As shown in the graphical abstract of this study, the attenuated strain of Salmonella, VNP20009, induces the apoptosis of acute leukemia cells by upregulated expression of apoptosis-promoting ...protein, Bax and cleaved caspase-3 to kill leukemia cells. Furthermore, the treatment of VNP20009 induced anti-tumor immune responses mediated by various cytokines & chemokines (IFN-γ, TNF-α, LIF, CXCL-10, CCL-2) and immune cells (NK cells, T lymphocytes, CD4+ IFN-γ+ and CD8+ IFN-γ+ effector T cells). VNP20009 activates the immune system, leading to the development of a strong and effective anti-tumor systemic response and tumor remission in acute leukemia. It may be applied as a stand alone or in combination with other therapies, to better treat acute leukemia or other hematologic malignancies.
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•The attenuated Salmonella, VNP20009, can effectively attenuate the growth of acute leukemia.•VNP20009 bacteria can significantly extend the survival of the AML-bearing mice.•VNP20009 bacteria are well tolerated by the acute leukemia bearing mice.•VNP20009 can potently induce apoptosis in cultured acute leukemia cells.•VNP20009 strongly activates native and adaptive immunity in MLL-AF9-derived AML mice.
Acute leukemia is a common hematological malignancy. Despite recent promising progress, the prognosis of acute leukemia patients remains to be improved. New therapies are therefore still needed. Salmonella typhimurium has been shown to be highly effective as an anti-tumor agent in many solid cancer models, but it has not been applied in acute leukemia. Here, we report an attenuated Salmonella typhimurium strain, VNP20009, can induce apoptosis in multiple types of leukemia cells both in vivo and in vitro. Furthermore, VNP20009 significantly inhibited the proliferation of MLL-AF9-induced acute myeloid leukemia cells and prolonged the survival of the AML-carrying mice. VNP20009 restored the counts of white blood cell (WBC) and its five subsets in peripheral blood (PB) to near-physiological values, and elevated the levels of certain cytokines, such as tumor necrosis factor-α (TNF-α), leukemia inhibitory factor (LIF), interferon-γ (IFN-γ), chemokine C-X-C motif ligand-10 (CXCL-10) and C-C motif ligand-2 (CCL-2). Moreover, the ratio of immune cells, including natural killer cells (NKs), CD4+ Th1-type cells and CD8+ IFN-γ-producing effector T cells were highly upregulated in the AML mice treated with VNP20009. The results of the present study potentially provide an alternative therapeutic strategy for hematologic malignancies through boosting the innate and adaptive anti-tumor immunity.
Objective To investigate the therapeutic effect of attenuated salmonella VNP20009-M that carries a methioninase gene on osteosarcoma. Methods Recombinant salmonella VNP20009-M was co-cultured with a ...human osteosarcoma cell line. After the methioninase gene was overexpressed in osteosarcoma cells, cell proliferation, migration and apoptosis were detected. Finally, we evaluated the effect of the attenuated salmonella VNP20009-M on the subcutaneous xenograft in the nude mice by intratumorally injecting different dosages of VNP20009-M. Results It was verified by plasmid PCR that the methioninase gene was only found in the target strain VNP20009-M and had high methioninase activity. The recombinant salmonella was successfully constructed. VNP20009-M significantly induced the apoptosis of MNNGHOS cells. Overexpression of the L-methioninase gene in the osteosarcoma cells significantly inhibited cell proliferation and migration, compared with the control group. The body weight of the subcutaneous tumorbearing mice af
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Background: It has been widely reported over the past 40 years that almost all human cancer cells examined are strongly dependent on methionine for growth and metastasis, largely owing to the ...deficiency of cancer cells in methionine salvage pathway. To specifically deprive cancer tissues of methionine without affecting systemic methionine content, we have developed the first oncolytic bacteria drug, SGN1, that is based on the attenuated Salmonella typhimurium and its tumor targeting ability, and overexpresses an L-methioninase gene. Currently, SGN1 has been approved for, and entered, clinical trials in the US and Taiwan, China (NCT05103345 & NCT05038150). Methods: Cellular and animal models were used for examining the tumor-targeting effects and safety profiles of SGN1. We calculated the role of engineered Salmonella in cancer cells by RNA-seq analysis. Results: In preclinical cellular and xenograft models, SGN1 specifically targeted solid tumors， induced a sharp regression of several very divergent models of human carcinomas, caused a significant decrease of tumor cell invasion, and essentially eliminated the growth and metastasis of the xenograft tumors. RNA-Seq analysis revealed that the engineered Salmonella reduced the expression of a series of genes promoting cell growth, cell migration and invasion. Like the original attenuated Salmonella typhimurium (VNP20009), SGN1 has displayed excellent safety profiles based on the GLP-evaluation in multiple animal models. In preclinical human tumor-derived models, SGN1 exhibited strong inhibitory effects on tumor growth and metastasis in a broad spectrum of tumors, including, but not limited to, small cell lung carcinoma, osteosarcoma, hepatocellular cancer, breast cancer (including triple negative breast cancer), pancreatic cancer, prostate cancer, and cervical cancer. In investigator-initiated trial (IIT) studies, SGN1 significantly shrank, or completely lysed, patients’ tumor and ameliorated cachexia, while patients showed no severe adverse reaction except some transient fever and nausea. Conclusions: The first-in-class oncolytic bacteria, SGN1, featured with the ability of tumor-targeting and methionine hydrolysis, exhibits broad-spectrum antitumor activity and great potential for cancer therapy. Clinical trial information: NCT05038150 . Clinical trial information: NCT05103345 .
In this study, the Ti-6.5Al-2.5Sn-9Zr-0.5Mo-1Nb-1W-0.3Si near-α titanium alloy was prepared by the rare-earth scandium (Sc) microalloying. Influences of Sc on microstructure and oxidation resistance ...were investigated by cycle oxidation at 650 ℃. Results showed that Sc promotes oxides refinement, adjusts the distribution of Al2O3 scales and reduces flocculent oxides formation by W-element segregation. However, the addition of Sc in alloy accelerates the dissolution of the residual β phase and the precipitation of silicides, resulting in the cracking of the oxide films and deteriorating the oxidation resistance. Finally, the 0.3 wt% Sc alloy exhibits superior resistance to high-temperature oxidation.
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•Investigated the oxidation resistance of scandium microalloying near-α high-temperature titanium alloys.•The microstructure and oxide scale are fined and the segregation of W element is reduced with the addition of Sc.•Sc can promote the precipitation of silicide, leading to the oxidation films cracking during oxidation.
The role of scandium, a rare-earth element, on the corrosion resistance of Ti64 alloy in 0.6 M of a sodium chloride (NaCl) solution is investigated through microstructure characterization, and ...electrochemical and slow strain rate tensile (SSRT) tests. The results indicate that the addition of scandium (Ti64–0.3Sc) increases the polarization resistance, reduces the corrosion rate and inhibits the formation of corrosion products. Besides, the tensile strength of Ti64–0.3Sc is enhanced with less susceptibility to stress corrosion. The microstructures show that scandium refines the grain size and increases the volume ratio of the β/α phase, the rate of production and stability of the passivation film are enhanced. Moreover, scandium readily reacts with interstitial oxygen in the matrix to form scandium (III) oxide (Sc2O3), hence reducing the aluminum equivalent and phase production in titanium aluminide (Ti3Al), which have a positive effect on increasing the resistance of the alloy to stress corrosion. The findings of this study provide theoretical guidance for the design of high strength and corrosion resistant titanium alloys.
•By adding Sc to Ti64, the UTS is enhanced and the stress corrosion sensitivity is reduced. Sc2O3 particles inhibit the movement of dislocations.•Sc refines the grain size of the alloy and increases the β/α phase volume ratio. Sc additionally prevents recrystallization and improves the dislocation density of the alloy during annealing.•Sc reacts with oxygen in the alloy, reduces the oxygen content, and prevents the formation of large amounts of Ti3Al.
