Search Results (10,443)

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibro-inflammatory lesions of the biliary tree. In the absence of available, effective medical therapies, many patients progress to liver failure, making PSC one of the leading indications for liver transplantation (LT), despite its rarity. While LT in PSC is associated with good overall short- and long-term survival, post-transplant outcomes are limited by recurrent PSC (rPSC), which affects up to one quarter of PSC recipients with a significant risk of graft loss and re-transplantation. The risk of rPSC reflects a complex interaction between donor and recipient factors including associated inflammatory bowel disease (IBD), and long-term exposure to immunosuppression. Therefore, post-transplant management requires an individualized multidisciplinary approach and tailored immunosuppressive regimens aimed at balancing the risk of rejection and rPSC with the risk of infection and malignancy. Optimal control of IBD has emerged as a key modifiable determinant of rPSC risk and post-transplant outcomes. In addition, patients with PSC, particularly PSC-IBD patients, carry a significantly increased risk of hepatobiliary and colorectal cancer. Importantly, this oncological risk persists after LT. Thus, long-term, structured cancer surveillance must remain an integral component of post-transplant care. Looking ahead, novel therapies targeting shared hepatic and intestinal fibro-inflammatory pathways are currently being investigated to modify disease activity in the pre-transplant setting. Future studies are needed to assess whether these agents might be applicable also in the post-transplant setting to improve long-term graft and patient survival. Full article

Colorectal cancer (CRC) is the third most prevalent cancer globally. TASK-1, encoded by the KCNK3 gene, is emerging as a putative target in cancer; it regulates resting membrane potential, cell proliferation, and apoptosis. A series of 27 novel xanthene derivatives, modified at position 9, were synthesized via azide coupling of 2-(9H-xanthen-9-yl)acetohydrazide with selected amines and amino acids, followed by hydrazine-mediated conversion to the corresponding hydrazides. The cytotoxic activity of selected compounds (5a–5g, 6a–6h, 7b, 7f–7h) was evaluated against the HCT-116 cell line in vitro. In addition, molecular docking and molecular dynamics simulations were performed to investigate binding interactions and assess the stability of the protein–ligand complexes. Several compounds (5f, 5g, 6c, 6d, 6f, 6g, 7b, 7f, and 7h) exhibited moderate cytotoxic activity against HCT-116 cells (IC₅₀: 66.97–99.62 µM), compared to cisplatin (IC₅₀: 18.25 µM). Compound 7h demonstrated pronounced antiproliferative effects, evidenced by DAPI staining showing chromatin condensation and apoptotic body formation, along with a marked reduction in cell count and coverage. Molecular docking indicated favorable binding within the TASK-1 potassium channel, and molecular dynamics simulations confirmed the stability of the protein–ligand complex, with consistent interactions, including a key hydrogen bond with Asn240. These findings support 7h as a promising lead candidate. These findings identify xanthene-based derivatives as promising lead compounds for further optimization as TASK-1-targeted therapeutic candidates in colorectal cancer Full article

This paper aims to describe what is currently known about Lynch syndrome within Asian American populations. According to data collected by the US Census, as of 2022, 24.7 million people of Asian descent live in the United States. Cancer is the leading cause of death within this population, and as a result, it is crucial to identify ways that cancer can be identified at earlier and more treatable stages. Colorectal cancer is the third most common cancer diagnosis within the Asian American population, with an incidence of 37.1 per 100,000 Asian American men and 26.5 per 100,000 Asian American women. Lynch syndrome, the most common hereditary cause of colorectal cancer, has been incompletely described in this diverse population. This review addresses the available literature on the prevalence of Lynch syndrome in Asian American and Asian populations and differences in the manifestations of this syndrome between and within these populations, as well as in comparison to the non-Hispanic white population. Based on these differences, variances in screening rates, outcomes, and management strategies with respect to Asian ethnicity are also explored. Potential barriers to optimal management of Lynch syndrome in Asian American populations, with particular consideration of primary language and degree of cultural assimilation, are assessed. Future directions for research and recommendations to help address disparities or differences to optimize care for this group are also described. Full article

