group pilot study including pre- and post-testing was carried out with Chinese couples having colorectal cancer. Six sessions were delivered consecutively by researchers via in-person or telephone for couples. By calculating the rates of recruitment and retention, the feasibility of the intervention was analyzed. Intervention acceptability was evaluated by analysis of the post-intervention quantitative and qualitative data. Outcomes were described as illness perception, cancer-related communication problems, dyadic coping, quality of life, anxiety and depression, and benefit finding. Effect sizes were computed to assess the preliminary program effects. ResultsThe feasibility was confirmed by the recruitment (67.6%) and retention (82.6%) rates. The acceptability was endorsed by the reported participant satisfaction. Validating the program’s preliminary effectiveness, the intervention program has moderate effect sizes (Cohen’s d: 0.33-0.79) that boost illness perception and major cancer adjustment results for patients and their spousal caregivers. ConclusionsThe research proved that the couple-based illness perception intervention among colorectal couples was feasible, acceptable, and initially effective. To investigate this intervention program more thoroughly and apply it to a wider range of disease backgrounds, an extensive randomized controlled experiment is necessary.

Patterns of Gene Expression Profiles Associated with Colorectal Cancer in Colorectal Mucosa by Using Machine Learning Methods.

Colorectal cancer (CRC) has a very high incidence and lethality rate and is one of the most dangerous cancer types. Timely diagnosis can effectively reduce the incidence of colorectal cancer. Changes in para-cancerous tissues may serve as an early signal for tumorigenesis. Comparison of the differences in gene expression between para-cancerous and normal mucosa can help in the diagnosis of CRC and understanding the mechanisms of development. This study aimed to identify specific genes at the level of gene expression, which are expressed in normal mucosa and may be predictive of CRC risk. A machine learning approach was used to analyze transcriptomic data in 459 samples of normal colonic mucosal tissue from 322 CRC cases and 137 non-CRC, in which each sample contained 28,706 gene expression levels. The genes were ranked using four ranking methods based on importance estimation (LASSO, LightGBM, MCFS, and mRMR) and four classification algorithms (decision tree [DT], K-nearest neighbor [KNN], random forest [RF], and support vector machine [SVM]) were combined with incremental feature selection [IFS] methods to construct a prediction model with excellent performance. The top-ranked genes, namely, HOXD12, CDH1, and S100A12, were associated with tumorigenesis based on previous studies. This study summarized four sets of quantitative classification rules based on the DT algorithm, providing clues for understanding the microenvironmental changes caused by CRC. According to the rules, the effect of CRC on normal mucosa can be determined.

Type I Diabetes Mellitus impairs cytotoxic immunity through CEACAM5 upregulation in colorectal cancer : Exploring the intersection of autoimmune dysfunction and cancer progression: the role of NF-κB p65 in colorectal cancer.

Type 1 diabetes (T1D) is characterized by an autoimmune-mediated destruction of pancreatic beta cells and a chronic inflammatory state, which may influence the progression of colorectal cancer (CRC) through immune system dysregulation and enhanced tumor immune evasion. This study aims to elucidate the role of p65 in modulating the tumor microenvironment in CRC within the context of T1D and to determine how this modulation affects tumor growth, immune cell infiltration, and the expression of immune evasion molecules such as CEACAM5. NOD mice, which model T1D, were inoculated with MC38 colon carcinoma cells engineered to knock down p65. Tumor growth was monitored, and the tumor microenvironment was analyzed using flow cytometry to assess the infiltration of immune cells. The expression of Ki-67 and CEACAM5 in tumor cells was also evaluated. Additionally, in vitro assays were conducted to study the proliferation and activation of T cells co-cultured with tumor cells. Knockdown of p65 in tumor cells significantly inhibited tumor growth in NOD mice. This was accompanied by an increased infiltration of cytotoxic CD8+ T cells and no significant change in CD4+ or Foxp3 + T regulatory cells within the tumor microenvironment. There was a notable reduction in the expression of Ki-67 and CEACAM5, indicating decreased proliferation and potential immune evasion capabilities of the tumor cells. Our findings demonstrate that the NF-κB p65 subunit plays a crucial role in promoting tumor growth and modulating the immune microenvironment in CRC, particularly in the context of T1D. Knocking down p65 not only reduces tumor progression but also enhances the anti-tumor immune response by decreasing immune evasion mechanisms. These results suggest that targeting the NF-κB pathway may be a viable strategy to improve the efficacy of cancer immunotherapy, especially in patients with autoimmune diseases like T1D. Physical activity enhances the effect of immune checkpoint blockade by inhibiting the intratumoral HIF1-α/CEACAM5 axis.