The strong dependency of almost all malignant tumors on methionine potentially offers a pathway for cancer treatment. We engineer an attenuated strain of Salmonella typhimurium to overexpress an ...L-methioninase with the aim of specifically depriving tumor tissues of methionine. The engineered microbes target solid tumors and induce a sharp regression in several very divergent animal models of human carcinomas, cause a significant decrease in tumor cell invasion, and essentially eliminate the growth and metastasis of these tumors. RNA sequencing analyses reveal that the engineered Salmonella reduce the expression of a series of genes promoting cell growth, cell migration, and invasion. These findings point to a potential treatment modality for many metastatic solid tumors, which warrants further tests in clinical trials.
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•An attenuated Salmonella strain is engineered to express a methioninase, named SGN1•The microbe SGN1 can preferentially target and deprive tumor tissues of methionine•SGN1 leads to oncolysis and suppression of metastasis in several types of cancer•SGN1 induces expression changes in those genes regulating growth and metastasis
Zhou et al. reveal a technology that uses a genetically engineered microbe to metabolically target methionine dependency, a feature common to the majority of malignancies. The microbe, SGN1, selectively depletes methionine in tumors, leading to oncolysis and suppression of metastasis in several types of tested cancer.
A new hole transporting material (HTM) named DMZ is synthesized and employed as a dopant‐free HTM in inverted planar perovskite solar cells (PSCs). Systematic studies demonstrate that the thickness ...of the hole transporting layer can effectively enhance the morphology and crystallinity of the perovskite layer, leading to low series resistance and less defects in the crystal. As a result, the champion power conversion efficiency (PCE) of 18.61% with JSC = 22.62 mA cm−2, VOC = 1.02 V, and FF = 81.05% (an average one is 17.62%) is achieved with a thickness of ≈13 nm of DMZ (2 mg mL−1) under standard global AM 1.5 illumination, which is ≈1.5 times higher than that of devices based on poly(3,4‐ethylenedioxythiophene)/poly(styrene sulfonic acid) (PEDOT:PSS). More importantly, the devices based on DMZ exhibit a much better stability (90% of maximum PCE retained after more than 556 h in air (relative humidity ≈ 45%–50%) without any encapsulation) than that of devices based on PEDOT:PSS (only 36% of initial PCE retained after 77 h in same conditions). Therefore, the cost‐effective and facile material named DMZ offers an appealing alternative to PEDOT:PSS or polytriarylamine for highly efficient and stable inverted planar PSCs.
A dopant‐free hole transporting material (HTM) named DMZ, is synthesized and applied in inverted planar perovskite solar cells (PSCs). High power conversion efficiency (PCE) (18.61%) and stable‐enhanced PSCs devices are achieved and after storage for nearly 560 h, 90% of the maximum PCE is retained in air with a relative humidity ≈ 45%–50% without any encapsulation.
The study of fractal percolation in shale pores is beneficial to the exploration and development of shale oil and gas, and the application of the fractal dimension to the characterization of ...percolation capacity can help to clarify the mechanism of gas percolation in shale. In this study, gas adsorption (CO2 and N2) and high-pressure mercury injection porosimetry (MICP) and gray correlation method are mainly used to investigate the shales of the Lower Silurian Longmaxi Formation in the Luzhou–Changning area in the southern Sichuan basin. In this study, we establish a new template to evaluate the degree of matching between the template and actual geological data considering the effects of shale fractal dimension, tortuosity, the Knudsen number (Kn), and porosity on permeability. The results reveal three observations. First, the deep organic shale pores of the Longmaxi Formation in the area have obvious multiscale fractal characteristics, and the fractal dimension (D) values reflect the complexity of shale pores at different scales. There are significant differences in the fractal dimensions among the three shale lithofacies types. Siliceous shale of D1 with the highest micropore fractal dimension, D2 with mesoporous, and D3 with macroporous indicate more complex pore structures, which provide plenty of gas adsorption and enrichment spaces. These structures are conducive to gas accumulation. Second, there are complex correlations between the total organics content (TOC), the mineral composition, and the inhomogeneity parameters of shale. The TOC, siliceous mineral content, and inhomogeneity parameters of porosity, tortuosity, Kn, and D are positively correlated. The carbonate mineral content and clay mineral content are negatively correlated with the inhomogeneity parameters porosity, tortuosity, Kn, and D. Third and finally, based on correlation analysis, the three main parameters of D, porosity, and tortuosity were ultimately determined, and corresponding templates were established. It reflects that permeability, which is a parameter of seepage capacity, has a high correlation with fractal dimension, tortuosity, and porosity.