Oxicam derivatives, a class of nonsteroidal anti-inflammatory drugs (NSAIDs), are important scaffolds for developing biologically active compounds. In this study, arylpiperazine oxicam derivatives (PR24–PR50) were examined for membrane interactions, cytotoxic activity, cyclooxygenase inhibition, and potential binding to COX-2 protein. Membrane interactions were examined using differential scanning calorimetry (DSC) in phospholipid bilayers formed from 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). All compounds altered the thermotropic properties of the lipid bilayer, showing concentration-dependent decreases in phase transition temperature, indicating incorporation to bilayer and partial disruption of lipid organization. Cytotoxicity, assessed using the MTT assay in breast cancer (MCF-7, MCF-7/DX), colorectal cancer (LOVO, LOVO/DX), and normal V79 cell lines, showed moderate effects, particularly against colorectal cancer cells. Cyclooxygenase inhibition was rather weak, with IC₅₀ values in the high micromolar range, indicating limited anti-inflammatory potential compared with reference COX inhibitors, although docking studies suggested possible interactions with the COX-2 active site. The obtained results indicate that the biological activity of the arylpiperazine oxicam derivatives is primarily associated with cytotoxicity and membrane effects rather than COX inhibition. These limitations should be considered in the design of future membrane-targeted bioactive compounds. Full article

Colorectal cancer remains a leading cause of morbidity and mortality worldwide with diverse pathways of carcinogenesis. Deficiencies in the DNA mismatch repair and resultant microsatellite instability are thought to make up roughly 15% of localized and 5% of metastatic cancers of the colon and rectum. Cancers arising through this pathway are characterized by poor response to traditional chemotherapies, but have demonstrated unprecedented responses to immunotherapy over the last decade. Thus, the management of mismatch repair-deficient/microsatellite-unstable colorectal cancer is a rapidly evolving field. In this review we provide a clinician-oriented update on the diagnosis and management of mismatch repair-deficient/microsatellite-unstable colorectal cancer. We explore the tools used for diagnosis as well as the causes and implications of the failure of these tools, along with practical recommendations to mitigate and circumvent such errors. Furthermore, we examine the changing treatment paradigm in the advanced setting with the implementation of mono and dual immunotherapy approaches and explore who is most likely to benefit from such strategies, and how to address treatment failures. Finally, we explore how immunotherapy may allow for non-surgical approaches in the localized setting and discuss the evolving evidence for neoadjuvant and adjuvant approaches when surgery is used. Full article

Liver transplant can significantly improve survival in patients with isolated colorectal liver metastases (CRLMs) not amenable to surgical resection. The use of evolving strict selection criteria to identify patients with CRLM best suited for transplant has greatly prolonged disease-free survival and resulted in a post-transplant overall survival similar to that of other established indications for transplant such as advanced cirrhosis or hepatocellular carcinoma. While recurrence of colorectal cancer is still seen in the majority of patients after transplant, lesions are typically slow-growing and treatable without significant mortality. Further profiling of patients’ tumor molecular and biologic activity before transplant can help risk-stratify them for aggressive recurrence. Our current understanding of recurrence after liver transplant for CRLM is based on only a small number of prospective studies but further trials are underway. Novel surgical approaches which could expand the pool of patients eligible for transplant are also being evaluated. We summarize and discuss the current state of the literature describing the patterns, risk factors, and treatment of recurrence after liver transplant for isolated CRLM. Full article

Radiomics involves the extraction of quantitative information from medical images and can offer valuable insights into the management of rectal cancer (RC). We aim to systematically review the current literature on radiomics’ role in the prediction of lymph nodes and distance metastases, local recurrence and survival outcomes in rectal cancer. Method: This systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and principles. We systematically searched PubMed, Cochrane, Google Scholar, and ResearchGate databases to identify the relevant articles. Result: After searching 3327 articles, only 50 articles were included after assessing the quality using a radiomics quality score (QRS) and finding a mean score of 14.74. Only eight studies used CT radiomics, with the rest based on MRI radiomics. Only three of the included studies are prospective, with the others being retrospective cohort studies and 14 having external validation. Most of the included studies concluded that radiomic models alone or combined models achieve better outcome predictions when compared with clinical and subjective analysis. Conclusions: Radiomics offers significant promise as a non-invasive tool for predicting lymph node status, distant metastasis (DM), recurrence, and survival outcomes in rectal cancer. There is a need for more robust prospective studies with cost benefit analysis for implementation into clinical practice. Full article

