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Diagnosis of adenocarcinoma in the liver is a frequent scenario in routine pathology and has a critical impact on clinical decision making. However, rendering a correct diagnosis can be challenging, and often requires the integration of clinical, radiologic, and immunohistochemical information. We present a deep learning model (HEPNET) to distinguish intrahepatic cholangiocarcinoma from colorectal liver metastasis, as the most frequent primary and secondary forms of liver adenocarcinoma, with clinical grade accuracy using H&E-stained whole-slide images. HEPNET was trained on 714,589 image tiles from 456 patients who were randomly selected in a stratified manner from a pool of 571 patients who underwent surgical resection or biopsy at Heidelberg University Hospital. Model performance was evaluated on a hold-out internal test set comprising 115 patients and externally validated on 159 patients recruited at Mainz University Hospital. On the hold-out internal test set, HEPNET achieved an area under the receiver operating characteristic curve of 0.994 (95% CI, 0.989–1.000) and an accuracy of 96.522% (95% CI, 94.521%–98.694%) at the patient level. Validation on the external test set yielded an area under the receiver operating characteristic curve of 0.997 (95% CI, 0.995–1.000), corresponding to an accuracy of 98.113% (95% CI, 96.907%–100.000%). HEPNET surpassed the performance of 6 pathology experts with different levels of experience in a reader study of 50 patients (P =.0005), boosted the performance of resident pathologists to the level of senior pathologists, and reduced potential downstream analyses. We provided a ready-to-use tool with clinical grade performance that may facilitate routine pathology by rendering a definitive diagnosis and guiding ancillary testing. The incorporation of HEPNET into pathology laboratories may optimize the diagnostic workflow, complemented by test-related labor and cost savings. [Display omitted] An innovative artificial intelligence algorithm predicts major forms of hepatic adenocarcinoma using conventional histopathologic slides with clinical grade performance, supporting pathologists in diagnosis making with explainable model decision. [ABSTRACT FROM AUTHOR]

Cancers of the breast, prostate and intestinal tract account for most cancer-associated deaths in humans and represent several of the highest incidence human neoplasms. Therefore, understanding the underlying pathophysiology, including the formation and propagation of these cancers, is key to designing potential treatments. Over the last 50 years or more, genetically engineered mouse models (GEMMs) have been instrumental platforms to our discovery of neoplastic disease as many follow near-identical molecular and histological progression as human tumours. In this mini review, we summarize three key preclinical models and focus on some of the major findings in relation to clinical care. We discuss the MMTV-PyMT (polyomavirus middle T antigen) mouse, TRAMP (transgenic adenocarcinoma mouse prostate) mouse and APCMin (multiple intestinal neoplasm mutation of APC gene) mouse, which mimic breast, prostate and intestinal cancers, respectively. We aim to describe the significant contributions these GEMMs have made to our collective understanding of high-incidence cancers as well as briefly discuss the limitations of each model as a device for therapeutic discovery. [ABSTRACT FROM AUTHOR]

• Increased IDH2 expression strongly associated with the progression of colorectal cancer (CRC) • Decreased IDH2 promotes α-ketoglutarate (α-KG) deposition by suppression of reductive citrate cycle. • Inhibitory IDH2-mediated deposition of α-KG dysregulate energy metabolism in CRC cells. • IDH2 promotes HIF-1A stabilization and facilitates CRC-liver metastasis. • Pharmacotherapy of IDH2 confers protection against CRC in vitro and in vivo. Changes in isocitrate dehydrogenases (IDH) lead to the production of the cancer-causing metabolite 2-hydroxyglutarate, making them a cause of cancer. However, the specific role of IDH in the progression of colon cancer is still not well understood. Our current study provides evidence that IDH2 is significantly increased in colorectal cancer (CRC) cells and actively promotes cell growth in vitro and the development of tumors in vivo. Inhibiting the activity of IDH2, either through genetic silencing or pharmacological inhibition, results in a significant increase in α-ketoglutarate (α-KG), indicating a decrease in the reductive citric acid cycle. The excessive accumulation of α-KG caused by the inactivation of IDH2 obstructs the generation of ATP in mitochondria and promotes the downregulation of HIF-1A, eventually inhibiting glycolysis. This dual metabolic impact results in a reduction in ATP levels and the suppression of tumor growth. Our study reveals a metabolic trait of colorectal cancer cells, which involves the active utilization of glutamine through reductive citric acid cycle metabolism. The data suggests that IDH2 plays a crucial role in this metabolic process and has the potential to be a valuable target for the advancement of treatments for colorectal cancer. [ABSTRACT FROM AUTHOR]

Digestive cancers are frequent and of late diagnosis in Africa. Palliative surgery therefore plays an important role. Our objective is to describe its indications, techniques and results in primary digestive cancers. Retrospective, bicentric, descriptive study of palliative surgery for primary digestive cancer, performed in Ouagadougou over the last twelve years. The results were assessed according to the degree of improvement in the patients' quality of life. We divided the patients into four groups according to the improvement of the quality of life after the operation. The results were considered very satisfactory when the symptoms disappeared completely. They were considered satisfactory when the symptoms decreased in intensity. They were unsatisfactory when the symptoms kept the same intensity. They were considered poor when the symptoms persisted with greater intensity. Six hundred and thirty-nine palliative digestive cancer surgeries were performed. All patients had clinical symptoms deteriorating their quality of life (56.7%) or even a surgical emergency (43.3%). Biliodigestive diversion, gastroentero-anastomosis and colostomy were the palliative procedures performed respectively in 26.6%, 16.9%, and 34.1%. Complications were noted in 11.7%. These were digestive fistulas in 9 cases, retraction and stomal prolapse in 11 cases. The improvement of the quality of life was very satisfactory in 76%. Palliative surgery is widely practiced in digestive cancers. It improves the quality of life. African surgeons should be aware and well-educated to safely perform surgical palliative procedures. [ABSTRACT FROM AUTHOR]

• Provide an overview of the CGAS-STING signaling pathway and activation mechanism, and explore the interaction of this signaling pathway with other pathways. • Exploring the role of the cGAS-STING signaling pathway in various intestinal diseases and research advances. • Summarize current natural products and other substances that target the cGAS-STING signaling pathway for therapeutic effects. • Exploring the effect of gut flora on this signaling pathway. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signal has drawn much consideration due to its sensitivity to DNA in innate immune mechanisms. Activation of the cGAS-STIN signaling pathway induces the production of interferon and inflammatory cytokines, resulting in immune responses, or inflammatory diseases. The intestinal tract is a vital organ for the body's nutrition absorption, recent studies have had various points of view on the job of cGAS-STING pathway in various intestinal sicknesses. Therefore, understanding its role and mechanism in the intestinal environment can help to develop new strategies for the treatment of intestinal diseases. This article examines the mechanism of the cGAS-STING pathway and its function in inflammatory bowel disease, intestinal cancer, and long-injury ischemia-reperfusion, lists the current medications that target it for the treatment of intestinal diseases, and discusses the impact of intestinal flora on this signaling pathway, to offer a theoretical and scientific foundation for upcoming targeted therapies for intestinal disorders via the cGAS-STING pathway. [ABSTRACT FROM AUTHOR]

Inactivation of the Apc gene is a critical early event in the development of sporadic colorectal cancer (CRC). Expression of serine-threonine kinase receptor-associated protein (STRAP) is elevated in CRCs and is associated with poor outcomes. We investigated the role of STRAP in Apc mutation–induced intestinal tumor initiation and progression. We generated Strap intestinal epithelial knockout mice (Strap ΔIEC) by crossing mice containing floxed alleles of Strap (Strap fl/fl) with Villin -Cre mice. Then we generated Apc Min/+; Strap fl/fl; Vill -Cre (Apc Min/+; Strap ΔIEC) mice for RNA-sequencing analyses to determine the mechanism of function of STRAP. We used human colon cancer cell lines (DLD1, SW480, and HT29) and human and mouse colon tumor–derived organoids for STRAP knockdown and knockout and overexpression experiments. Strap deficiency extended the average survival of Apc Min/+ mice by 80 days and decreased the formation of intestinal adenomas. Expression profiling revealed that the intestinal stem cell signature, the Wnt/β-catenin signaling, and the MEK/ERK pathway are down-regulated in Strap-deficient adenomas and intestinal organoids. Correlation studies suggest that these STRAP-associated oncogenic signatures are conserved across murine and human colon cancer. STRAP associates with MEK1/2, promotes binding between MEK1/2 and ERK1/2, and subsequently induces the phosphorylation of ERK1/2. STRAP activated Wnt/β-catenin signaling through MEK/ERK-induced phosphorylation of LRP6. STRAP was identified as a target of mutated Apc and Wnt/β-catenin signaling as chromatin immunoprecipitation and luciferase assays revealed putative binding sites of the β-catenin/TCF4 complex on the Strap promoter. STRAP is a target of, and is required in, Apc mutation/deletion-induced intestinal tumorigenesis through a novel feed-forward STRAP/MEK-ERK/Wnt-β-catenin/STRAP regulatory axis. [Display omitted] A cellular protein that mediates intestinal tumor initiation and progression and that can be targeted for anti-tumor response. [ABSTRACT FROM AUTHOR]