The Roles of Cytoplasmic Polyadenylation Element Binding Protein 1 in Tumorigenesis.

CPEB1 is an alternative polyadenylation binding protein that promotes or suppresses the expression of related mRNAs and proteins by binding to a highly conserved Cytoplasmic Polyadenylation Element (CPE) in the mRNAs 3'UTR. It is found to express abnormally in multiple tumors and affect tumorigenesis through many pathways. This review summarizes the functions and mechanisms of CPEB1 in a variety of cancers and suggests new directions for future related treatments. A total of 95 articles were eligible for inclusion based on the year, quality of the research, and the strength of association with CPEB1. In this review, current research about how CPEB1 affects the initiation and progression of glioblastoma, breast cancer, hepatocellular carcinoma, gastric cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, and melanoma are dissected, and the biomedical functions and mechanisms are summarized. CPEB1 mostly presents as a tumor suppressor for breast cancer, endometrial carcinoma, hepatocellular carcinoma, non-small cell lung cancer, prostate cancer, and melanoma. However, for glioblastoma, gastric cancer, and colorectal cancer, CPEB1 exhibts two opposing properties of tumorigenesis, either promoting or inhibiting it. CPEB1 is likely to serve as a target and dynamic detection index or prognostic indicator for its function of apoptosis, activity, proliferation, migration, invasion, stemness, drug resistance, and even ferroptosis in various cancers.

GraphCVAE: Uncovering cell heterogeneity and therapeutic target discovery through residual and contrastive learning.

Advancements in Spatial Transcriptomics (ST) technologies in recent years have transformed the analysis of tissue structure and function within spatial contexts. However, accurately identifying spatial domains remains challenging due to data sparsity and noise. Traditional clustering methods often fail to capture spatial dependencies, while spatial clustering methods struggle with batch effects and data integration. We introduce GraphCVAE, a model designed to enhance spatial domain identification by integrating spatial and morphological information, correcting batch effects, and managing heterogeneous data. GraphCVAE employs a multi-layer Graph Convolutional Network (GCN) and a variational autoencoder to improve the representation and integration of spatial information. Through contrastive learning, the model captures subtle differences between cell types and states. Extensive testing on various ST datasets demonstrates GraphCVAE's robustness and biological contributions. In the dorsolateral prefrontal cortex (DLPFC) dataset, it accurately delineates cortical layer boundaries. In glioblastoma, GraphCVAE reveals critical therapeutic targets such as TF and NFIB. In colorectal cancer, it explores the role of the extracellular matrix in colorectal cancer. The model's performance metrics consistently surpass existing methods, validating its effectiveness. GraphCVAE's advanced visualization capabilities further highlight its precision in resolving spatial structures, making it a powerful tool for spatial transcriptomics analysis and offering new insights into disease studies.

STING agonists and PI3Kγ inhibitor co-loaded ferric ion-punicalagin networks for comprehensive cancer therapy

