Anti-Helicobacter pylori activity and gastroprotective effects of human stomach-derived Lactobacillus paragasseri strain LPG-9.

The eradication of Helicobacter pylori is an urgent global issue. However, the traditional regimens have several limitations. Thus, we propose the idea of treating bacterial gastric disease with the objective of eliminating gastric pathogenic bacteria and enhancing gastroprotective effects using gastric probiotics. In this study, a total of 12 Lactobacillus strains were isolated from the gastric mucosa of healthy donors. After evaluation using a weight scoring system, Lactobacillus paragasseri strain LPG-9 was identified as the most promising probiotic for gastric disease, with the highest acid-resistance and the best adhesion characteristics. Gastric colonisation, H. pylori inhibition, anti-inflammatory, and gastric homeostasis effects of LPG-9 were confirmed in C57BL/6 mice. Finally, a safety evaluation and whole-genome sequencing were performed. Based on the results of this study, LPG-9 originates from the gastric microbiota and is a promising probiotic for gastric disease, particularly H. pylori-induced gastritis, providing a solution to this global issue.

Low doses of IFN-γ maintain self-renewal of leukemia stem cells in acute myeloid leukemia.

Conventional therapies for acute myeloid leukemia (AML) often fail to eliminate the disease-initiating leukemia stem cell (LSC) population, leading to disease relapse. Interferon-γ (IFN-γ) is a known inflammatory cytokine that promotes antitumor responses. Here, we found that low serum IFN-γ levels correlated with a higher percentage of LSCs and greater relapse incidence in AML patients. Furthermore, IFNGR1 was overexpressed in relapsed patients with AML and associated with a poor prognosis. We showed that high doses (5-10 µg/day) of IFN-γ exerted an anti-AML effect, while low doses (0.01-0.05 µg/day) of IFN-γ accelerated AML development and supported LSC self-renewal in patient-derived AML-LSCs and in an LSC-enriched MLL-AF9-driven mouse model. Importantly, targeting the IFN-γ receptor IFNGR1 by using lentiviral shRNAs or neutralizing antibodies induced AML differentiation and delayed leukemogenesis in vitro and in mice. Overall, we uncovered essential roles for IFN-γ and IFNGR1 in AML stemness and showed that targeting IFNGR1 is a strategy to decrease stemness and increase differentiation in relapsed AML patients.

The promotion strategies and dynamic evaluation model of exhibition-driven sustainable tourism based on previous/prospective tourist satisfaction after COVID-19.

After COVID-19, all art exhibitions in 2020 were forced to close and postponed until 2021 in Japan. The current paper studies the dynamic evaluation model and exhibition-driven event tourism promotion strategies based on previous/prospective tourist satisfaction surveys. Echigo-Tsumari Art Triennale (ETAT) was selected for the evaluation case. A new methodology, prospective-importance previous-performance analysis (PIPPA), was used for the previous tourist satisfaction questionnaire survey (by term frequency-inverse document frequency (TF-IDF)) and prospective tourist satisfaction questionnaire survey for the restart. It is an attempt not only for ETAT 2021 but also a sample for the others (hundreds of art exhibitions) in Japan and other countries.

Copper-catalyzed three-component annulation toward pyrroles via the cleavage of two C-C bonds in 1,3-dicarbonyls.

The first copper-catalyzed three-component annulation of α,ß-unsaturated ketoximes, 1,3-dicarbonyls and paraformaldehyde has been documented. This novel strategy achieved the two C-C bond cleavage of 1,3-dicarbonyl compounds directly as a single-carbon synthon and provided a new and highly efficient method for the synthesis of 2,3-disubstituted pyrroles in moderate to good yields with broad functional group compatibility.

N6-methyladenosine RNA modifications: a potential therapeutic target for AML.

N6-methyladenosine (m6A) RNA modification has recently emerged as an essential regulator of normal and malignant hematopoiesis. As a reversible epigenetic modification found in messenger RNAs and non-coding RNAs, m6A affects the fate of the modified RNA molecules. It is essential in most vital bioprocesses, contributing to cancer development. Here, we review the up-to-date knowledge of the pathological functions and underlying molecular mechanism of m6A modifications in normal hematopoiesis, leukemia pathogenesis, and drug response/resistance. At last, we discuss the critical role of m6A in immune response, the therapeutic potential of targeting m6A regulators, and the possible combination therapy for AML.

Loss of EPS8 sensitizes non-small-cell lung carcinoma to chemotherapy-induced DNA damage.