• Extracts from Samoan indigenous species Myristica hypargyraea and Myristica inutilis. • Aril extract of M. hypargyraea possessed the highest anti-staphylococcal activity. • Aril extract of M. inutilis showed the highest selective antiproliferative effect. • Malabaricone A, otobain, licarin A, and licarin B identified as the major components. Hexane extracts derived from the arils and seeds of two Samoan indigenous plant species, Myristica hypargyraea A. Gray and Myristica inutilis Rich ex A. Gray, were assessed for their in vitro anti-staphylococcal effect using a broth microdilution assay. Additionally, their cytotoxic activity against human colon cancer and normal intestinal cell lines was determined. In this study, all plant extracts tested showed a certain degree of growth-inhibitory effect against various strains of Staphylococcus aureus with minimum inhibitory concentrations (MICs) ranging from 8 to 1,024 µg/mL. The aril extract of M. hypargyraea possessed the highest antibacterial activity with MIC value 8 µg/mL against one standard strain and three clinical isolates of S. aureus , the effective concentrations of this extract were found to be safe for the intestinal cells. The aril extract of M. inutilis showed the highest selective antiproliferative effect on intestinal cancer cells with a lower toxicity to normal cell lines. Using gas chromatography-mass spectrometry analysis, malabaricone A, otobain, licarin A, and licarin B were identified as the major components of both the aril and seed extracts of M. hypargyraea and M. inutilis. [ABSTRACT FROM AUTHOR]

The intestine is the well-acknowledged important organ where the nutritional molecules are absorbed. Meanwhile, intestinal ailments, including intestinal mucosal atrophy, barrier dysfunction (leaky gut), inflammation bowel disease (ulcerative colitis and Crohn's disease), irritable bowel syndrome (IBS), dysbacteriosis, and cancers (sporadic and colitis-associated intestinal cancers), have always been the top-ranking diseases that we are confronting. However, although there are several reports on the intestinal modulatory effects for the food macromolecular components (polysaccharides and prebiotics), the effects of low-molecular-weight phytochemicals from foods, especially those from functional foods, on intestinal ailments have not been methodically understood. Various functional foods and their low-molecular-weight phytochemicals that help protect intestinal homeostasis have been demonstrated. The preliminary in vitro results are not included due to the uncertainty of their in vivo efficacy. This review compiles only in vivo bioactive reports and findings with solid pieces of evidence (both human and animal-based ones) to demonstrate the practical use of the food and its low-molecular-weight phytochemicals as complementary therapies or dietary supplements for intestinal health and their underlying mechanism of action. Functional foods (both the whole food and extracts) and their low-molecular-weight phytochemicals can benefit intestinal health of both small and large intestines at different stages of intestinal ailments through promoting intestinal epithelial renewal and barrier function, restoring intestinal flora, inhibiting intestinal inflammation and tumor growth, and exerting intestinal-cancer preventive effects. Therefore, depending on the circumstances of the intestinal ailment, intake of certain functional foods or their low-molecular-weight phytochemicals can relieve the symptom of intestinal ailments and contribute to the maintenance of intestinal homeostasis at different levels. • The effects of foods and their phytochemicals on intestinal homeostasis are summarized. • Only clinical and in vivo results are compiled to assure the credibility of the conclusion in this paper. • Recommendations are suggested with respect to different intestinal ailments. [ABSTRACT FROM AUTHOR]

Inhibition of K-RAS effectors like B-RAF or MEK1/2 is accompanied by treatment resistance in cancer patients via re-activation of PI3K and Wnt signaling. We hypothesized that myotubularin-related-protein-7 (MTMR7), which inhibits PI3K and ERK1/2 signaling downstream of RAS, directly targets RAS and thereby prevents resistance. Using cell and structural biology combined with animal studies, we show that MTMR7 binds and inhibits RAS at cellular membranes. Overexpression of MTMR7 reduced RAS GTPase activities and protein levels, ERK1/2 phosphorylation, c- FOS transcription and cancer cell proliferation in vitro. We located the RAS-inhibitory activity of MTMR7 to its charged coiled coil (CC) region and demonstrate direct interaction with the gastrointestinal cancer-relevant K-RASG12V mutant, favouring its GDP-bound state. In mouse models of gastric and intestinal cancer, a cell-permeable MTMR7-CC mimicry peptide decreased tumour growth, Ki67 proliferation index and ERK1/2 nuclear positivity. Thus, MTMR7 mimicry peptide(s) could provide a novel strategy for targeting mutant K-RAS in cancers. • RAS mutations underlie resistance of gastrointestinal cancers to clinical therapies. • We identified the lipid phosphatase MTMR7 as a novel physiological inhibitor of mutant RAS. • MTMR7 peptide derived from its coiled coil domain stabilized the inactive form of GDP bound K-RAS G12V. • Cell permeable MTRM7-derived peptide mitigated growth of gastric and colorectal cancer in mice. • We may develop new treatments based on the MTMR7-derived peptide for patients with RAS mutant cancers. [ABSTRACT FROM AUTHOR]

Large intestine cancer is one of the most relevant chronic diseases taking place at present. Despite therapies have evolved very positively, this pathology is still under deep investigation. One of the recent approaches is the prevention by natural compounds such as pectin. In this paper, we have assessed the impact of citrus pectin and modified citrus pectin on colorectal cancer in rats (Rattus norvegicus F344) to which azoxymethane and DSS were supplied. The lowest intake of food and body weight were detected in animals fed with citrus pectin, together with an increase in the caecum weight, probably due to the viscosity, water retention capacity and bulking properties of pectin. The most striking feature was that, neither citrus pectin nor modified citrus pectin gave rise to a tumorigenesis prevention. Moreover, in both, more than 50% of rats with cancer died, probably ascribed to a severe dysbiosis state in the gut, as shown by the metabolism and metagenomics studies carried out. This was related to a decrease of pH in caecum lumen and increase in acetate and lactic acid levels together with the absence of propionic and butyric acids. A relevant increase in Proteobacteria (Enterobacteriaceae) were thought to be one of the reasons for enteric infection that could have provoked the death of rats and the lack of cancer prevention. However, a reduction of blood glucose and triacylglycerides level and an increase of Bifidobacterium and Lactobacillaceae were found in animals that intake pectin, as compared to universal and modified citrus pectin feeding. • Effect of citrus pectins was evaluated in an AOM/DSS cancer rat model. • A reduction in weight and blood glucose levels was observed in pectin fed rats. • A high mortality was observed in pectin and modified pectin fed individuals. • pH decrease and high increase in Proteobacteria were observed in these individuals. • Pectin and modified citrus pectin did not reduce the tumorigenesis in the used model. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine drug absorption profile utilizing human intestinal tissues from ulcerative colitis (UC) patients and to compare with normal tissues from intestinal cancer patients. Human intestinal tissues from UC and cancer patients mounted in a mini-Ussing chamber were used to evaluate the permeation of drugs, including FD-4, a very low permeable marker, rebamipide, a low permeable marker, and metoprolol, a high permeable marker. The transport index, an index of sum of permeated and tissue-accumulated molecules, of the model drugs was in accordance with their absorption rank order, and was almost kept constant irrespective of autopsy grade based on tissue fibrosis. On the other hand, UC tissues of grade 2 showed the decreased X corr , an index of permeated amount of molecules and increased T corr , an index of tissue-accumulated molecules for every tested compound. Our finding of the transport characteristics in intestinal tissues of severe UC patients in mini-Ussing chamber system demonstrated that autopsy grade of UC patients did not drastically change membrane permeability of the tested compounds. Furthermore, it was suggested that morphological changes of intestinal tissues caused by fibrosis led to limited permeation and subsequently increased accumulation with little change of total absorption. [ABSTRACT FROM AUTHOR]