Nanoparticles-based drug delivery system has been a promising approach for the treatment of colorectal cancer (CRC), which can be combined with chemotherapy, targeted therapy and immunotherapy to improve the treatment of CRC. 2′3’ cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) is an agonist of the STING signaling pathway activating antitumor immunity. IPI-549 is a small-molecule inhibitor for phosphatidylinositol 3-kinase γ (PI3Kγ), which can induce M1 macrophages polarization to provide pro-inflammatory microenvironment to suppress tumors. Here, we developed a ferric ion-punicalagin network (Fe-PU), which can be not only used as an inducer of ferroptosis, but also serve as a carrier to load cGAMP and IPI-549 to obtain nanohybrid (Fe-PU/CD-IPI). In order to improve the delivery effect and targeted ability to CRC, a cyclic arginine-glycine-aspartic acid peptide linked-bovine serum albumin were utilized to modify Fe-PU/CD-IPI to prepare nanohybrid Fe-PU/CD-IPI@cBSA. The therapeutic effect of various nanohybrids were validated in the mice with spontaneous tumor in the colorectal area and tumor-bearing mice, which lead to the increase of ferroptosis, the activation of STING signaling pathway, and the repolarization of macrophages. Collectively, the cGAMP and IPI-549 co-loaded nanohybrids effectively reshaped the tumor immune microenvironment, and exhibited prominent treatment effect of anti-colorectal cancer in vitro, patient-derived organoids, and in vivo.

Body mass index and the prevalence of high-risk colorectal adenomas in a population undergoing screening colonoscopy in Alberta, Canada.

There is limited evidence regarding body mass index (BMI) as an early marker of high-risk adenoma (HRA) at the time of screening colonoscopy. Because high-risk adenomas (HRA) can develop into colorectal cancer (CRC), BMI could serve as an important clinical predictor of future risk of CRC. We examined data from 1831 adults undergoing screening colonoscopy at the Forzani & MacPhail Colon Cancer Screening Center in Alberta, Canada. We fit multivariable logistic regression models to examine the association between BMI and HRA. Non-linear relationships for BMI on HRA were also evaluated using restricted cubic splines. The mean BMI in patients with HRA was 28.2kg/m2 compared to 27.4kg/m2 in patients without adenomas (t test: p=0.003). In the adjusted models, those with a BMI over 30kg/m2 had 1.45 (95% CI 1.05-2.00) times the odds of HRA detected during colonoscopy compared to those with a BMI below 25kg/m2. Examining BMI as continuous, the odds of HRA were 1.20 (95% CI 1.04-1.37) times higher for every 5kg/m2 increase in BMI. The findings of this study suggest that excess body mass is associated with higher risk of HRA among a screening population and may be useful an early marker of future disease.

The role of CD98 heavy chain in cancer development.

The glycoprotein CD98, or CD98 heavy chain (CD98hc), encoded by the SLC3A2 gene, plays a crucial role in cancer development and progression. CD98hc, forming heterodimeric complexes with various light chains, regulates neutral amino acid transport across cell membranes. The intricate interplay between CD98hc, integrins, and amino acid transporters shapes the tumor microenvironment and contributes to tumor growth. Elevated expression of CD98hc in various cancers correlates with poor prognosis, making it a potential prognostic marker. In colorectal cancer, CD98hc emerges as a potential therapeutic target, along with its partner LAT1, and inhibitors like JPH203 exhibit promise in preclinical studies. Targeting CD98hc/LAT1, alone or with conventional therapies, shows promise in inhibiting tumor growth. This review focuses on elucidating the multifaceted roles of CD98hc and its partner LAT1 in cancer, particularly its involvement in amino acid transport, signaling pathways, and its prognostic relevance in cancer.

The use of SP/Neurokinin-1 as a Therapeutic Target in Colon and Rectal Cancer.

Different studies have highlighted the role of Substance P / Neurokinin 1 Receptor (SP/NK-1R) axis in multiple hallmarks of cancer including cell transformation, proliferation, and migration as well as angiogenesis and metastasis of a wide range of solid tumors including colorectal cancer. Until now, the selective high-affinity antagonist of human SP/NK1-R aprepitant (Emend) has been authorized by the Food and Drug Administration as a low dosage medication to manage and treat chemotherapy-induced nausea. However, increasing evidence in recent years support the potential utility of high doses of aprepitant as an antitumor agent and thus, opening the possibility to the pharmacological repositioning of SP/NK1-R antagonists as an adjuvant therapy to conventional cancer treatments. In this review, we summarize current knowledge on the molecular basis of colorectal cancer as well as the pathophysiological importance of SP/NK1-R and the potential utility of SP/NK-1R axis as a therapeutic target in this malignancy.

