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  • 1
    In: Gastroenterology, Elsevier BV, Vol. 164, No. 3 ( 2023-03), p. 407-423.e17
    Type of Medium: Online Resource
    ISSN: 0016-5085
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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  • 2
    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 65, No. 5 ( 2017-05), p. 1628-1644
    Abstract: Potential biomarkers that can be used to determine prognosis and perform targeted therapies are urgently needed to treat patients with hepatocellular carcinoma (HCC). To meet this need, we performed a screen to identify functional genes associated with hepatocellular carcinogenesis and its progression at the transcriptome and proteome levels. We identified aldehyde dedydrogenase‐2 (ALDH2) as a gene of interest for further study. ALDH2 levels were significantly lower at the mRNA and protein level in tumor tissues than in normal tissues, and they were even lower in tissues that exhibited increased migratory capacity. A study of clinical associations showed that ALDH2 is correlated with survival and multiple migration‐associated clinicopathological traits, including the presence of metastasis and portal vein tumor thrombus. The result of overexpressing or knocking down ALDH2 showed that this gene inhibited migration and invasion both in vivo and in vitro . We also found that ALDH2 altered the redox status of cells by regulating acetaldehyde levels and that it further activated the AMP‐activated protein kinase (AMPK) signaling pathway. Conclusion: Decreased levels of ALDH2 may indicate a poor prognosis in HCC patients, while forcing the expression of ALDH2 in HCC cells inhibited their aggressive behavior in vitro and in mice largely by modulating the activity of the ALDH2‐acetaldehyde‐redox‐AMPK axis. Therefore, identifying ALDH2 expression levels in HCC might be a useful strategy for classifying HCC patients and for developing potential therapeutic strategies that specifically target metastatic HCC. (H epatology 2017;65:1628‐1644).
    Type of Medium: Online Resource
    ISSN: 0270-9139 , 1527-3350
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 1472120-X
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  • 3
    In: Advanced Materials, Wiley, Vol. 30, No. 17 ( 2018-04)
    Abstract: Patients are increasingly being diagnosed with neuropathic diseases, but are rarely cured because of the loss of neurons in damaged tissues. This situation creates an urgent clinical need to develop alternative treatment strategies for effective repair and regeneration of injured or diseased tissues. Neural stem cells (NSCs), highly pluripotent cells with the ability of self‐renewal and potential for multidirectional differentiation, provide a promising solution to meet this demand. However, some serious challenges remaining to be addressed are the regulation of implanted NSCs, tracking their fate, monitoring their interaction with and responsiveness to the tissue environment, and evaluating their treatment efficacy. Nanomaterials have been envisioned as innovative components to further empower the field of NSC‐based regenerative medicine, because their unique physicochemical characteristics provide unparalleled solutions to the imaging and treatment of diseases. By building on the advantages of nanomaterials, tremendous efforts have been devoted to facilitate research into the clinical translation of NSC‐based therapy. Here, recent work on emerging nanomaterials is highlighted and their performance in the imaging and treatment of neurological diseases is evaluated, comparing the strengths and weaknesses of various imaging modalities currently used. The underlying mechanisms of therapeutic efficacy are discussed, and future research directions are suggested.
    Type of Medium: Online Resource
    ISSN: 0935-9648 , 1521-4095
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 1474949-X
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 18 ( 2021-09-15), p. 4778-4793
    Abstract: N6-methyladenosine (m6A) has been reported as an important mechanism of posttranscriptional regulation. Programmed death-ligand 1 (PD-L1) is a primary immune inhibitory molecule expressed on tumor cells that promotes immune evasion. Here we report ALKBH5 as an important m6A demethylase that orchestrates PD-L1 expression in intrahepatic cholangiocarcinoma (ICC). Regulation of PD-L1 expression by ALKBH5 was confirmed in human ICC cell lines. Sequencing of the m6A methylome identified PD-L1 mRNA as a direct target of m6A modification whose levels were regulated by ALKBH5. Furthermore, ALKBH5 and PD-L1 mRNA were shown to interact. ALKBH5 deficiency enriched m6A modification in the 3′UTR region of PD-L1 mRNA, thereby promoting its degradation in a YTHDF2-dependent manner. In vitro and in vivo, tumor-intrinsic ALKBH5 inhibited the expansion and cytotoxicity of T cells by sustaining tumor cell PD-L1 expression. The ALKBH5-PD-L1–regulating axis was further confirmed in human ICC specimens. Single-cell mass cytometry analysis unveiled a complex role of ALKBH5 in the tumor immune microenvironment by promoting the expression of PD-L1 on monocytes/macrophages and decreasing the infiltration of myeloid-derived suppressor-like cells. Analysis of specimens from patients receiving anti-PD1 immunotherapy suggested that tumors with strong nuclear expression patterns of ALKBH5 are more sensitive to anti-PD1 immunotherapy. Collectively, these results describe a new regulatory mechanism of PD-L1 by mRNA epigenetic modification by ALKBH5 and the potential role of ALKBH5 in immunotherapy response, which might provide insights for cancer immunotherapies. Significance: This study identifies PD-L1 mRNA as a target of ALKBH5 and reveals a role for ALKBH5 in regulating the tumor immune microenvironment and immunotherapy efficacy.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    In: Engineering, Elsevier BV, Vol. 22 ( 2023-03), p. 159-170