Fusobacterium nucleatum (Fn) has emerged as one of the most extensively studied tumor-associated opportunistic pathogens in colorectal cancer (CRC). The central question in Fn–CRC research has shifted from species-level detection or enrichment toward identifying specific lineages with enhanced persistence and tumor-promoting potential under defined host and ecological contexts. Accumulating evidence suggests substantial heterogeneity within Fn at the subspecies and clade levels. Among these, the F. nucleatum subsp. animalis C2 (Fna C2) lineage has been proposed as a candidate high-risk clade with potentially greater adaptability to the gastrointestinal tract and tumor microenvironment. However, current support for Fna C2 is derived mainly from ecological enrichment, comparative genomics, inferred metabolic features, and limited functional observations, while direct clinical and mechanistic validation at the clade level remains limited. Fn has been implicated in CRC progression through multiple interconnected processes, including adhesion and colonization, host signaling activation, inflammatory amplification, immune suppression, and metabolic adaptation. Notably, these pathogenic outputs are unlikely to be uniformly distributed across all Fn lineages, but instead appear to be shaped by the combined influence of bacterial lineage, host molecular context, microbial community structure, and spatial organization within the tumor microenvironment. In this review, we summarize the lineage heterogeneity of Fn, its association with CRC, and the underlying host–pathogen interaction mechanisms. We further discuss implications for high-resolution stratification, risk classification, and clinical translation, emphasizing the need to move from species-level associations toward lineage-resolved and context-aware frameworks. Full article

Colorectal cancer screening is challenged by variations in polyp morphology, indistinct polyp boundaries, and the high computational costs associated with current models. To address these issues, a lightweight medical image segmentation model, WCEDSAM, has been developed. WCEDSAM is based on a modified, compact version of MedSAM, which incorporates a Wavelet Transform-based component to extract and separate overlapping features at the pixel level. Additionally, a DSConv-ECA module is positioned before the ViT encoder to capture local features efficiently while reducing parameter count and enhancing inter-channel communication. Experimental results demonstrate that WCEDSAM achieves top performance on five public datasets, including Kvasir-SEG and CVC-ClinicDB, with 15.38 million parameters, achieving mean Dice (mDice) scores of 0.9383 on Kvasir-SEG and 0.9376 on CVC-ClinicDB. Cross-domain evaluations yield mDice scores of 0.9189 on CVC-ColonDB, 0.8961 on CVC-300, and 0.7765 on ETIS datasets, respectively, substantially outperforming other methods such as UNet++ and TransUNet. Full article

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an E3 ubiquitin ligase that plays a crucial role in inflammation, immune responses, and tumor development. It was reported that TRAF6 primarily catalyzes K63-linked polyubiquitination to stabilize substrate proteins, thereby facilitating the malignant phenotype of tumors. Beyond its cytoplasmic roles, TRAF6 undergoes nuclear translocation in response to specific stimuli, where it interacts with chromatin modifiers. TRAF6 acts as a central mediator in key signaling pathways downstream of the Toll-like receptor, interleukin-1 receptor, and tumor necrosis factor receptor superfamilies, including NF-κB activation. TRAF6 exerts diverse oncogenic functions, including promoting cell proliferation, migration, metastasis, immune evasion, and therapy resistance. This involves modulating cellular pathways such as NF-κB and MAPK signaling, which contribute to malignant progression. Aberrant TRAF6 activation contributes to the pathogenesis of multiple malignancies, including colorectal cancer, melanoma, hepatocellular carcinoma, and acute myeloid leukemia, making it a promising therapeutic target for cancer treatment. This review summarizes the structural features, substrate diversity, and multifaceted roles of TRAF6 in cancer, as well as the development of TRAF6-targeting drugs and strategies. We hope this review can provide a comprehensive perspective on TRAF6-targeted therapeutic strategies for cancer. Full article