Most cancers are caused by somatic mutations. Some common mutations in the same cancer type can form a "signature" to specifically predict the prognosis or to distinguish it from other cancers. In this study, 710 somatic cell mutations were identified in 142 cases, including digestive, lung and urogenital cancers, and the digestive cancers were further divided into liver, stomach, intestinal, esophageal and cardia cancer. The above mutations were located in 166 genes. In addition, a group of high-frequency mutation genes with specific characteristics were screened to form predictive signatures for each cancer. Verification using TCGA suggested that the signatures could predict the stages, progression-free survival, and overall survival of digestive, intestinal, and liver cancers (P < 0.05). The validation cases further confirmed the predictive role of digestive and liver cancers signatures in diagnosis and prognosis. Overall, this study established predictive signatures for different cancer systems and their subtypes. These findings enable a better understanding in cancer genome, and contribute to the personalized diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Intestinal obstructions caused by intestinal tumors pose life-threatening risks to patients. Adjuvant treatment using intestinal stents carrying drug loaded membranes has the advantages of timely relief of intestinal obstruction, as well as effective inhibition of tumor progression. The present work is to develop an intestinal stent loaded with a combination of traditional Chinese medicines capable of good biocompatibility, degradability, sustained drug release and anti-tumor properties. The drug combination extract was obtained from Psoralea corylifolia formula (PCF) and then was loaded into silk fibroin (SF)/polycaprolactone (PCL) fibrous membranes using emulsion electrospinning technology. Results showed that the membrane prepared by emulsion electrospinning technology has apparent core-shell structure, and the mechanical property and hydrophilicity of the membrane are gradually improved with the addition of PCF. Drug sustained release results demonstrated that there were no bursting phenomena, and showed a gradual sustained release up to 400 h. The antitumor efficacy was assessed in vitro using a human colorectal cancer cell line HCT-116 and an epithelial cell line NCM-460. Results showed that this drug-loaded membrane sustained antitumor cell growth performance, indicating its great potential for clinical treatment for intestinal cancer in the near future. [Display omitted] • SF/PCL fibrous membrane carries a combination of traditional Chinese medicines. • The drugs loaded membrane has good biocompatibility & sustained anti-tumor effect. • The core-shell fibrous drug membrane has a gradual sustained release up to 400 h. • Effective antitumor effect in vitro shows potential for treating intestinal cancer. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is associated with complex complications that may lead to tumors. However, research on the mechanisms underlying susceptibility to chronic immune diseases and cancer pathogenesis triggered by the inflammatory environment remains limited. An imbalance in the host gut microbiota often accompanies intestinal inflammation. The delayed recovery of the dysregulated intestinal microbiota may exacerbate systemic inflammatory responses, multiorgan pathology, and metabolic disorders. This delay may also facilitate bacterial translocation. This review examined the relationship between gut barrier disruption and unbalanced microbial translocation and their impact on the brain, liver, and lungs. We also explored their potential roles in tumor initiation. Notably, the role of the intestinal microbiota in the development of inflammation is linked to the immune surveillance function of the small intestine and the repair status of the intestinal barrier. Moreover, adherence to a partially anti-inflammatory diet can aid in preventing the malignant transformation of inflammation by repairing the intestinal barrier and significantly reducing inflammation. In conclusion, enhancing intestinal barrier function may be a novel strategy for preventing and treating chronic malignancies in the intestine and other body areas. [Display omitted] • Intestinal microbial translocation promotes the formation of multiple foci and increases the risk of cancer. • Interleukin (IL)-10 and IL-22 is an important mediator of probiotic repair of the intestinal barrier. • The host's ability to defend the inflammatory response caused by microbiota is related to the small intestine function. • The anti-inflammatory capacity of dietary active substances depends on their ability to repair the intestinal barrier. [ABSTRACT FROM AUTHOR]

The precise role of intestinal ILC3s in cancer remains largely unknown. Published in Cell , Goc et al. describe ILC3 function and plasticity in tumors. ILC3s may lose their identity and thus become either ILC1s or exhausting-ILC3s, which could in turn reshape the gut microbiome for colorectal cancer progression and immunotherapy resistance. [ABSTRACT FROM AUTHOR]

Three articles in Nature show that intestinal stem cells with cancer-promoting mutations could shape the surrounding normal tissue in their favor to promote clonal fixation and field expansion, raising the possibility of developing therapeutic strategies that maintain or enhance the health of normal cells to out-compete the mutant cells. [ABSTRACT FROM AUTHOR]

Intestinal cancer is a disease with high morbidity and high mortality in China. Previous studies have shown that Codonopsis foetens can inhibit cellular autophagy and promote the apoptosis of intestine cancer cells. Based on metabolomics method coupled with liquid chromatography-mass spectrometry (LC-MS) technology, we aimed to analyze intestinal small molecule metabolites in the intestinal cancer model group and the Codonopsis foetens treated group. Principal component analysis (PCA) and Partial Least Squares (PLS-DA) were used to identify the pattern of the data. And the metabolic characteristics of the cancer model group were explored based on the metabolic differences between the groups. Multivariate statistical analysis revealed that metabolites presented with differences included: Acetamide, Phosphoric acid, Hydrogen sulfite, Pyruvic acid, Cytosine, 2-Hydroxypyridine, Phosphoric acid, Uracil, Gamma-Aminobutyric acid, Glycerol alpha-monochlorohydrin, Thiosulfic acid, L-Valine, Cysteamine, Taurine, Creatine, Homocysteine, Hypoxanthine, Se-Methylselenocysteine, 5-Hydroxymethyluracil, Oxoglutaric acid, LysoPC(20:0), LysoPC(22:4(7Z,10Z,13Z,16Z)), LysoPC(18:2(9Z,12Z)), LysoPC(16:1(9Z)), LysoPE(0:0/16:0), LysoPE(0:0/18:2(9Z,12Z)), LysoPE(18:0/0:0), LysoPE(20:1(11Z)/0:0), etc. Combined with metabolic pathway analysis, pathways presented with differences included: Citrate cycle (TCA cycle), ABC transporters, 2-Oxocarboxylic acid metabolism, Taurine and hypotaurine metabolism, Butanoate metabolism), Phenylalanine, tyrosine and tryptophan biosynthesis, Biosynthesis of amino acids, Protein digestion and absorption, Aminoacyl-tRNA biosynthesis, C5-Branched dibasic acid metabolism, GABAergic synapse, Proximal tubule bicarbonate reclamation, Mineral absorption, Phenylalanine metabolism. The results showed that the proliferation of intestinal cancer cells caused cell metabolism disorders, manifesting as changes in metabolic pathways and resulting in changes in metabolites. [ABSTRACT FROM AUTHOR]

Nanoparticles (NP) have gained importance as drug delivery systems for pharmaceutical challenging drugs. Their size properties allow passive targeting of cancer tissue by exploiting the enhanced permeability and retention (EPR) effect. Furthermore, surface modifications enable an active drug targeting for diseased regions in the human body. Besides the advantages, the drug release from commonly used biodegradable NP is mostly depending on physiological circumstances. Hence, there is a need for a more controllable drug release. The use of light-responsive polymers is an innovative conception enabling a more distinct drug release by an external light stimulus. The idea provides potential for an increase in efficiency and safety of local therapies. In this study, innovative light-sensitive NP were investigated for a photodynamic therapy (PDT) of gastrointestinal tumors. Nanoparticles based on a newly developed light-responsive polycarbonate (LrPC) and poly(lactic-co-glycolic-acid) (PLGA) were loaded with the approved photosensitizer 5,10,15,20-tetrakis(m -hydroxyphenyl)chlorin (m THPC). Mucus penetrating properties were obtained by surface PEGylation of the nanoparticles either by using LrPC in combination with a PEGylated PLA (PEG-PLA) or by a combination with PEGylated LrPC (LrPC-PEG). Cytotoxic potential in dependency of a light-induced drug release was investigated in different cytotoxicity assays. Intracellular accumulation in mucus producing colon-carcinoma cell line HT-29-MTX was analysed by HPLC and confocal laser microscopy. [ABSTRACT FROM AUTHOR]