    Type of Medium: Online Resource
    ISSN: 2095-8099
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2886869-9
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  • 6
    In: npj Precision Oncology, Springer Science and Business Media LLC, Vol. 6, No. 1 ( 2022-08-18)
    Abstract: Immunotherapies have been explored in treating solid tumors, albeit with disparate clinical effects in distinct cancer types. Systematic interrogation of immune cells in the tumor microenvironment (TME) is vital to the prediction of immunotherapy response and the development of innovative immunotherapeutics. To comprehensively characterize the immune microenvironment in advanced biliary tract cancer (BTC), we utilized single-cell RNA sequencing in unselected viable cells from 16 matched samples, and identified nineteen cell subsets from a total of 45,851 cells, in which exhausted CD8 + T cells, macrophages, and dendritic cells (DCs) in BTC were shown to augment and communicate within the TME. Transcriptional profiles coupled with T cell receptor (TCR) sequences revealed that exhausted CD8 + T cells retained clonal expansion and high proliferation in the TME, and some of them highly expressed the endoplasmic reticulum stress (ER) response gene, XBP1 , indicating the role of ER stress in remodeling TME. Functional assays demonstrated that XBP1 and common immune checkpoints (PD1, TIGIT) were significantly upregulated in CD8 + T cells cocultured within the TME of BTC cells (GBC-SD, HCCC-9810). When treating the coculture groups with the specific inhibitor of IRE1α-XBP1 (4μ8C), the downregulation of TIGIT was observed in the treatment group. Collectively, comprehensive transcriptome profiling provides deep insights into the immune atlas in advanced BTC, which might be instrumental in exploring innovative immunotherapy strategies.
    Type of Medium: Online Resource
    ISSN: 2397-768X
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2891458-2
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  • 7
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2019
    In:  BMC Medical Genomics Vol. 12, No. 1 ( 2019-12)
    In: BMC Medical Genomics, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2019-12)
    Abstract: Hepatocellular carcinoma (HCC) is the major type of primary liver cancer. Intrahepatic metastasis, such as portal vein tumor thrombosis (PVTT), strongly indicates poor prognosis of HCC. But now, there are limited understandings of the molecular features and mechanisms of those metastatic HCCs. Methods To characterize the molecular alterations of the metastatic HCCs, we implemented an integrative analysis of the copy number variations (CNVs), DNA methylations and transcriptomes of matched adjacent normal, primary tumor and PVTT samples from 19 HCC patients. Results CNV analysis identified a frequently amplified focal region chr11q13.3 and a novel deletion peak chr19q13.41 containing three miRNAs. The integrative analysis with RNA-seq data suggests that CNVs and differential promoter methylations regulate distinct oncogenic processes. Then, we used individualized differential analysis to identify the differentially expressed genes between matched primary tumor and PVTT of each patient. Results show that 5 out of 19 studied patients acquire evidential progressive alterations of gene expressions (more than 1000 differentially expressed genes were identified in each patient). While, another subset of eight patients have nearly identical gene expressions between the corresponding matched primary tumor and PVTT. Twenty genes were found to be recurrently and progressively differentially expressed in multiple patients. These genes are mainly associated with focal adhesion, xenobiotics metabolism by cytochrome P450 and amino acid metabolism. For several differentially expressed genes in metabolic pathways, their expressions are significantly associated with overall survivals and vascular invasions of HCC patients. The following transwell assay experiments validate that they can regulate invasive phenotypes of HCC cells. Conclusions The metastatic HCCs with PVTTs have significant molecular alterations comparing with adjacent normal tissues. The recurrent alteration patterns are similar to several previously published general HCC cohorts, but usually with higher severity. By an individualized differential analysis strategy, the progressively differentially expressed genes between the primary tumor and PVTT were identified for each patient. A few patients aquire evidential progressive alterations of gene expressions. And, experiments show that several recurrently differentially expressed genes can strongly regulate HCC cell invasions.