Background/Objectives: Quality of life (QoL) and functional recovery are essential outcomes in patients undergoing rectal cancer surgery. In addition to oncological results, bowel dysfunction and stoma-related issues may significantly affect postoperative well-being. We aimed to evaluate QoL changes at 1 and 6 months postoperatively and functional outcomes in rectal cancer patients who underwent curative surgical treatment, sphincter-preserving surgeries (SPS) or abdominoperineal resection (APR). Owing to its impact on QoL, several functions were assessed using the Low Anterior Resection Syndrome (LARS) score. Methods: This retrospective observational study consisted of 99 patients who underwent curative rectal cancer surgery, of which 38 patients had colostomy, and 61 no colostomy. To assess patient-reported outcomes related to QoL, the EORTC QLQ-C30 questionnaire, QLQ-CR29 questionnaire, and LARS instrument were sent to the patients at 1 and 6 months postoperatively. Changes over time were analyzed using paired statistical tests, and subgroup analyses were performed according to colostomy status and surgical approach. Results: Significant improvements were observed in the global health status and all major functional domains between 1 and 6 months postoperatively. The global health status increased from 74.9% to 86.5% (p < 0.001). Symptom burden decreased significantly, particularly for fatigue (−18.31), pain (−14.48), diarrhea (−12.46), and insomnia (−11.45), representing clinically meaningful improvements. Patients who underwent abdominoperineal resection or resection with colostomy had lower QoL scores at 1 month but showed substantial improvement at 6 months, becoming comparable to those who underwent SPS. LARS outcomes demonstrated progressive functional recovery, with the proportion of patients without LARS increasing from 39 to 46, while major LARS decreased from 7 to 3 patients. However, approximately 40% of patients in the SPS group continued to report moderate-to-severe LARS symptoms. Conclusions: In this study, QoL and bowel function improved significantly during the first 6 months after colorectal cancer surgery. Although most patients demonstrated recovery, persistent bowel dysfunction and stoma-related challenges remain important issues. These findings highlight the need for comprehensive postoperative care and routine assessment of both QoL and functional outcomes. Full article

Background: Tumour glycosylation regulates immune modulation and progression, but whether the CRC sialylome—the complete repertoire of sialylated glycans—defines a biologically distinct subtype remains unclear. We investigated how the “sugar code” shapes CRC biology, immunity, and therapeutic response. Methods: Transcriptomic data from three CRC cohorts (TCGA, Sidra-LUMC, and CPTAC-2; n = 988) were batch-corrected and integrated. Single-sample gene set enrichment analysis (ssGSEA) quantified sialyltransferase expression, sialic acid metabolism, EMT, MDR mechanisms, immune phenotypes, and Siglec-associated transcriptional signatures. GSEA, gene ontology enrichment analysis (GOEA), and drug ontology enrichment analysis (DOEA) characterised pathways and identified drug response-associated transcriptional signatures. Results: High sialylome activity defined a genomically stable but clinically advanced CRC subset enriched for left-sided tumours, mucinous histology, MSI, and BRAF mutations. At the transcriptional level, Sialyl-High tumours were associated with a mesenchymal, stromal-remodelling programme accompanied by reduced proliferative activity. They demonstrated enrichment of vesicular trafficking-related pathways alongside reduced representation of canonical efflux-associated programmes. Critically, the sialylome was associated with Siglec-related immune signatures, with sialylated glycan-related gene expression correlating with Siglec receptor expression (CD33 and SIGLEC7/9/10), consistent with an immune-inflamed yet structurally excluded microenvironment. DOEA identified selective enrichment of drug-response signatures related to sialic acid metabolism inhibitors (oseltamivir and Neu5Ac) and glycocalyx-disrupting agents (ginsenosides and soyasaponins). Conclusions: The CRC sialylome is associated with tumour phenotypic variation, including immune-excluded states linked to Siglec-associated transcriptional signatures and patterns consistent with non-canonical drug resistance programmes. These findings position the “sugar code” as a central organising principle in CRC and identify glycan-directed therapies as a promising strategy for the targeting of this aggressive subtype. Full article