Abstract Over the last years nanoparticles (NP) have become a promising vehicle as drug delivery systems for photodynamic therapy (PDT), combining the advantages of an effective drug transport to the target cells and the reduction of undesired side effects. The in vitro evaluation of new nanoparticulate formulations has become a rising problem since cell culture models differ from the in vivo situation of the human body to a large extent. Particularly, in case of gastrointestinal tumors, after peroral application nanoparticles are challenged by overcoming the mucus layer as a first physical barrier before reaching the target cells, an aspect often neglected in literature. However, the presence of mucus is crucial for in vitro models to evaluate mucus-penetrating potential of surface-modified nanoparticulate drug carrier systems. Biodegradable poly(dl -lactide- co -glycolide) (PLGA) NP loaded with the model photosensitizer 5,10,15,20-tetrakis(m -hydroxyphenyl)porphyrin (m THPP) were surface modified with either poly(ethylene glycol) (PEG) or chitosan (CS) to gain mucus-penetrating or mucoadhesive particle properties. All NP systems were compared to each other and to free m THPP regarding cytotoxicity and cellular uptake in HT-29 cells and mucus producing HT-29-MTX cells. For PEGylated m THPP-PLGA-PEG-NP a significantly higher accumulation was obtained in HT-29-MTX cells compared to all other tested nanoparticles and the free drug. Additionally, a mucus-containing Transwell® model, consisting of HT-29-MTX cells, confirmed these results, representing a promising in vitro screening method for mucus-penetrating particle properties. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Nanoparticles based on biodegradable polymers are well-known as approved carrier systems for a diversity of drugs. Despite their advantages, such as the option of an active drug targeting or the physicochemical protection of instable payloads, the controlled drug release often underlies intra- and interindividual influences and is therefore difficult to predict. To circumvent this limitation, the release behavior can be optimized using light-responsive materials for the nanoparticle preparation. The resulting light-responsive nanoparticles are able to release the embedded drug after an external light-stimulus, thereby increasing efficacy and safety of the therapy. In the present study light-responsive self-immolative polymers were used for the nanoparticle manufacturing. Light-responsive polycarbonates (LrPC) as well as PEGylated LrPC (LrPC-PEG) were synthesized via ring-opening polymerization of trimethylene carbonate-based monomers and fully physico-chemically characterized. Light-responsive nano formulations were obtained by blending LrPC or (LrPC-PEG) with the FDA-approved polymer poly(DL-lactide- co -glycolide) (PLGA). The nanoparticles were loaded with the photosensitizer 5,10,15,20-tetrakis(m -hydroxyphenyl)chlorin (m THPC). The light-induced nanoparticle degradation was analyzed as well as the drug release behavior with and without illumination. Furthermore, biological safety of the degradation products was investigated in an in vitro cell culture study. [ABSTRACT FROM AUTHOR]

Abstract The ApcMin/+ mouse, carrying an inactivated allele of the adenomatous polyposis coli (Apc) gene, is a widely used animal model of human colorectal tumorigenesis. While crossed with other gene knockout or knock-in mice, these mice possess advantages in investigation of human intestinal tumorigenesis. Intestinal tumor pathogenesis involves multiple gene alterations; thus, various double gene deficiency models could provide novel insights into molecular mechanisms of tumor biology, as well as gene-gene interactions involved in intestinal tumor development and assessment of novel strategies for preventing and treating intestinal cancer. This review discusses approximately 100 double gene deficient mice and their associated intestinal tumor development and progression phenotypes. The dual gene knockouts based on the Apc mutation background consist of inflammation and immune-related, cell cycle-related, Wnt/β-catenin signaling-related, tumor growth factor (TGF)-signaling-related, drug metabolism-related, and transcription factor genes, as well as some oncogenes and tumor suppressors. Future studies should focus on conditional or inducible dual or multiple mouse gene knockout models to investigate the molecular mechanisms underlying intestinal tumor development, as well as potential drug targets. [ABSTRACT FROM AUTHOR]

Abstract Background Primary cutaneous peripheral T-cell lymphomas (PC-PTCLs) are classified into mycosis fungoides (MF) and other rare specific types; and those do not fit into any specific entities are designated as PTCL, not otherwise specified (NOS), an aggressive neoplasm. Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is an aggressive primary intestinal T-cell lymphoma with enteropathy in the non-neoplastic mucosa. We report a rare case of PC-PTCL-NOS with a late relapse solely in the ileum after complete remission. We discuss the importance of evaluating enteropathy, megakaryocyte-associated tyrosine kinase (MATK) immunostaining, and the implication of clonal relationship of metachronous lymphomas. Case report We reviewed the histopathology and immunohistochemistry of the skin tumor from a 68-year-old female and the relapsed intestinal T-cell lymphoma. The tumor cells "trans-regressed" from large and pleomorphic in the skin to small/medium-sized cells with clear cytoplasm in the ileum; and furthermore, there was immunophenotypic alteration. However, there was no enteropathy in the non-tumoral ileal mucosa adjacent to the tumor proper and both the cutaneous and ileal tumors were negative for MATK. Clonality study showed clonal TRG and TRB rearrangement with identical band sizes of the amplicons, confirming primary cutaneous tumor with a late relapse in the ileum. Conclusions Although PC-PTCL-NOS is an aggressive neoplasm, rare cases such as this might have a long-term survival. Furthermore, the late relapse mimicking MEITL is intriguing and exceptional, in spite the fact that MEITL is a primary intestinal T-cell lymphoma with a typical histopathology and immunophenotype. Detailed clinicopathological and molecular studies are mandatory to elucidate the clonal relationship of metachronous lymphomas, as this has important clinical implication for treatment. Evaluation of the non-tumoral intestinal mucosa for enteropathy and immunostaining for MATK might help to differentiate a mimicker from a true MEITL. [ABSTRACT FROM AUTHOR]

Abstract We have compared the anti-proliferative activity in vitro, of R 2 SnGala (1-3) [R = Me, n-Bu, Ph] and novel R 3 SnGala (4 , 5) [R = Me, n-Bu] with D-(+)-Galacturonic acid [HGala; Galaq-, q = (2) and (1) for R 2 SnGala and R 3 SnGala, respectively] compounds, towards human tumor cell lines of intestinal carcinoma (HCT-116) and breast adenocarcinoma (MCF-7). The new synthesized 4 and 5 compounds were characterized, in solution, by 1H, 13C and 119Sn NMR, that showed that HGala acts as monoanionic moiety and evidenced the dynamic behavior of the compounds, due to inter-conversions involving the anomeric carbon atom of the ligand. Cell viability, apoptosis induction and cell cycle distribution were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay and flow cytometry, respectively. The cytotoxicity of the compounds, in the micro-submicromolar range, changed in the order of the organotin(IV) moieties, according to 5 > 3 > 2 , while 1 and 4 , containing Me n Sn(IV) (n = 2,3) moieties, were ineffective. Compound 5 showed peculiar cytotoxic effects. It did not cause time dependent inhibition of cell growth nor accumulated into the cells. Cell death induced by the active 2 , 3 , and 5 , was shown to be apoptotic by measuring the exposure of phosphatidylserine to the outer membrane and the loss of mitochondrial potential. All the cytotoxic compounds induced an accumulation of cells in the subG0/G1phase, while only 2 and 3 perturbed the cell cycle confining viable cells in G0/G1phase. Finally, none of the compounds investigated affected the viability of normal intestinal or liver cells, indicating selectivity towards tumor cells. Graphical abstract Di- and tri-organotin(IV) compounds with D-Galacturonic acid showed higher anti-proliferative activity, compared to cisplatin, towards MCF-7 or HCT-116 cell lines, while they were ineffective towards normal-like differentiated Caco-2 and Chang liver cells. Unlabelled Image Highlights • Two organotin(IV) compounds with D-(+)-galacturonic acid synthesized and characterized. • Antiproliferative activity of di- and tri-organotin(IV) – galacturonate compounds tested. • Superior activity of three of the tested compounds relative to cis-platin established. • The compounds studied are then proposed as promising organometallic-based drugs. [ABSTRACT FROM AUTHOR]