•Four dominant bacterial species were isolated from the stem ends of cut gerberas.•Each bacterial species cause stem bending and short vase life of cut gerberas.•Nano-silver (NS) strongly inhibited ...the growth of each bacterial species in vitro.•NS pretreatment reduced stem bending and improved water uptake of cut gerberas.•NS pretreatment alleviated bacterial proliferation in stem ends of cut gerberas.
Stem bending during vase time is a major problem in many cultivars of cut gerbera flowers. In this study, we focused on the involvement of postharvest bacteria and evaluated the efficacy of nano-silver (NS) in reducing bacterial proliferation and stem bending in cut gerbera ‘Real’ flowers in vitro and in vivo. Four species of dominant bacteria, Pseudomonas sp., Acinetobacter junii, Bacillus stearothermophilus, and Myroides sp., were isolated from the stem ends of cut gerberas. Exogenous addition of 3–5 log10 colony forming units (CFU) mL−1 of each bacterial species resulted in a sharp reduction in vase life, relative fresh weight, and water uptake of cut gerbera flowers. However, Pseudomonas sp. had little impact on their vase life and ornamental quality at concentrations of 3–4 log10 CFU mL−1. In vitro assessments showed that the minimum inhibitory concentrations (MICs) of NS for both A. junii and Myroides sp. were 2.5 mg L−1, and NS MICs for B. stearothermophilus and Pseudomonas sp. were 5 and 7.5 mg L−1, respectively. Additionally, compared with the control, pretreatment with 5 and 10 mg L−1 NS for 24 h nearly doubled the vase life of cut gerberas, maintained their relative fresh weight, and improved water uptake. Furthermore, scanning electron microscopy revealed that the NS pretreatment reduced bacterial colonization on the stem ends. Overall, our findings indicate that all four genera of dominant bacterial species isolated from the stem ends of cut gerberas are involved in stem bending, and NS pretreatment effectively alleviated bacteria-induced xylem blockage and improved water uptake, thereby reducing the incidence of stem bending and extending the vase life of cut gerberas.
Background: Meningitis is a severe and fatal neurological disease and causes lots of disease burden. The purpose of this study was to assess the global, regional, and national burdens and trends of ...meningitis by age, sex, and etiology. Methods: Data on the burden of meningitis were collected from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. R and Joinpoint were used for statistical analysis and charting. Results: In 2019, meningitis caused 236,222 deaths and 15,649,865 years of life lost (YLL) worldwide. The age-standardized death rate and age-standardized YLL rate of meningitis were 3.29 and 225, which decreased steadily. Burden change was mainly driven by epidemiological changes. Regionally, meningitis burden was the highest in Sub-Saharan Africa. Burden of disease increasingly concentrated in low sociodemographic index countries, and this was most pronounced in meningitis caused by N. meningitidis. Countries such as Mali, Nigeria, Sierra Leone, etc., especially need to enhance the rational allocation of public health resources to reduce the disease burden. Children and men were more likely to be affected by meningitis. PM2.5 was found to be an important risk factor. Conclusions: This study provides the first comprehensive understanding of the global disease burden of meningitis caused by specific pathogens and highlights policy priorities to protect human health worldwide, with particular attention to vulnerable regions, susceptible populations, environmental factors, and specific pathogens.
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