Epidermal growth factor receptor pathway substrate number 8 (EPS8) has been reported to be critical in mediating tumor progression. However, the molecular and biological consequences of EPS8 overexpression remain unclear. Here we evaluated whether EPS8 increased DNA damage repair in non-small-cell lung carcinoma (NSCLC) cells and the mechanism of EPS8-mediated DNA damage repair which influenced chemosensitivity. Serial studies of functional experiments revealed that EPS8 knockdown inhibited cell growth, induced cell-cycle arrest and increased cisplatin therapeutic effects on NSCLC. EPS8 was found to induce DNA damage repair via upregulation of phosphorylated-ATM and downregulation of the tumor suppressor p53 and G1 cell kinase inhibitor p21. Moreover, in conjunction with cisplatin, decreasing EPS8 protein levels further increased p53 protein level and inhibited ATM signaling. Transplanted tumor studies were also performed to demonstrate that EPS8 knockdown inhibited tumor growth and sensitized tumors to cisplatin treatment. In conclusion, we have described a novel molecular mechanism through which EPS8 is likely to be involved in cancer progression and chemoresistance via DNA damage repair, indicating that EPS8 expression may influence the response to chemotherapy. Therefore, targeting EPS8 may be a potential therapeutic approach for patients with NSCLC.

The immunometabolic landscape of the bone marrow microenvironment in acute myeloid leukemia.

The bone marrow microenvironment of acute myeloid leukemia (AML) consists of various cell types and signaling factors, which serve as a niche supporting leukemia cells in their invasion of the human body. However, a systematic landscape of metabolic heterogeneity and its relationship with immunity in the AML microenvironment at single-cell resolution has not yet been established. Herein, we addressed this issue by analyzing 208,543 bone marrow cells from 40 AML patients and 3 healthy donors obtained from GSE130756. We focused on the metabolic preference of AML progenitor cells and diverse immune cells, especially myeloid immune cells and T cells. Accordingly, the immune evasion mechanism of leukemia cells was proposed from the view of the allocation of energy and oxygen, providing a novel direction of treatment. Finally, we tentatively proposed potential targets for AML metabolic therapy, including ENO1, GSTP1, MT-ND4L and UQCR11. Collectively, our analysis facilitates the development of personalized therapies targeting unique immunometabolic profiles.

Amino acid metabolism: challenges and opportunities for the therapeutic treatment of leukemia and lymphoma.

Leukemia and lymphoma-the most common hematological malignant diseases-are often accompanied by complications such as drug resistance, refractory diseases and relapse. Amino acids (AAs) are important energy sources for malignant cells. Tumor-mediated AA metabolism is associated with the immunosuppressive properties of the tumor microenvironment, thereby assisting malignant cells to evade immune surveillance. Targeting abnormal AA metabolism in the tumor microenvironment may be an effective therapeutic approach to address the therapeutic challenges of leukemia and lymphoma. Here, we review the effects of glutamine, arginine and tryptophan metabolism on tumorigenesis and immunomodulation, and define the differences between tumor cells and immune effector cells. We also comment on treatments targeting these AA metabolism pathways in lymphoma and leukemia and discuss how these treatments have profound adverse effects on tumor cells, but leave the immune cells unaffected or mildly affected.

Systematic pan-cancer landscape identifies CARM1 as a potential prognostic and immunological biomarker.

BACKGROUND: Belonging to the protein arginine methyltransferase (PRMT) family, the enzyme encoded by coactivator associated arginine methyltransferase 1 (CARM1) catalyzes the methylation of protein arginine residues, especially acts on histones and other chromatin related proteins, which is essential in regulating gene expression. Beyond its well-established involvement in the regulation of transcription, recent studies have revealed a novel role of CARM1 in tumorigenesis and development, but there is still a lack of systematic understanding of CARM1 in human cancers. An integrated analysis of CARM1 in pan-cancer may contribute to further explore its prognostic value and potential immunological function in tumor therapy. RESULTS: Based on systematic analysis of data in multiple databases, we firstly verified that CARM1 is highly expressed in most tumors compared with corresponding normal tissues, and is bound up with poor prognosis in some tumors. Subsequently, relevance between CARM1 expression level and tumor immune microenvironment is analyzed from the perspectives of tumor mutation burden, microsatellite instability, mismatch repair genes, methyltransferases genes, immune checkpoint genes and immune cells infiltration, indicating a potential relationship between CARM1 expression and tumor microenvironment. A gene enrichment analysis followed shortly, which implied that the role of CARM1 in tumor pathogenesis may be related to transcriptional imbalance and viral carcinogenesis. CONCLUSIONS: Our first comprehensive bioinformatics analysis provides a broad molecular perspective on the role of CARM1 in various tumors, highlights its value in clinical prognosis and potential association with tumor immune microenvironment, which may furnish an immune based antitumor strategy to provide a reference for more accurate and personalized immunotherapy in the future.

Metabolic regulation of the bone marrow microenvironment in leukemia.

Most leukemia patients experience little benefit from immunotherapy, in part due to the immunosuppressive bone marrow microenvironment. Various metabolic mechanisms orchestrate the behaviors of immune cells and leukemia cells in the bone marrow microenvironment. Furthermore, leukemia cells regulate the bone marrow microenvironment through metabolism to generate an adequate supply of energy and to escape antitumor immune surveillance. Thus, the targeting of the interaction between leukemia cells and the bone marrow microenvironment provides a new therapeutic avenue. In this review, we describe the concept of the bone marrow microenvironment and several important metabolic processes of leukemia cells within the bone marrow microenvironment, including carbohydrate, lipid, and amino acid metabolism. In addition, we discuss how these metabolic pathways regulate antitumor immunity and reveal potential therapeutic targets.