Cancer diagnosis and treatment have been of broad interest among scientists in the last decades due to the high death rate, widespread occurrence, and recurrence after treatment. The survival rate of cancer patients depends greatly on early detection and appropriate treatments. Therefore developing new technologies applicable to sensitive and specific methods of cancer detection is an inevitable task for cancer researchers. Abnormal miRNA expression is contributed to severe diseases such as cancers and since their expression level and type differ strictly during carcinogenesis and later metastasis and treatments, the improved detection accuracy of these miRNAs would undoubtedly lead to early diagnosis, prognosis, and targeted therapy. Biosensors are accurate and straightforward analytical devices that have had practical applications especially in the last decade. Their domain is still growing through a combination of attractive nanomaterials and amplification methods, leading to innovative biosensing platforms for the efficient detection of miRNAs as diagnostic and prognostic biomarkers. In this review, we will provide the recent developments in biosensors to detect intestine cancer miRNA biomarkers and also discuss the challenges and outcomings of this field. • Intestinal cancer is one of the commonly diagnosed cancers and leading cause of death worldwide. • The feasibility of miRNAs as promising cancer biomarkers was confirmed. • Rapid and sensitive detection of miRNAs is helpful for early detection of intestine cancer. • The emergence of biosensors provides a cheap, sensitive, less invasive tool for detecting miRNA biomarkers. • Improvements in the detection approaches for intestinal miRNAs are reviewed here. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is an auspicious therapy approach for the treatment of cancer. Despite its numerous benefits, the drug delivery of the used photosensitizer (PS) to target locations inside the human body remains a main therapy challenge, since the standard intravenous PS injection often causes systemic side-effects. To circumvent this therapy drawback, the oral application represents a promising administration alternative. Especially for the treatment of intestinal cancer it offers the possibility of a local treatment with a reduced likelihood for adverse drug reactions. To establish a suitable drug delivery system for intestinal PDT, we developed nanoparticles (NP) of the biodegradable and biocompatible polymer poly(lactic-co-glycolic) acid (PLGA), loaded with the model PS 5,10,15,20-tetrakis(m-hydroxyphenyl)porphyrin ( m THPP). By functionalizing the particle surface with either poly(ethylene glycol) (PEG) or chitosan (CS), mucus-penetrating or mucoadhesive properties were obtained. These particle characteristics are important to enable an overcoming of the intestinal mucus barrier and thus lead to a PS accumulation close to and in the target cells. In permeation studies with a biosimilar mucus and in cell culture experiments with mucus-covered Caco-2 cells, PEG-modified NP were identified as a superior drug vehicle for an intestinal PDT, compared to surface unmodified or mucoadhesive NP. [ABSTRACT FROM AUTHOR]

Objectives: To investigate immunohistochemical predictors for intestinal and pancreatobiliary types of adenocarcinoma of ampulla of Vater and identify clinicopathological characteristics associated with the histological types and patient survival.Methods: Immunohistochemical markers included MUC1, MUC2, MUC5AC, CDX2, CK7, and CK20. The data were analyzed by univariate and multivariate methods. The two-step cluster method was used to determine the best immunohistochemical markers to discriminate the intestinal from the pancreatobiliary type.Results: This study identified 9 (33.3%) intestinal and 21 (66.7%) pancreatobiliary tumors. CK7 and CDX2 achieved the highest value (= 1) as predictor markers, while CK20, MUC1, and MUC2 showed degrees of importance equal to 0.77, 0.71, and 0.68, respectively. MUC5AC did not reach 0.50 of importance. In the univariate analysis, lymph node involvement, staging (TNM), and angiolymphatic and perineural invasions were associated with histological types. The independent clinicopathological variable in the multivariate model to predict the histological type was angiolymphatic invasion (p = 0.005), OR = 17 (95% CI 2.33 to 123.83). The final model showed positive nodes (N1) associated with shorter survival (HR = 9.5; p = 0.006). Overall survival at 12, 36, and 60 months was 88.5, 67.0, and 47.6%, respectively.Conclusions: CDX2 and CK7 were the immunohistochemical markers that best discriminated the intestinal from the pancreatobiliary type. Lymph node involvement had a high impact on survival and proved to be more frequent in the pancreatobiliary type. [ABSTRACT FROM AUTHOR]

Oncogenic BRAF V600E mutation confers constitutive activation for the kinase and is closely related to the pathogenesis of metastasic bowel cancer (MBC). Here, the V600E-induced conformational change in MBC BRAF kinase domain is characterized systematically at structural, energetic and dynamic levels. The mutation is observed to cause a conformational conversion of the kinase’s activation loop from DFG-out to DFG-in, thus activating the kinase. Electrostatic force is primarily responsible for the conformational conversion and stabilization of DFG-in associated with the mutation. Molecular docking calculations are employed to analyze the binding mode difference of mutant-selective inhibitors between the DFG-out and DFG-in conformations of BRAF kinase. It is revealed that the mutation can reshape inhibitor selectivity profile by altering kinase loop conformation. Several compounds are determined to have a high or moderate selectivity for mutant over wild-type kinase. The selectivity is primarily originated from hydrogen bond interactions of inhibitor ligands with mutant rather than wild type due to the conformational difference in kinase domain. [ABSTRACT FROM AUTHOR]

Artificial intelligence (AI) algorithms and their application to disease detection and decision support for healthcare professions have greatly evolved in the recent decade. AI has been widely applied and explored in gastroenterology for endoscopic analysis to diagnose intestinal cancers, premalignant polyps, gastrointestinal inflammatory lesions, and bleeding. Patients' responses to treatments and prognoses have both been predicted using AI by combining multiple algorithms. In this review, we explored the recent applications of AI algorithms in the identification and characterization of intestinal polyps and colorectal cancer predictions. AI-based prediction models have the potential to help medical practitioners diagnose, establish prognoses, and find accurate conclusions for the treatment of patients. With the understanding that rigorous validation of AI approaches using randomized controlled studies is solicited before widespread clinical use by health authorities, the article also discusses the limitations and challenges associated with deploying AI systems to diagnose intestinal malignancies and premalignant lesions. • Article highlights the trends in intestinal polyp identifications, characterization and prediction of colorectal cancer. • Summarises AI-based prediction models with performance indicators that may assist doctors to diagnose, prognose, and treat patients. • Future challenges with artificial intelligence in large-scale clinical uses beyond restricted clinical studies. [ABSTRACT FROM AUTHOR]

