Green and Low-Cost Modified Pisha Sandstone Geopolymer Gel Materials for Ecological Restoration: A Phase Review.

Pisha sandstone (PS) is a special interbedded rock in the middle reaches of the Yellow River that experiences severe weathering and is loose and broken. Due to severe multiple erosion events, the Pisha sandstone region is called "the most severe water loss and soil erosion in the world" and "the ecological cancer of the earth". As a special pozzolanic mineral, PS has the potential to be used as precursors for the synthesis of green and low-carbon geopolymer gel materials and applied in ecological restoration. This paper aims to undertake a phase review of the precursors for geopolymer gel materials. The genesis and distribution, physical and chemical characterization, erosion characteristics, and advances in the ecological restoration of PS are all summarized. Furthermore, current advances in the use of PS for the synthesis of geopolymer gel materials in terms of mechanical properties and durability are discussed. The production of Pisha sandstone geopolymer gels through the binder jetting technique and 3D printing techniques is prospected. Meanwhile, the prospects for the resource application of PS in mine rehabilitation and sustainable ecology are discussed. In the future, multifactor-driven comprehensive measures should be further investigated in order to achieve ecological restoration of the Pisha sandstone region and promote high-quality development of the Yellow River Basin.

Immunomodulatory Function of Pien Tze Huang in T Cell-Mediated Anti-tumor Activity against B16-F10, MC38 and Hep1-6 Tumor Models.

OBJECTIVE: To investigate the anti-tumor effects of Pien Tze Huang (PZH) in mouse models of B16-F10 melanoma, MC38 colorectal cancer, Hep1-6 hepatocellular carcinoma and chemically induced hepatocellular carcinoma model. METHODS: Various tumor models, including B16-F10, MC38 and Hep1-6 tumor hypodermic inoculation models, B16-F10 and Hep1-6 pulmonary metastasis models, Hep1-6 orthotopic implantation model, and chemically induced hepatocellular carcinoma model, were utilized to evaluate the anti-tumor function of PZH. Tumor growth was assessed by measuring tumor size and weight of solid tumors isolated from C57BL/6 mice. For cell proliferation and death of tumor cells in vitro, as well as T cell activation markers, cytokine production and immune checkpoints analysis, single-cell suspensions were prepared from mouse spleen, lymph nodes, and tumors after PZH treatment. RESULTS: PZH demonstrated significant therapeutic efficacy in inhibiting tumor growth (P<0.01). Treatment with PZH resulted in a reduction in tumor size in subcutaneous MC38 colon adenocarcinoma and B16-F10 melanoma models, and decreased pulmonary metastasis of B16-F10 melanoma and Hep1-6 hepatoma (P<0.01). However, in vitro experiments showed that PZH only had slight impact on the cell proliferation and survival of tumor cells (P>0.05). Nevertheless, PZH exhibited a remarkable ability to enhance T cell activation and the production of interferon gamma, tumor necrosis factor alpha, and interleukin 2 in CD4+ T cells in vitro (P<0.01 or P<0.05). Importantly, PZH substantially inhibited T cell exhaustion and boosted cytokine production by tumor-infiltrating CD8+ T cells (P<0.01 or P<0.05). CONCLUSION: This study has confirmed a novel immunomodulatory function of PZH in T cell-mediated anti-tumor immunity, indicating that PZH holds promise as a potential therapeutic agent for cancer treatment.

Glycogen synthase kinase 3 controls T-cell exhaustion by regulating NFAT activation.

Cellular immunity mediated by CD8+ T cells plays an indispensable role in bacterial and viral clearance and cancers. However, persistent antigen stimulation of CD8+ T cells leads to an exhausted or dysfunctional cellular state characterized by the loss of effector function and high expression of inhibitory receptors during chronic viral infection and in tumors. Numerous studies have shown that glycogen synthase kinase 3 (GSK3) controls the function and development of immune cells, but whether GSK3 affects CD8+ T cells is not clearly elucidated. Here, we demonstrate that mice with deletion of Gsk3α and Gsk3ß in activated CD8+ T cells (DKO) exhibited decreased CTL differentiation and effector function during acute and chronic viral infection. In addition, DKO mice failed to control tumor growth due to the upregulated expression of inhibitory receptors and augmented T-cell exhaustion in tumor-infiltrating CD8+ T cells. Strikingly, anti-PD-1 immunotherapy substantially restored tumor rejection in DKO mice. Mechanistically, GSK3 regulates T-cell exhaustion by suppressing TCR-induced nuclear import of NFAT, thereby in turn dampening NFAT-mediated exhaustion-related gene expression, including TOX/TOX2 and PD-1. Thus, we uncovered the molecular mechanisms underlying GSK3 regulation of CTL differentiation and T-cell exhaustion in anti-tumor immune responses.

Novel exopolysaccharide derived from probiotic Lactobacillus pantheris TCP102 strain with immune-enhancing and anticancer activities.