    Type of Medium: Online Resource
    ISSN: 1755-8794
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2411865-5
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  • 8
    In: Journal of Vascular Research, S. Karger AG, Vol. 56, No. 1 ( 2019), p. 17-27
    Abstract: Vitamin D has an important protective effect on chronic inflammatory disease. Angiotensin II (AngII) triggers vascular damage and plays a key role in vascular diseases via several mechanisms, including inflammation. Conversely, vitamin D has been shown to have an important protective effect on chronic inflammation. There is evidence showing that vitamin D can reverse the effects of AngII, but the molecular mechanisms by which this occurs are not known. Our results demonstrate that vitamin D improved the viability, migration ability, and tube formation of AngII-pretreated endothelial progenitor cells (EPCs) and inhibited the apoptosis of EPCs induced by AngII. Vitamin D also reversed reactive oxygen species production, vascular inflammatory cytokine generation, and nuclear factor kappa-B activation in EPCs induced by AngII. Furthermore, EPC pretreatment with GW9662 (the antagonist for PPAR-γ) or siHO-1 decreased the protective effect of vitamin D on AngII-induced EPC injury. Overall, our data indicate that vitamin D ameliorated AngII-induced abnormal EPC injury by decreasing oxidative stress and inflammatory cytokine levels. These findings also suggest that vitamin D protected EPCs from AngII-induced vascular injury via the activation of the PPAR-γ/HO-1 signaling pathway.
    Type of Medium: Online Resource
    ISSN: 1018-1172 , 1423-0135
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2019
    detail.hit.zdb_id: 1482726-8
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  • 9
    In: Advanced Science, Wiley, Vol. 7, No. 13 ( 2020-07)
    Abstract: The spatial heterogeneity of immune microenvironment in hepatocellular carcinoma (HCC) remains elusive. Here, a single‐cell study involving 17 432 600 immune cells of 39 matched HCC (T), nontumor (N), and leading‐edge (L) specimens by mass cytometry is conducted. The tumor‐associated CD4/CD8 double‐positive T (DPT) cells are found enriched in L regions with synergetic expression of PD‐1/HLA‐DR/ICOS/CD45RO and exhibit a higher level of IFN‐ γ , TNF‐ α , and PD‐1 upon stimulation. The enrichment of DPT and PD‐1 + DPT in L regions indicates favorable prognosis. These tumor‐associated DPT cells with similar phenotype are also verified in other tumors and HCC animal models. Single‐cell RNA‐seq further characterizes the molecular features of DPT cells and uncovers 11 clusters with different cytotoxicity, exhaustion, and activation scores. TCR‐based trajectory analysis reveals that tumor‐associated DPT clusters share separated ancestries with local CD4 + or CD8 + SPT cells rather than CD3 + PBMC cells. TCR clones with frequency above 10 are mainly found coexisting in DPT and CD8 + SPT cells. Specifically, PD‐1 high DPT cluster (TDPT_10) shares the same ancestry with exhausted CD8 + SPT cluster (TCD8T_2) and shows higher expression similarity and closer pathological location to PD‐1 + CD8 + than PD‐1 + CD4 + T cells. Together, this study systematically characterizes the unique distribution of PD‐1 + DPTs in HCC and puts forward new insights for the function and origin of tumor‐associated DPT cells.
    Type of Medium: Online Resource
    ISSN: 2198-3844 , 2198-3844
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2808093-2
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  • 10
    Online Resource
    Online Resource
    American Association for the Advancement of Science (AAAS) ; 2021
    In:  Science Advances Vol. 7, No. 51 ( 2021-12-17)
    In: Science Advances, American Association for the Advancement of Science (AAAS), Vol. 7, No. 51 ( 2021-12-17)
    Abstract: Heterogeneity is the major challenge for cancer prevention and therapy. Here, we first constructed high-resolution spatial transcriptomes of primary liver cancers (PLCs) containing 84,823 spots within 21 tissues from seven patients. The progressive comparison of spatial tumor microenvironment (TME) characteristics from nontumor to leading-edge to tumor regions revealed that the tumor capsule potentially affects intratumor spatial cluster continuity, transcriptome diversity, and immune cell infiltration. Locally, we found that the bidirectional ligand-receptor interactions at the 100-μm-wide cluster-cluster boundary contribute to maintaining intratumor architecture and the PROM1 + and CD47 + cancer stem cell niches are related to TME remodeling and tumor metastasis. Last, we proposed a TLS-50 signature to accurately locate tertiary lymphoid structures (TLSs) spatially and unveiled that the distinct composition of TLSs is shaped by their distance to tumor cells. Our study provides previous unknown insights into the diverse tumor ecosystem of PLCs and has potential benefits for cancer intervention.
    Type of Medium: Online Resource
    ISSN: 2375-2548
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2021
    detail.hit.zdb_id: 2810933-8
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