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  • Ovid Technologies (Wolters Kluwer Health)  (2)
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  • Ovid Technologies (Wolters Kluwer Health)  (2)
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  • 1
    Online Resource
    Online Resource
    Intestinal Dysbiosis Correlates With Sirolimus-induced Metabolic Disorders in Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Transplantation Vol. 105, No. 5 ( 2021-05), p. 1017-1029
    Details
    In: Transplantation, Ovid Technologies (Wolters Kluwer Health), Vol. 105, No. 5 ( 2021-05), p. 1017-1029
    Abstract: Long-time use of pharmacological immunosuppressive agents frequently leads to metabolic disorders. Most studies have focused on islet toxicity leading to posttransplantation diabetes mellitus. In contrast, the link between intestinal dysbiosis and immunosuppressive drug-induced metabolic disorders remains unclear. Methods. We established a mouse model of metabolic abnormality via sirolimus treatment. Fecal microbiota was examined using 16S rRNA gene MiSeq sequencing. Intestinal barrier function was assessed using fluorescein isothiocyanate-dextran assay and mucus immunostaining. Systemic inflammation was determined using a multiplexed fluorescent bead-based immunoassay. Results. Sirolimus induced dyslipidemia and glucose intolerance in mice in a dose-dependent manner. Interestingly, the clinical-mimicking dose of sirolimus altered the intestinal microbiota community, which was characterized by the enrichment of Proteobacteria, depletion of Akkermansia , and potential function shifts to those involved in lipid metabolism and the immune system. In addition, the clinical-mimicking dose of sirolimus reduced the thickness of the intestinal mucosal layer, increased the intestinal permeability, and enriched the circulating pro-inflammatory factors, including interleukin (IL)-12, IL-6, monocyte chemotactic protein 1, granulocyte-macrophage colony stimulating factor, and IL-1β. Our results showed a close association between intestinal dysbiosis, intestinal barrier failure, systemic inflammation, and metabolic disorders. Furthermore, we demonstrated that oral intervention in the gut microbiota by Lactobacillus rhamnosus HN001 protected against intestinal dysbiosis, especially by depleting the lipopolysaccharide-producing Proteobacteria, and attenuated the sirolimus-induced systemic inflammation, dyslipidemia, and insulin resistance. Conclusions. Our study demonstrated a potentially causative role of intestinal dysbiosis in sirolimus-induced metabolic disorders, which will provide a novel therapeutic target for transplant recipients.
    Type of Medium: Online Resource
    ISSN: 0041-1337
    URL: Article
    DOI: 10.1097/TP.0000000000003494
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2035395-9
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  • 2
    Online Resource
    Online Resource
    B2M and JAK1/2–mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Journal of Immunotherapy Vol. 45, No. 4 ( 2022-05), p. 187-193
    Details
    In: Journal of Immunotherapy, Ovid Technologies (Wolters Kluwer Health), Vol. 45, No. 4 ( 2022-05), p. 187-193
    Abstract: β2-microglobulin ( B2M ) and Janus kinases 1 and 2 ( JAK1/2 ) mutations have been suggested as genetic mechanisms of immune evasion for anti–programmed cell death protein 1 (PD-1) therapy. Whether B2M and JAK 1/2 lose-of-function mutation can cause primary resistance to anti-PD-1 therapy in colorectal carcinoma (CRC) patients remains controversial. Here, we sought to compare the efficacy of anti-PD-1 therapy in DNA mismatch repair deficient/microsatellite instability–high CRC patients with or without B2M or JAK1/2 mutations. Thirty-Five CRC patients who received anti-PD-1 therapy were enrolled in this study. All tumor samples underwent next-generation sequencing. The clinical and molecular data from 110 CRC patients sequenced with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay and accessed through cBioportal were also analyzed in this study. Of the 35 CRC patients from our center, 10 (28.6%) had a B2M loss-of-function mutation, and 8 (22.9%) had a JAK1/2 loss-of-function mutation. Compared with B2M wild-type CRCs, B2M -mutated CRCs did not show a higher frequency of resistance to anti-PD-1 therapy ( P =0.71). There was even better response to anti-PD-1 therapy in patients with JAK1/2 mutation than in those without ( P =0.015). Of the 110 CRC patients in the MSK-IMPACT datasets, 13 (11.8%) had a B2M mutation, and 15 (13.6%) had a JAK1/2 mutation. After analyzing the response to anti-PD-1 therapy in these 110 patients, we found similar results ( P =0.438 and 0.071, respectively). Moreover, patients with B2M or JAK1/2 mutation had a lower tumor mutational burden score compared with those without. B2M and JAK1/2 loss-of-function mutations occur frequently in microsatellite instability–high CRC. Our study demonstrated that patients with CRC harboring B2M or JAK1/2 mutations should not be excluded from anti-PD-1 therapy.
    Type of Medium: Online Resource
    ISSN: 1524-9557
    URL: Article
    DOI: 10.1097/CJI.0000000000000417
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2048797-6
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