The safety and efficacy of systemic delivery of a new liver-de-targeted TGFβ signaling inhibiting adenovirus in an immunocompetent triple negative mouse mammary tumor model

Aberrant TGFβ signaling is linked to metastasis and tumor immune escape of many cancers including metastatic triple negative breast cancer (mTNBC). Previously, we have found that oncolytic adenoviruses expressing a TGFβ signaling inhibitory protein (sTGFβRIIFc) induced immune activation in a mouse TNBC (4T1) immunocompetent subcutaneous model with intratumoral injection. Systemic administration of adenoviruses can be a superior route to treat mTNBC but faces the challenges of increased toxicity and viral clearance. Thus, we created a liver-de-targeted sTGFβRIIFc- and LyP-1 peptide-expressing adenovirus (mHAdLyp.sT) with enhanced breast cancer cell tropism. Its safety and immune response features were profiled in the 4T1 model. Our data showed that the systemic administration of mHAdLyp.sT resulted in reduced hepatic and systemic toxicity. mHAdLyp.sT was also effective in increasing Th1 cytokines and anti-tumor cell populations by cytokine analysis, spleen/tumor qRT-PCR, and flow cytometry. We further tested the therapeutic effects of mHAdLyp.sT alone and in combination with immune checkpoint inhibitors (ICIs). mHAdLyp.sT alone and with all ICI combinations elicited significant inhibition of lung metastasis by histological analysis. When mHAdLyp.sT was combined with both anti-PD-1 and anti-CTLA-4 antibodies, primary 4T1 tumor growth was also significantly inhibited. We are confident in advancing this new treatment option for mTNBC

Systemic Delivery of Oncolytic Adenoviruses Targeting Transforming Growth Factor-β Inhibits Established Bone Metastasis in a Prostate Cancer Mouse Model

Abstract We have examined whether Ad.sT?RFc and TAd.sT?RFc, two oncolytic viruses expressing soluble transforming growth factor-? receptor II fused with human Fc (sTGF?RIIFc), can be developed to treat bone metastasis of prostate cancer. Incubation of PC-3 and DU-145 prostate tumor cells with Ad.sT?RFc and TAd.sT?RFc produced sTGF?RIIFc and viral replication; sTGF?RIIFc caused inhibition of TGF-?-mediated SMAD2 and SMAD3 phosphorylation. Ad(E1-).sT?RFc, an E1? adenovirus, produced sTGF?RIIFc but failed to replicate in tumor cells. To examine the antitumor response of adenoviral vectors, PC-3-luc cells were injected into the left heart ventricle of nude mice. On day 9, mice were subjected to whole-body bioluminescence imaging (BLI). Mice bearing hind-limb tumors were administered viral vectors via the tail vein on days 10, 13, and 17 (2.5?1010 viral particles per injection per mouse, each injection in a 0.1-ml volume), and subjected to BLI and X-ray radiography weekly until day 53. Ad.sT?RFc, TAd.sT?RFc, and Ad(E1-).sT?RFc caused significant inhibition of tumor growth; however, Ad.sT?RFc was the most effective among all the vectors. Only Ad.sT?RFc and TAd.sT?RFc inhibited tumor-induced hypercalcemia. Histomorphometric and synchrotron micro-computed tomographic analysis of isolated bones indicated that Ad.sT?RFc induced significant reduction in tumor burden, osteoclast number, and trabecular and cortical bone destruction. These studies suggest that Ad.sT?RFc and TAd.sT?RFc can be developed as potential new therapies for prostate cancer bone metastasis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98454/1/hum%2E2012%2E040.pd

Corrigendum: Hu H et al. (2023) Taxonomic and phylogenetic characterisations of six species of Pleosporales (in Didymosphaeriaceae, Roussoellaceae and Nigrogranaceae) from China. MycoKeys 100: 123–151. https://doi.org/10.3897/mycokeys.100.109423

Four new species, Xynobius azonius sp. nov., X. brevifemora sp. nov., X. duoferus sp. nov., and X. stipitoides sp. nov., are described and illustrated, and one species X. geniculatus (Thomson, 1895) is newly reported from South Korea. Xynobius geniculatus (Thomson, 1895) is redescribed and illustrated, and a new combination, Xynobius (Stigmatopoea) cubitalis (Fischer, 1959), comb. nov. is suggested. An identification key to the Xynobius species known from South Korea is provided