Introduction Information on primary small intestinal lymphoma is more limited than for gastric lymphoma because most of the previous studies did not focus on the former. Few prognostic indicators in primary intestinal lymphoma have been reliably established because of limited patient numbers and variations in criteria for patient selection. In this study, we retrospectively reviewed the clinical and pathological characteristics of small intestinal lymphoma cases from our hospital, to determine prognostic factors and to clarify the effect of surgical resection on prognosis. Methods Eighty-two patients were enrolled in this retrospective study between January 1997 and December 2012. Patients were divided into two groups based on whether or not they underwent surgical management. Gross resection was defined as complete removal of the primary lesion(s), as confirmed by the naked eye. Combined therapy refers to concurrent surgery and chemotherapy. The clinicopathological characteristics and long-term outcomes of patients were analyzed and compared between the two groups. Results Most of the patients had abdominal pain (75.6%), and some had loss of body weight (29.3%) and bowel perforation (22.0%). Sixty-two patients (75.6%) underwent surgical management. Patients in the surgery group presented with fewer B symptoms (fever, night sweats, and weight loss; P = 0.035) but more bulky disease ( P = 0.009). The ileocecal region was the most common site of solitary involvement (34.1%). The most common reason for surgery was for tumor-related complications (61.3%). Seven patients (11.3%) developed major complications of surgery, but these were not related to the indication, timing, or type of surgery. Only major surgical complications were statistically significant in relation to early mortality ( P = 0.004). The estimated 5-year progression-free survival (PFS) was 35.1% and 5-year overall survival (OS) was 43.2%. Univariate analysis revealed that patients in the surgery group had improved 5-year PFS ( P = 0.028). T-cell lymphoma, involvement of multiple gastrointestinal regions and extranodal involvement, higher scores for International Prognostic Index (IPI), more advanced Ann Arbor stage, lactate dehydrogenase (LDH) levels above 215 U/L, and management without combined therapy were prognostic for shorter PFS and OS in univariate analyses. Individuals who received R0 resection or gross resection had improved 5-year PFS and OS. Cox regression analysis demonstrated that primary T-cell lymphoma was an independent negative prognostic factor for both OS and PFS. Conclusion Combined therapy is an independent prognostic factor for long-term survival in small intestinal lymphoma. Gross resection is recommended in patients with small intestinal lymphoma and leads to improved PFS without significantly increasing the risk of complications. Emergency surgery does not lead to poor prognosis. However, caution is warranted in the management of all patients, because of the high risk of post-operative complications and potential for early mortality. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are innate immune receptors for sensing microbial molecules and damage-associated molecular patterns released from host cells. Double-stranded RNA and the synthetic analog polyinosinic:polycytidylic acid (poly(I:C)) bind and activate TLR3. This stimulation leads to recruitment of the adaptor molecule TRIF (Toll/IL-1 resistance (TIR) domain-containing adapter-inducing interferonβ) and activation of the transcription factors nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF-3), classically inducing IFNβ production. Here we report that, unlike non-metastatic intestinal epithelial cells (IECs), metastatic IECs express TLR3 and that TLR3 promotes invasiveness of these cells. In response to poly(I:C) addition, the metastatic IECs also induced the chemokine CXCL10 in a TLR3-, TRIF-, and IRF3-dependent manner but failed to produce IFNβ. This was in contrast to healthy and nonmetastatic IECs, which did not respond to poly(I:C) stimulation. Endolysosomal acidification and the endosomal transporter protein UNC93B1 was required for poly(I:C)-induced CXCL10 production. However, TLR3-induced CXCL10 was triggered by immobilized poly(I:C), was only modestly affected by inhibition of endocytosis, and could be blocked with an anti-TLR3 antibody, indicating that TLR3 can still signal from the cell surface of these cells. Furthermore, plasma membrane fractions from metastatic IECs contained both full-length and cleaved TLR3, demonstrating surface expression of both forms of TLR3. Our results imply that metastatic IECs express surface TLR3, allowing it to sense extracellular stimuli that trigger chemokine responses and promote invasiveness in these cells. We conclude that altered TLR3 expression and localization may have implications for cancer progression. [ABSTRACT FROM AUTHOR]

Western-type diet (WD) is a risk factor for colorectal cancer, but the underlying mechanisms are poorly understood. We investigated the interaction of WD and heterozygous mutation in the Apc gene on adenoma formation and metabolic and immunological changes in the histologically normal intestinal mucosa of ApcMin/+ (Min/+) mice. The diet used was high in saturated fat and low in calcium, vitamin D, fiber and folate. The number of adenomas was twofold higher in the WD mice compared to controls, but adenoma size, proliferation or apoptosis did not differ. The ratio of the Min to wild-type allele was higher in the WD mice, indicating accelerated loss of Apc heterozygosity (LOH). Densities of intraepithelial CD3ε+ T lymphocytes and of mucosal FoxP3+ regulatory T cells were higher in the WD mice, implying inflammatory changes. Western blot analyses from the mucosa of the WD mice showed suppressed activation of the ERK and AKT pathways and a tendency for reduced activation of the mTOR pathway as measured in phosphoS6/S6 levels. The expression of pyruvate dehydrogenase kinase 4 was up-regulated in both mRNA and protein levels. Gene expression analyses showed changes in oxidation/reduction, fatty acid and monosaccharide metabolic pathways, tissue organization, cell fate and regulation of apoptosis. Together, our results suggest that the high-risk Western diet primes the intestine to tumorigenesis through synergistic effects in energy metabolism, inflammation and oxidative stress, which culminate in the acceleration of LOH of the Apc gene. [ABSTRACT FROM AUTHOR]

[Display omitted] Upon exposure to internal or external stressors, ribosomes stand sentinel via modulation of ribosome assembly and protein translation. Ribosome-dependent cellular dysfunctions have been associated with pathophysiological processes during inflammation and tumorigenesis. In the present study, ribosome biogenesis was assessed to determine its effects on tumor chemokines, potentially contributing to cancer cell malignant features. In particular, ribosome biogenesis inhibition by antibiotic actinomycin D (ActD) enhanced the expression of chemokines in intestinal cancer cells under endoplasmic reticulum stress that governs multiple pro-tumoral reprogramming. Mechanistically, ribosome biogenesis inhibition superinduced proinflammatory chemokines via transcriptional and post-transcriptional regulation. Moreover, ribosomal stress-responsive p53 and its target macrophage inhibitory cytokine 1 (MIC-1) mediated chemokine superinduction by activating TGF-β–activated kinase 1 (TAK-1) and nuclear factor-kappa B (NF-κB) in intestinal cancer cells. Cancer cell-based regulation of chemokine induction via MIC-1 signaling was verified using clinical transcriptome datasets. Clinical tumor tissue-derived MIC-1 was a positive regulator of chemokines and genes involved in the ribosome biogenesis pathway, supporting the in vitro assessments. Moreover, MIC-1-correlated chemokine expressions predicted poor prognoses in patients with colorectal cancer. Ribosome-based chemokine regulation via MIC-1 signaling would provide novel insights into translational interventions against malignant inflammatory insults. [ABSTRACT FROM AUTHOR]

Objective: This paper reviewed the relationship between non-clinical, client-oriented promotional campaigns to raise bowel cancer awareness and screening engagement.Method: An integrative literature review using predefined search terms was conducted to summarise the accumulated knowledge. Data was analysed by coding and categorising, then synthesized through development of themes.Results: Eighteen of 116 studies met inclusion criteria. Promotional campaigns had varying impact on screening uptake for bowel cancer. Mass media was found to moderately increase screening, predominately amongst "worried well". Small media used in conjunction with other promotional activities, thus its effect on screening behaviours was unclear. One-on-one education was less effective and less feasible than group education in increasing intention to screen. Financial support was ineffective in increasing screening rates when compared to other promotional activities. Screening engagement increased because of special events and celebrity endorsement.Conclusion: Non-clinical promotional campaigns did impact uptake of bowel cancer screening engagement. However, little is evident on the effect of single types of promotion and most research is based on clinician-directed campaigns.Practice Implications: Cancer awareness and screening promotions should be implemented at community and clinical level to maximize effectiveness. Such an approach will ensure promotional activities are targeting consumers, thus strengthening screening engagement. [ABSTRACT FROM AUTHOR]

Phosphatidylcholine (PC) is the most abundant phospholipid in intestinal mucus, indicative of a specific transport system across the mucosal epithelium to the intestinal lumen. To elucidate this transport mechanism, we employed a transwell tissue culture system with polarized CaCo2 cells. It was shown that PC could not substantially be internalized by the cells. However, after basal application of increasing PC concentrations, an apical transport of 47.1 ± 6.3 nmol h − 1 mM PC − 1 was observed. Equilibrium distribution studies with PC applied in equal concentrations to the basal and apical compartments showed a 1.5-fold accumulation on the expense of basal PC. Disruption of tight junctions (TJ) by acetaldehyde or PPARγ inhibitors or by treatment with siRNA to TJ proteins suppressed paracellular transport by at least 50%. Transport was specific for the choline containing the phospholipids PC, lysoPC and sphingomyelin. We showed that translocation is driven by an electrochemical gradient generated by apical accumulation of Cl − and HCO 3 − through CFTR. Pretreatment with siRNA to mucin 3 which anchors in the apical plasma membrane of mucosal cells inhibited the final step of luminal PC secretion. PC accumulates in intestinal mucus using a paracellular, apically directed transport route across TJs. [ABSTRACT FROM AUTHOR]