Anti-Tumor Activity of Indole: A Review

: Generally, heterocyclic compounds are included in a large class of pharmacologically active compounds. The indole scaffold in this category is widely distributed in nature and present in many active compounds, especially anti-cancer agents. Due to its unique physicochemical and biological properties, the indole platform has been considered a favorable scaffold in anti-cancer drug design and development. Various indole compounds (synthetic, semisynthetic, and natural) show remarkable anti-proliferative activity. According to the recent literature, this review describes the role of indole scaffolds as anti-cancer agents. Indole was reported to induce anti-tumor activity through multiple mechanisms, for example, Epidermal Growth Factor Receptors (EGFR), histone deacetylase (HDAC), kinase, DNA-topoisomerases, and tubulin inhibition. The current review focuses on some indole compounds with amazing effects against different types of cancers as there are too many FDA-approved drugs, for example, osimertinib, alectinib, and anlotinib in NSCLC treatment, panobinostat in multiple myeloma, midostaurin in acute myeloid leukemia treatment, etc. Moreover, several compounds are still in clinical trials to treat different cancer types. Additionally, there are some oxindole derivatives with potent inhibition against different types of tumors, such as ovarian cancer, colorectal cancer, and prostate cancer. Different series of oxindoles are promising and recommended for further studies due to their remarkable inhibition of tumor cells. Accordingly, the collection of data on a pharmacologically significant motif might aid researchers in further employing indoles in developing novel anti-cancer drugs with potentially fewer side effects and higher potency against this rapidly spreading disease.

In silico Exploration of a Novel ICMT Inhibitor with More Solubility than Cysmethynil against Membrane Localization of KRAS Mutant in Colorectal Cancer.

ICMT (isoprenylcysteine carboxyl methyltransferase) is an enzyme that plays a key role in the post-translational modification of the K-Ras protein. The carboxyl methylation of this protein by ICMT is important for its proper localization and function. Cysmethynil (2-[5-(3-methylphenyl)-l-octyl-lH-indolo-3-yl] acetamide) causes K-Ras mislocalization and interrupts pathways that control cancer cell growth and division through inhibition of ICMT, but its poor water solubility makes it difficult and impractical for clinical use. This indicates that relatively high amounts of cysmethynil would be required to achieve an effective dose, which could result in significant adverse effects in patients. The general objective of this work was to find virtually new compounds that present high solubility in water and are similar to the pharmacological activity of cysmethynil. Pharmacophore modeling, pharmacophore-based virtual screening, prediction of ADMET properties (absorption, distribution, metabolism, excretion, and toxicity), and water solubility were performed to recover a water-soluble molecule that shares the same chemical characteristics as cysmethynil using Discovery Studio v16.1.0 (DS16.1), SwissADME server, and pkCSM server. In this study, ten pharmacophore model hypotheses were generated by exploiting the characteristics of cysmethynil. The pharmacophore model validated by the set test method was used to screen the "Elite Library®" and "Synergy Library" databases of Asinex. Only 1533 compounds corresponding to all the characteristics of the pharmacophore were retained. Then, the aqueous solubility in water at 25°C of these 1533 compounds was predicted by the Cheng and Merz model. Among these 1533 compounds, two had the optimal water solubility. Finally, the ADMET properties and Log S water solubility by three models (ESOL, Ali, and SILICOS-IT) of the two compounds and cysmethynil were compared, resulting in compound 2 as a potential inhibitor of ICMT. According to the results obtained, the identified compound presented a high solubility in water and could be similar to the pharmacological activity of cysmethynil.