Colorectal cancer (CRC) remains a major cause of cancer-related death, and resistance to chemotherapy and radiotherapy continues to limit durable disease control. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has therefore emerged as a potential therapeutic strategy. However, models focused solely on glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) do not fully explain why CRC cells differ in their sensitivity to ferroptosis. In this review, we examine how ferroptosis in CRC is shaped by iron trafficking and selenium-dependent antioxidant defense. We first discuss the poly(rC)-binding proteins 1 and 2 (PCBP1/2)-nuclear receptor coactivator 4 (NCOA4) axis, which regulates iron storage, trafficking, and ferritinophagy. We then review the AlkB homolog 8 (ALKBH8)-directed selenoprotein network, which supports the detoxification of lipid peroxides and maintenance of redox homeostasis. We next consider how these two systems intersect and how their interplay influences ferroptosis sensitivity. We also discuss why concurrent disruption of iron handling and selenium-dependent defense mechanisms may enhance therapeutic efficacy. Finally, we outline potential clinical applications, including combination strategies and biomarker development. Full article

Gastrointestinal (GI) malignancies—which comprise esophageal, gastric, colorectal, hepatobiliary, and pancreatic cancers—remain a leading global cause of oncologic morbidity and mortality. The prognosis for many patients (especially those diagnosed with advanced-stage disease) remains poor despite conventional therapies—namely, surgery, chemotherapy, and radiation. Immunotherapy, however, has emerged as a new strategy in oncology, and, in particular, the advent of cancer vaccines now provides an investigational approach to improving clinical outcomes in patients with GI malignancies. This review aims to provide a comprehensive overview of multiple vaccine-based strategies developed to better target GI cancers, spanning from early preclinical studies to the most recently completed clinical trials. We first introduce the main vaccine therapy classes and the immunologic rationale underlying each. We then summarize key findings from past and ongoing trials using a cancer-type-based approach, primarily focusing on vaccine safety and immunogenicity, and commenting on limitations in overall efficacy. Finally, we identify the challenges of applying mostly early-phase trials to clinical practice as well as future directions for integrating these vaccine-based approaches into personalized treatments for GI cancer patients. Full article

Colorectal cancer (CRC) is a digestive tract malignant tumor with a relatively high incidence and mortality rate worldwide. The occurrence and development of CRC are closely associated with disturbances in the gut microbiota. Paraclostridium tenue (synonym Eubacterium tenue) is generally considered a harmless commensal and can be isolated from fecal samples of healthy adults. However, whether this bacterium is a beneficial organism with an antitumor effect is unknown. This study systematically evaluated the anti-CRC effects of P. tenue strain Pt517 on CRC cells in vitro and in the CT26 syngeneic mouse model. Pt517 culture supernatant (Pt517CS) inhibited the proliferation, colony formation, and migration ability of CRC cells; induced cell apoptosis; and altered cell cycle distribution. Daily intragastric administration of Pt517 significantly inhibited tumor growth in mice; increased the expression levels of TNF-α, INF-γ, and CD8 in tumor tissues; and decreased the levels of IL-6, IL-10, and TGF-β. Pt517 intervention significantly modulated the gut microbiota composition with increased relative abundance of Parabacteroides goldsteinii, Lachnospiraceae, and Enterorhabdus caecimuris B7. The long-chain fatty acids (LCFAs), stearic acid and palmitic acid, were increased in the serum of treatment group mice and detected in Pt517CS. Functional verification indicated that stearic acid and palmitic acid directly inhibited the proliferation of CT26 cells in a dose-dependent manner, suggesting that Pt517 might exert its anti-CRC effect by secreting LCFAs. These findings indicate that P. tenue Pt517 is a potential new candidate for the microbial treatment of CRC, which warrants further validation for its safety and efficacy before clinical translation. Full article