Glyoxal is formed endogenously and at a higher rate in the case of hyperglycemia. Glyoxal is also a food processing contaminant and has been shown to be mutagenic and genotoxic in vitro. The tumourigenic potential of glyoxal was investigated using the multiple intestinal neoplasia (Min) mouse model, which spontaneously develops intestinal tumours and is susceptible to intestinal carcinogens. C57BL/6J females were mated with Min males. Four days after mating and throughout gestation and lactation, the pregnant dams were exposed to glyoxal through drinking water (0.0125%, 0.025%, 0.05%, 0.1%) or regular tap water. Female and male offspring were housed separately from PND21 and continued with the same treatment. One group were only exposed to 0.1% glyoxal from postnatal day (PND) 21. There was no difference in the number of intestinal tumours between control and treatment groups. However, exposure to 0.1% glyoxal starting in utero and at PND21 caused a significant increase in tumour size in the small intestine for male and female mice in comparison with respective control groups. This study suggests that glyoxal has tumour growth promoting properties in the small intestine in Min mice. [ABSTRACT FROM AUTHOR]

Epidemiological studies have linked increased incidence of inflammatory diseases and intestinal cancers in the developed parts of the world to the consumption of diets poor in dietary fibers and rich in refined carbohydrates. Gut bacteria residing in the intestinal lumen exclusively metabolize dietary fibers. Butyrate, propionate and acetate, which are collectively called short-chain fatty acids (SCFAs), are generated by fermentation of dietary fibers by gut microbiota. Evidences indicate that SCFAs are key players in regulating beneficial effect of dietary fibers and gut microbiota on our health. SCFAs interact with metabolite-sensing G protein-coupled receptors GPR41, GPR43 and GPR109A expressed in gut epithelium and immune cells. These interactions induce mechanisms that play a key role in maintaining homeostasis in gut and other organs. This review summarizes the protective roles of GPR41, GPR43 and GPR109A in dietary fibers-, gut microbiota- and SCFAs-mediated suppression of inflammation and carcinogenesis in gut and other organs. [ABSTRACT FROM AUTHOR]

Background & Aims MUTYH-associated polyposis (MAP) is similar to familial adenomatous polyposis (FAP), in that it increases the risk for duodenal adenomas and cancer. Almost all patients with FAP develop duodenal adenomas and 5% develop duodenal cancer. Little is known about the prevalence of duodenal adenomas and cancer in patients with MAP, but current surveillance recommendations are the same for patients with FAP—they should begin surveillance when they are 25 years old. We aimed to assess the prevalence, extent, and progression of duodenal adenomas in patients with MAP and evaluate upper gastrointestinal tract surveillance recommendations. Methods In a retrospective study, we collected data on all patients (n = 92) with MAP undergoing surveillance esophagogastroduodenoscopy from registries at St Mark’s Hospital (London, UK) and the Academic Medical Center (Amsterdam, The Netherlands) from 2002 through 2014. We collected information on adenoma development, age at adenoma detection, interventions, and disease progression. Results Duodenal adenomas were detected in 31 patients (34%), at a median age of 50 years. When duodenal polyposis first was detected, it was Spigelman stages I or II in 84% of patients; most had few small polyps, without high-grade dysplasia or villous features. Subsequent esophagogastroduodenoscopy evaluation of 18 of these patients found that 14 (78%) had Spigelman stages 0 to II disease (median follow-up period, 7.8 y). Disease progressed in stage in 6 patients, over 9.5 years, because of lesion size or villous features (2 reached stage IV disease). Adenomas were down-staged in 8 patients after biopsy or polypectomy analyses, and were unchanged for 3 patients. Conclusions In a data analysis from 92 patients with MAP, duodenal polyposis seemed to develop less frequently than in patients with FAP, and developed at a later age. Increasing lesion size and villous change appear to promote adenoma progression, rather than polyp number or dysplasia. It may be time to consider a new staging system for patients with MAP, to better determine disease severity and surveillance strategies. [ABSTRACT FROM AUTHOR]

Purpose: There are uncertainties associated with the prediction of colorectal cancer (CRC) risk from highly energetic heavy ion (HZE) radiation. We undertook a comprehensive assessment of intestinal and colonic tumorigenesis induced after exposure to high linear energy transfer (high-LET) HZE radiation spanning a range of doses and LET in a CRC mouse model and compared the results with the effects of low-LET γ radiation.Methods and Materials: Male and female APC(1638N/+) mice (n=20 mice per group) were whole-body exposed to sham-radiation, γ rays, (12)C, (28)Si, or (56)Fe radiation. For the >1 Gy HZE dose, we used γ-ray equitoxic doses calculated using relative biological effectiveness (RBE) determined previously. The mice were euthanized 150 days after irradiation, and intestinal and colon tumor frequency was scored.Results: The highest number of tumors was observed after (28)Si, followed by (56)Fe and (12)C radiation, and tumorigenesis showed a male preponderance, especially after (28)Si. Analysis showed greater tumorigenesis per unit of radiation (per cGy) at lower doses, suggesting either radiation-induced elimination of target cells or tumorigenesis reaching a saturation point at higher doses. Calculation of RBE for intestinal and colon tumorigenesis showed the highest value with (28)Si, and lower doses showed greater RBE relative to higher doses.Conclusions: We have demonstrated that the RBE of heavy ion radiation-induced intestinal and colon tumorigenesis is related to ion energy, LET, gender, and peak RBE is observed at an LET of 69 keV/μm. Our study has implications for understanding risk to astronauts undertaking long duration space missions. [ABSTRACT FROM AUTHOR]

[Display omitted] • The digestible nanofiber hydrogel promotes intestinal peristalsis and maintains intestinal flora balance. • The CDDP@SulBC hydrogel presents an excellent anti-tumor efficacy and reduction of irradiation-induced ulcerative colitis. • The CDDP@SulBC hydrogel shows great performance in CT imaging and sensitivity to the intestinal reductive environment. • The radiosensitive CDDP@SulBC hydrogel provides a promising strategy for chemo-radiotherapy of intestinal cancer. Although various types of radiosensitive nanoplatforms are explored to enhance radiotherapy, digestible and radiosensitive nanofiber hydrogel with sensitive responsiveness to the intestinal environment, greatly amplified radiation-induced intestinal tumor destruction, as well as the ability to regulate gut microbiome is still demanded. Herein, sulfhydryl crosslinked bacterial cellulose hydrogel (SulBC gel) was synthesized through silylation and oxidation reaction. Anticancer drug, cis -dichlorodiamineplatinum (CDDP) is loaded into the hydrogel (CDDP@SulBC gel) for precision radiotherapy of intestinal cancer. The CDDP@SulBC gel selectively degrades and consequently exhibits an accelerated drug release behavior in reductive environments. Meanwhile, the CDDP@SulBC gel can increase X-ray-induced double-strand breaks, induce G2/M phase arrest, and enhance the radio-sensitivity to intestinal tumor cells. Upon intragastric administration of CDDP@SulBC gel, the hydrogel is noninvasively monitored in the gastrointestine by micro-CT imaging contributed to the relative high Z -element of silicon and shows an excellent anti-tumor efficacy under X-ray-irradiation of the human intestinal cancer xenograft nude mice. Additionally, the hydrogel can also elevate the ratio of Bacteroidetes / Firmicutes and reconstruct gut microbiome balance, benefiting to the reduction of colitis induced by irradiation. This work thus presents a digestible nanofiber hydrogel-based radiosensitizer with in vivo micro-CT imaging, intestine-specific decomposition/drug release profiles, and great efficacy in chemo-radiotherapy of cancer. [ABSTRACT FROM AUTHOR]

Four varieties of common beans, Negro 8025 (N), Bayo Victoria (BV), Pinto Durango (PD), and Pinto Saltillo (PS) were evaluated and compared for phenolic composition, antioxidant activity and anti-inflammatory effects by in vitro human intestinal cell model. Beans were processed by canning and boiling in open pot. Acetone/Water extracts were analyzed for phenolic composition by HPLC-PAD and HPLC-MS, screened for antioxidant activities, as lipid peroxidation inhibition and chelating capacities by inhibition of deoxi-D-ribose degradation. It was investigated their anticarcinogenic effect by inhibiting cell proliferation, decreasing interleukin-8 (IL-8), modulating interleukin-10 (IL-10), inhibiting tumor necrosis factor alpha (TNFα) and regulating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ). Canning induced antioxidant compounds in order N > PD > BV > PS associated with potential for scavenging hydroxyl radicals and metal chelating capacities. Effect of cooking on bioactive compounds was cultivar dependent, being more quantitative than qualitative due to release of bonded phenolics. Inhibition of cyclooxygenase-2 (COX-2), TNFα and NF-κβ was observed, and the induced expression of IL-10. Both effects were also cultivar and process dependent, particularly in PD beans. [ABSTRACT FROM AUTHOR]