Taxonomic and phylogenetic characterisations of six species of Pleosporales (in Didymosphaeriaceae, Roussoellaceae and Nigrogranaceae) from China

Pleosporales comprise a diverse group of fungi with a global distribution and significant ecological importance. A survey on Pleosporales (in Didymosphaeriaceae, Roussoellaceae and Nigrogranaceae) in Guizhou Province, China, was conducted. Specimens were identified, based on morphological characteristics and phylogenetic analyses using a dataset composed of ITS, LSU, SSU, tef1 and rpb2 loci. Maximum Likelihood (ML) and Bayesian analyses were performed. As a result, three new species (Neokalmusia karka, Nigrograna schinifolium and N. trachycarpus) have been discovered, along with two new records for China (Roussoella neopustulans and R. doimaesalongensis) and a known species (Roussoella pseudohysterioides). Morphologically similar species and phylogenetically close taxa are compared and discussed. This study provides detailed information and descriptions of all newly-identified taxa

Macrophage-mediated trogocytosis contributes to destroying human schistosomes in a non-susceptible rodent host, Microtus fortis

Schistosoma parasites, causing schistosomiasis, exhibit typical host specificity in host preference. Many mammals, including humans, are susceptible to infection, while the widely distributed rodent, Microtus fortis, exhibits natural anti-schistosome characteristics. The mechanisms of host susceptibility remain poorly understood. Comparison of schistosome infection in M. fortis with the infection in laboratory mice (highly sensitive to infection) offers a good model system to investigate these mechanisms and to gain an insight into host specificity. In this study, we showed that large numbers of leukocytes attach to the surface of human schistosomes in M. fortis but not in mice. Single-cell RNA-sequencing analyses revealed that macrophages might be involved in the cell adhesion, and we further demonstrated that M. fortis macrophages could be mediated to attach and kill schistosomula with dependence on Complement component 3 (C3) and Complement receptor 3 (CR3). Importantly, we provided direct evidence that M. fortis macrophages could destroy schistosomula by trogocytosis, a previously undescribed mode for killing helminths. This process was regulated by Ca2+/NFAT signaling. These findings not only elucidate a novel anti-schistosome mechanism in M. fortis but also provide a better understanding of host parasite interactions, host specificity and the potential generation of novel strategies for schistosomiasis control

Reliability assessment of discrete-time k/n (G) retrial system based on different failure types and the δ-shock model

The k/n (G) system is a typical reliability system in engineering practice. However, research on this system under discrete-time and retrial conditions is still limited. This paper establishes a k/n (G) retrial system model under a discrete-time condition based on different failure types and the δ-shock model, whose objective is to investigate its various reliability measures and the relationship between measures and parameters. Two methodologies are utilized in this paper to evaluate the system’s various measures: the analytical method for the discrete-time Markov process and the Monte Carlo simulation method. The two methodologies are compared, and optimization is performed on certain measures concerning system parameters. A discrete PH distribution representation method for component lifetime under the δ-shock is presented, the relationship between various reliability measures of the system and various parameters is determined, and a novel approach for system reliability research based on the discrete PH distribution and the δ-shock is provided in this paper

Phytoextraction and Migration Patterns of Cadmium in Contaminated Soils by <i>Pennisetum hybridum</i>

This study was conducted to identify soil cadmium (Cd) removal pathways and their contribution rates during phytoremediation by Pennisetum hybridum, as well as to comprehensively assess its phytoremediation potential. Multilayered soil column tests and farmland-simulating lysimeter tests were conducted to investigate the Cd phytoextraction and migration patterns in topsoil and subsoil simultaneously. The aboveground annual yield of P. hybridum grown in the lysimeter was 206 ton·ha−1. The total amount of Cd extracted in P. hybridum shoots was 234 g·ha−1, which was similar to that of other typical Cd-hyperaccumulating plants such as Sedum alfredii. After the test, the topsoil Cd removal rate was 21.50–35.81%, whereas the extraction efficiency in P. hybridum shoots was only 4.17–8.53%. These findings indicate that extraction by plant shoots is not the most important contributor to the decrease of Cd in the topsoil. The proportion of Cd retained by the root cell wall was approximately 50% of the total Cd in the root. Based on column test results, P. hybridum treatment led to a significant decrease in soil pH and considerably enhanced Cd migration to subsoil and groundwater. P. hybridum decreases Cd in the topsoil through multiple pathways and provides a relatively ideal material for phytoremediation of Cd-contaminated acid soils