Probiotics are gaining attention due to their functions of regulating the intestinal barrier and promoting human health. The production of exopolysaccharide (EPS) is one of the important factors for probiotics to exert beneficial properties. This study aimed to screen exopolysaccharides-producing lactic acid bacteria (LAB) and evaluate the probiotic potential. we obtained three exopolysaccharide fractions (EPS1, EPS2, and EPS3) from Lactobacillus pantheris TCP102 and purified by a combination of ion-exchange chromatography and gel permeation chromatography. The structures of the fractions were characterized by FT-IR, UV, HPLC, and scanning electron microscopy (SEM) analysis. The Mw of EPS1, EPS2, and EPS3 were approximately 20.3, 23.0, and 19.3 kDa, and were mainly composed of galactose, glucose, and mannose, with approximate molar ratios of 2.86:1:1.48, 1.26:1:1, 1.58:1.80:1, respectively. Furthermore, SEM analysis demonstrated that the three polysaccharide fractions differ in microstructure and surface morphology. Additionally, preliminary results for immune-enhancing and anticancer activities reveal that these EPSs significantly induced the production of nitric oxide (NO), TNF-α, and IL-6 in Ana-1 cells and peritoneal macrophage cells. Meanwhile, the EPSs also significantly suppressed the proliferation of HCT-116, BCG-803, and particularly A-2780 cells. The results suggest that the three novel EPSs isolated from Lactobacillus pantheris TCP102 can be regarded as potential application value in functional food and natural antitumor drugs.

Glycogen synthase kinase 3 drives thymocyte egress by suppressing ß-catenin activation of Akt.

Molecular pathways controlling emigration of mature thymocytes from thymus to the periphery remain incompletely understood. Here, we show that T cell­specific ablation of glycogen synthase kinase 3 (GSK3) led to severely impaired thymic egress. In the absence of GSK3, ß-catenin accumulated in the cytoplasm, where it associated with and activated Akt, leading to phosphorylation and degradation of Foxo1 and downregulation of Klf2 and S1P1 expression, thereby preventing emigration of thymocytes. A cytoplasmic membrane-localized ß-catenin excluded from the nucleus promoted Akt activation, suggesting a new function of ß-catenin independent of its role as a transcriptional activator. Furthermore, genetic ablation of ß-catenin, retroviral expression of a dominant negative Akt mutant, and transgenic expression of a constitutively active Foxo1 restored emigration of GSK3-deficient thymocytes. Our findings establish an essential role for GSK3 in thymocyte egress and reveal a previously unidentified signaling function of ß-catenin in the cytoplasm.

Levamisole promotes murine bone marrow derived dendritic cell activation and drives Th1 immune response in vitro and in vivo.

Our lab previously found that levamisole (LMS) as an adjuvant enhanced the efficacy of vaccine against infectious pathogens. However, the cellular and molecular mechanisms remain to be defined. In this study, we showed that BALB/c bone marrow-derived DC stimulated with LMS resulted in enhanced cell-surface expression of CD80, CD86, CD40 and MHC class II, as well as enhanced production of IL-12p70, TNF-α and IL-1ß. Interestingly, the LMS activated DCs were able to stimulate CD4(+) T cell proliferation and facilitated Th1 differentiation by increasing the secretion of IFN-γ in an allogeneic mixed leukocyte reaction. Furthermore, to confirm the in vitro data, we investigated the effect of LMS on antigen-specific antibody and cytokine production in BALB/c mice. Immunization with LMS plus OVA showed that anti-OVA IgG2a and IFN-γ were increased significantly compared with OVA alone in BALB/c mice. In conclusion, our results suggested that murine bone marrow-derived DC, played a crucial role in the effect of LMS on the induction of Th1 responses, which probably was due to its ability to promote DC maturation and secrete proinflammatory cytokines.

[Multi-center phase II clinical trial of humanized anti-epidermal factor receptor monoclonal antibody h-R3 combined with radiotherapy for locoregionally advanced nasopharyngeal carcinoma].

OBJECTIVE: To evaluate the efficacy and safty of the humanized anti-epidermal factor receptor monoclonal antibody h-R3 in combination with radiotherapy for locoregionally advanced nasopharyngeal carcinoma. METHODS: Totally, 137 patients from 7 medical center around China were randomly divided into combined therapy group or control group. There was no difference in Karnofsky performance score between two groups. All patients in both groups received radical conventionally fractionated radiotherapy to the total dose of D(T) 70-76 Gy. For the combined therapy group, h-R3 was added at a dose of 100 mg i.v. weekly for 8 weeks started at the beginning of radiotherapy. RESULTS: Of the 137 eligilbe patients, 70 were in the combined therapy group treated by h-R3 plus radiotherapy and 67 in the control group by radiotherapy alone. The intent-to-treat (ITT) population consisted of 130 patients, while the per-protocol (PP) population was composed of 126 patients. The efficacy was assessed respectively at three point of time: the end of treatment, the 5th- and 17th-week after treatment. The complete response (CR) of the combined therapy group was significantly higher than that of the control group in both ITT and PP (ITT: 65.63%, 87.50%, 90.63% versus 27.27%, 42.42%, 51.52%; PP: 67.21%, 90.16%, 93.44% versus 27.69%, 43.08%, 52.31%; P < 0.05, respectively). The most common h-R3-related adverse reactions were fever (4.3%), hypotension (2.9%), nausea (1.4%), dizziness (2.9%) and rash (1.4%), which could be reversible if treated properly. Radiotherapy combined with 100 mg h-R3 i. v. weekly was tolerable and did not aggravate the side effects of radiation. The quality of life in the combined therapy group was comparable to that in the control group. CONCLUSION: This phase 1 multicenter clinical trial shows that h-R3 in combination with radiotherapy is effective and well-tolerated for the treatment of locoregionally advanced nasopharyngeal carcinoma.