Orchestrated Copper-Loaded Nanoreactor for Simultaneous Induction of Cuproptosis and Immunotherapeutic Intervention in Colorectal Cancer

Ion interference, including intracellular copper (Cu) overload, disrupts cellular homeostasis, triggers mitochondrial dysfunction, and activates cell-specific death channels, highlighting its significant potential in cancer therapy. Nevertheless, the insufficient intracellular Cu ions transported by existing Cu ionophores, which are small molecules with short blood half-lives, inevitably hamper the effectiveness of cuproptosis. Herein, the ESCu@HM nanoreactor, self-assembled from the integration of H-MnO2 nanoparticles with the Cu ionophore elesclomol (ES) and Cu, was fabricated to facilitate cuproptosis and further induce relevant immune responses. Specifically, the systemic circulation and tumoral accumulation of Cu, causing irreversible cuproptosis, work in conjunction with Mn2+, resulting in the repolarization of tumor-associated macrophages (TAMs) and amplification of the activation of the cGAS-STING pathway by damaged DNA fragments in the nucleus and mitochondria. This further stimulates antitumor immunity and ultimately reprograms the tumor microenvironment (TME) to inhibit tumor growth. Overall, ESCu@HM as a nanoreactor for cuproptosis and immunotherapy, not only improves the dual antitumor mechanism of ES and provides potential optimization for its clinical application, but also paves the way for innovative strategies for cuproptosis-mediated colorectal cancer (CRC) treatment.

CT assessment of liver fat fraction and abdominal fat composition can predict postoperative liver metastasis of colorectal cancer

ObjectiveThe aim of this study is to investigate the clinical value of liver fat fraction assessed by CT(CT-LFF) and abdominal fat components. We focus on predicting liver metastasis (LM) after colorectal cancer (CRC) surgery. MethodsClinical and imaging data from 79 patients who underwent radical CRC surgery between January 2019 and December 2021 were retrospectively collected. Semi-automatic software was used to quantify the area of different body tissues at the level of the third lumbar vertebra, and liver fat fraction was calculated based on the CT values. Patients were grouped according to BMI, tumor grade, T stage, N stage, vascular invasion (VI), perineural invasion (PNI), and preoperative levels of CEA and CA199. A multivariate logistic regression model was used to identify independent risk factors for early LM after surgery. The diagnostic performance was assessed using the receiver operating characteristic analysis with 5-fold cross-validation. The Kaplan-Meier method was used to draw survival curves, and Log-Rank test was used for survival analysis. ResultsThe study found that the occurrence of LM after CRC surgery was significantly associated with CA199 positivity, VI, PNI, N1-2 stage, CT-LFF, VAT index (VATI). Multivariate logistic regression analysis showed that CA199 positivity (OR = 7.659), N1-2 stage (OR = 6.394), CT-LFF (OR = 1.271), VATI (OR = 1.043) were independent risk factors for predicting LM after CRC surgery. The multivariate logistic regression model, constructed using these independent risk factors, demonstrated robust predictive performance across 5-fold cross-validations, with an average AUC of 0.898 (95 % CI: 0.828–0.969). Survival analysis showed a significant difference in liver metastasis-free survival rates between the high-risk and low-risk groups (P < 0.001). ConclusionCT-LFF and VATI assessed by CT are independent risk factors for predicting LM after CRC surgery. The multivariate prediction model combining CA199 and N stage shows high predictive performance.

Management of primary sclerosing cholangitis: Current state-of-the-art

Primary sclerosing cholangitis is a chronic liver disease characterized by progressive inflammation and fibrosis of medium-large bile ducts, most commonly in association with inflammatory bowel disease. Most patients have a progressive disease course, alongside a heightened risk of hepatobiliary and colorectal cancer. Medical therapies are lacking, and this, in part, reflects a poor grasp of disease biology. As a result, current management is largely supportive, with liver transplantation an effective life-prolonging intervention when needed, but not one that cures disease. Emerging therapies targeting disease progression, as well as symptoms such as pruritus, continue to be explored. The trial design is increasingly cognizant of the application of thoughtful inclusion criteria, as well as better endpoints aimed at using surrogates of disease that can identify treatment benefits early. This is hoped to facilitate much-needed advances toward developing safe and effective interventions for patients.