Microbiota on the mucosal surfaces of the gastrointestinal (GI) tract greatly outnumbers the cells in the human body. Effects of antibiotics indicate that GI tract bacteria may be determining the fate of distal cancers. Recent data implicate dysregulated host responses to enteric bacteria leading to cancers in extra-intestinal sites. Together these findings point to novel anti-cancer strategies aimed at promoting GI tract homeostasis. [ABSTRACT FROM AUTHOR]

While absent from normal epithelia, an actin bundling protein, fascin, becomes expressed in invasive carcinoma of different origins. It is highly enriched at the tumors’ invasive front suggesting that it could play a role in cancer invasion. Multiple studies have shown that fascin, through its role in formation of cellular protrusions such as filopodia and invadopodia, enhances cancer cell migration and invasion in vitro . However, the role of fascin in vivo remains unknown. We have generated a compound transgenic mouse model that allows expression of fascin in the intestinal epithelium in the Apc-mutated background. Conditional expression of fascin led to decrease in mice survival and increase in tumor burden compared to control animals. Induction of fascin expression in adult tumor-bearing animals accelerated tumor progression and led to formation of invasive adenocarcinoma. Altogether, our study shows that fascin can promote tumor progression in vivo , but also unravels an unexpected role of fascin in tumor initiation. [ABSTRACT FROM AUTHOR]

Background Notch signaling plays diverse roles not only in physiologic processes, including development and differentiation but also in tumorigenesis, either as a tumor promoter or suppressor depending on the cellular context, level of expression and cross-talk with other signaling pathways. In this study we investigated the expression of Notch3 and MUC proteins and their clinicopathological significance in small intestinal adenocarcinoma (SIAC). Methods Surgically resected 191 SIACs and their clinical data were collected. Immunohistochemistry for Notch3, MUC2, MUC5AC, and MUC6 using tissue microarrays from formalin-fixed paraffin-embedded normal and matched tumor tissues was performed. Results Notch3 expression was found in 52 (29.9%) cases of the tumors. MUC2, MUC5AC, and MUC6 were expressed in 52 (27.5%), 51 (31.9%), and 42 (22.0%) cases of the tumor, respectively. Notch3 expression was correlated with the absence of lymphovascular invasion (p=0.009), lower T stage (p=0.038), and histological subtype of tubular adenocarcinoma (p=0.01), respectively. MUC2 was correlated with large tumor size (p=0.013) and mucinous and signet ring cell adenocarcinomas (p=0.01). MUC5A was correlated with proximal tumor location (p<0.0001) and tumor differentiation (p=0.027). MUC6 was correlated with proximal tumor location (p<0.0001) and lower pT stage (p=0.009), and absence of lymphovascular invasion, respectively. A significant correlation was noted between Notch3 and MUC5AC expression (p=0.019). Notch3 expression was a relatively favorable prognostic factor in SIACs by univariate (p=0.05) and multivariate analysis (p=0.08, Cox Hazard ratio 0.841). Conclusion Our findings indicate that Notch3 signaling, associated with MUC5AC expression, could be a more favorable prognostic factor in SIACs. [ABSTRACT FROM AUTHOR]

Aim: Lung cancer is mostly diagnosed at the advanced stage of disease. This review focused on prevalence, clinicopathological characteristics, treatment, and prognosis of intestine metastasis of primary lung cancer. Methods: Published literature was searched using PubMed/Medline databases to extract studies on primary lung cancer metastasized to the intestine and then analyzed statistically. Results: A total of 57 case reports and 3 retrospective studies were obtained from PubMed database. The prevalence of small bowel metastasis of primary lung cancer ranged between 2.6 and 10.7%. Histologically, poor tumor differentiation and advanced T and N stages of primary lung cancer associated with intestinal metastasis. Clinically, primary lung cancer metastasized to the intestine led to three frequent clinical presentations, i.e., intestine perforation, obstruction, and bleeding. The time interval between diagnosis of primary tumor and manifestation of intestinal metastasis ranged between 2 week and 4 years, while the time was within one year for 36 reported cases. 70% (45 of 63 cases) of patients did have an extra-intestinal metastasis at diagnosis of intestine metastasis. The median survival rate of 79 patients with follow-up data was 2.3 month and the old age, extra-intestinal metastasis, and intestine perforation were associated with poor prognosis. Conclusion: This study suggests that the primary lung cancer metastasized to the small bowel is not so rare as it is thought. Clinical management and treatment decision will be warranted and considered accordingly. [ABSTRACT FROM AUTHOR]

Abstract: The mammalian intestine encounters many more microorganisms than any other tissue in the body thus making it the largest and most complex component of the immune system. Indeed, there are greater than 100 trillion (1014) microbes within the healthy human intestine, and the total number of genes derived from this diverse microbiome exceeds that of the entire human genome by at least 100-fold. Our coexistence with the gut microbiota represents a dynamic and mutually beneficial relationship that is thought to be a major determinant of health and disease. Because of the potential for intestinal microorganisms to induce local and/or systemic inflammation, the intestinal immune system has developed a number of immune mechanisms to protect the host from pathogenic infections while limiting the inflammatory tissue injury that accompanies these immune responses. Failure to properly regulate intestinal mucosal immunity is thought to be responsible for the inflammatory tissue injury observed in the inflammatory bowel diseases (IBD; Crohn disease, ulcerative colitis). An accumulating body of experimental and clinical evidence strongly suggests that IBD results from a dysregulated immune response to components of the normal gut flora in genetically susceptible individuals. The objective of this review is to present our current understanding of the role that enteric microbiota play in intestinal homeostasis and pathogenesis of chronic intestinal inflammation. [Copyright &y& Elsevier]

Abstract: Sphingosine-1-phosphate (S1P), a pleiotropic bioactive lipid mediator, and the kinase that produces it have now emerged as key regulators of numerous cellular processes involved in inflammation and cancer. Here, we review the importance of S1P in colitis and colitis-associated cancer (CAC) and discuss our recent work demonstrating that S1P produced by upregulation of SphK1 during colitis and associated cancer is essential for production of the multifunctional NF-κB-regulated cytokine IL-6, persistent activation of the transcription factor Stat3, and consequent upregulation of the S1P receptor, S1PR1. The effectiveness of the pro-drug FTY720 (known as fingolimod), approved for the treatment of multiple sclerosis, has become the gold standard for S1P-centric drugs, and will be used to illustrate the therapeutic value of modulating SphK1 and S1P receptor functions. We will discuss our recent results showing that FTY720/fingolimod administration interferes with the SphK1/S1P/S1PR1 axis and suppresses the NF-κB/IL-6/Stat3 malicious amplification loop and CAC. These preclinical studies suggest that FTY720/fingolimod may be useful in treating colon cancer in individuals with ulcerative colitis. [Copyright &y& Elsevier]

Abstract: Variations in tissue autofluorescence (AF) can be exploited to detect early signs of intestinal cancer, however current endoscopic AF systems are only able to inspect the oesophegus and large intestine. We present the design, fabrication and testing of a pill capable of inducing and detecting AF from mammalian intestinal tissue. The prototype comprises an application specific integrated circuit (ASIC), illumination LED, optical filters to minimise sensor response to crosstalk from the illumination wavelength, a pulse counter/control unit and a radio transmitter. The ASIC implements a single photon avalanche diode detector (SPAD), and integrated high voltage (up to 37.9V) charge pump power supply. The SPAD is biased above its breakdown voltage to operate in Geiger mode, and exhibits a detection efficiency peak at 465nm, sufficiently close to human tissue autofluorescence's peak of 520±10nm. The ASIC was fabricated using a commercial high-voltage CMOS process. The complete device uses an average power of only 21.4mW. The implemented system has been characterised against controlled solutions of fluorophores and tested in vitro with biological samples. It has been proven to be capable of inducing and detecting fluorescence in fluorophore solution concentration as low as 1nM, and with mammalian intestinal tissue. [Copyright &y& Elsevier]