Screening of specific intestinal flora and establishment of model in patients with immunotherapy sensitive cholangiocarcinoma and pancreatic tumor
Ontology highlight
ABSTRACT:
DISEASE(S): Biliary Pancreatic Tumor
PROVIDER: 83665 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Cholangiocarcinoma (CCA) is a malignancy arising from multiple locations along the biliary tree, which is still lacking effective diagnostic biomarkers. The present study aimed to provide a comprehensive differential gene expression profile for the disease. The differentially expressed genes (DEGs) for CCA were explored in-depth using a Gene Expression Omnibus (GEO) dataset, an internal cohort of clinical participants as well as in vitro experiments with the HUCCT1 cell line. Based on the GEO dataset, potential biomarker genes were proposed and the enriched biological processes as well as signaling pathways were further investigated. A protein-protein interaction network of target genes was established. In the clinical specimens, the functions of the primary candidate, FBJ murine osteosarcoma viral oncogene homolog B (FOSB), were evaluated by reverse transcription-quantitative (RT-q)PCR and western blot analysis. A Cell Counting Kit-8 (CCK-8) assay was used for a functional study on FOSB. The results indicated that, compared with non-tumor bile duct tissues, primary CCA samples had 676 differentially expressed genes, including 277 downregulated and 399 upregulated ones. Among these, HBD, FOSB, HBB, ITIH2, FCGBP, MT1JP, PIJR, SLC38A1, COL10A1 and MMP19 were determined to be the most significant DEGs. At the same time, upregulated genes were enriched in 'vasculature development' and 'IL-17 signaling pathways'. Downregulated genes were enriched in 'extracellular matrix progress' and 'glucuronate signaling pathway'. The patients with CCA displayed decreased levels of hemoglobin. Compared with paracancerous tissues, CCA cancerous tissues exhibited increased RNA and protein expression levels of FOSB according to RT-qPCR and western blot analysis, respectively. Furthermore, FOSB expression influenced the proliferation/viability of the CCA cell line HUCCT1. In conclusion, the present study suggested that the FOSB gene may serve as a primary biomarker candidate for CCA, providing a valuable reference for its clinical implementation.
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Primary outcome(s): disease free survival
Study Design: Sequential
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Project description:Cholangiocarcinoma (CCA) is a type of aggressive tumor that involves the intrahepatic, perihilar and distal biliary tree, and is usually diagnosed at an advanced stage. The standard first-line systemic therapy for patients with advanced CCA is a combination of gemcitabine and cisplatin; targeted therapies and angiogenesis inhibitors are not widely used clinically at present. However, with the development of precision medicine, immunotherapy has started to play a more important role. Programmed cell death protein 1 inhibitors are now considered a good therapeutic option for CCA. Treatments using chimeric antigen receptor T cells, bispecific antibodies, oncolytic viruses and cancer vaccines have also achieved satisfactory results. In addition, combinations of immunotherapy with a variety of conventional therapies have shown some efficacy, and several studies have provided insights into their use in antitumor therapy. Although there are numerous challenges in the treatment of advanced CCA, immunotherapy remains a noteworthy breakthrough. The current evidence on the immunotherapy of CCA is discussed in the present review.
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Project description:Interventions: Case series:Nil
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Primary outcome(s): toxic and adverse effects
Study Design: Sequential
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Project description:BackgroundCachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC-associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D P53R172H Pdx-Cre+/+ (KPC) mouse.MethodsMale and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development.ResultsAll routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil-dominant leukocytosis and anaemia, and decreased serum testosterone.ConclusionsSyngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies.
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Project description:Interventions: case series:N/A
Primary outcome(s): Overall survival time;Recurrence-free time
Study Design: Sequential
| 2701335 | ecrin-mdr-crc