Flow of nitrous oxide in a venturi tube under conditions of a hybrid rocket motor

A Venturi tube is typically used as the flow control element of hybrid rocket motors (HRMs) for the precise control of the flow of a liquid oxidizer, e.g., nitrous oxide, which can efficiently realize the thrust throttling of motors. The flow rate of nitrous oxide in the venturi tube was calculated for a heterogeneous non-equilibrium flow by considering the influence of the variation in the compressibility temperature. In addition, a nitrous-oxide flow rate measurement system was established to calibrate the flow rate coefficient and obtain the corresponding calculation parameters. Results revealed that upstream pressure is not affected by back pressure when the throat pressure is less than a saturated vapor pressure of 4.2 MPa at the local temperature for the venturi tube with a throat diameter of 1.65 mm; however, cavitation disappeared at a back pressure of greater than 6.35 MPa. A flow rate evaluation error of less than 6 wt% was achieved by using the experimentally determined non-equilibrium parameter in the flow rate calculation method

Effects of Multi-Bacteria Solid-State Fermented Diets with Different Crude Fiber Levels on Growth Performance, Nutrient Digestibility, and Microbial Flora of Finishing Pigs

This study aimed to investigate the effects of multi-bacteria solid-state fermented diets with different crude fiber (CF) levels on growth performance, nutrient digestibility, and microbial flora of finishing pigs. The multi-bacteria solid-state fermented diets were made up of Lactobacillus amylovorus, Enterococcus faecalis, Bacillus subtilis, and Candida utilis. According to a 2 (factors) × 2 (levels) design, with the two factors being multi-bacteria solid-state fermentation (fed non-fermented diet or multi-bacteria fermentation) or CF levels (fed a basal diet containing 2.52% CF or 7.00% CF), a total of 36 finishing pigs (70.80 ± 5.75 kg) were divided into 4 treatments with 9 barrows per group: (1) pigs fed a diet containing 7.00% CF (HF), (2) pigs fed a multi-bacteria fermentation diet containing 7.00% CF (HFM), (3) pigs fed a diet containing 2.52% CF (LF), and (4) piglets fed a multi-bacteria fermentation diet containing 2.52% CF (LFM). This experiment lasted 28 days. The multi-bacteria solid-state fermented diet increased the backfat thickness (p p p Lactobacillus, Oscillospira, and Coprococcus (p p p p Streptococcaceae (p p p p Clostridiaceae_Clostridium and Coprococcus (p p p p p Akkermansia and Oscillospira (p p < 0.05). The 7.00% CF had a negative effect on the digestion of nutrients, but multi-bacteria solid-state fermentation diets could relieve this negative effect and increase backfat thickness. High-fiber diets and multi-bacteria solid-state fermentation improved the diversity and abundance of fecal microorganisms in finishing pigs

Genistein induces apoptosis of colon cancer cells by reversal of epithelial-to-mesenchymal via a Notch1/NF-κB/slug/E-cadherin pathway

Abstract Background Genistein has been known to inhibit proliferation and induce apoptosis in several kinds of cancer cells. While knowledge of genistein in regulating epithelial mesenchymal transition (EMT) of colon cancer cells is unknown. Methods To investigate the effects and mechanisms of genistein on EMT of colon cancer cells, HT-29 cells were used and treated by genistein and TNF-α in this paper. EMT was determined by cell invasion assays using a transwell chamber and the expression changes of EMT-related markers were confirmed by RT–PCR, Western blotting, and immunofluorescence staining. Results Genistein inhibited cell migration at 200 μmol/L. Genistein reversed the EMT of colon cancer cells by upregulation of E-cadherin and downregulation of N-cadherin, accompanied by the suppression of EMT related makers, such as Snail2/slug, ZEB1, ZEB2, FOXC1, FOXC2 and TWIST1. Moreover, genistein can inhibit the expression of notch-1, p-NF-κB and NF-κB, while promote the expression of Bax/Bcl-2 and caspase-3 in HT-29 cells. Conclusion The present study demonstrated that genistein suppressed the migration of colon cancer cells by reversal the EMT via suppressing the Notch1/NF-κB/slug/E-cadherin pathway. Genistein may be developed as a potential antimetastasis agent to colon cancer