Search

Highly desmoplastic and immunosuppressive tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) contributes to tumor progression and resistance to current therapies. Clues targeting the notorious stromal environment have offered hope for improving therapeutic response whereas the underlying mechanism remains unclear. Here, we find that prognostic microfibril associated protein 5 (MFAP5) is involved in activation of cancer-associated fibroblasts (CAFs). Inhibition of MFAP5highCAFs shows synergistic effect with gemcitabine-based chemotherapy and PD-L1-based immunotherapy. Mechanistically, MFAP5 deficiency in CAFs downregulates HAS2 and CXCL10 via MFAP5/RCN2/ERK/STAT1 axis, leading to angiogenesis, hyaluronic acid (HA) and collagens deposition reduction, cytotoxic T cells infiltration, and tumor cells apoptosis. Additionally, in vivo blockade of CXCL10 with AMG487 could partially reverse the pro-tumor effect from MFAP5 overexpression in CAFs and synergize with anti-PD-L1 antibody to enhance the immunotherapeutic effect. Therefore, targeting MFAP5highCAFs might be a potential adjuvant therapy to enhance the immunochemotherapy effect in PDAC via remodeling the desmoplastic and immunosuppressive microenvironment.

The gut microbiota and liver cancer have a complex interaction. However, the role of gut microbiome in liver tumor initiation remains unknown. Herein, liver cancer was induced using hydrodynamic transfection of oncogenes to explore liver tumorigenesis in mice. Gut microbiota depletion promoted liver tumorigenesis but not progression. Elevated sterol regulatory element-binding protein 2 (SREBP2) was observed in mice with gut flora disequilibrium. Pharmacological inhibition of SREBP2 or Srebf2 RNA interference attenuated mouse liver cancer initiation under gut flora disequilibrium. Furthermore, gut microbiota depletion impaired gut tryptophan metabolism to activate aryl hydrocarbon receptor (AhR). AhR agonist Ficz inhibited SREBP2 posttranslationally and reversed the tumorigenesis in mice. And, AhR knockout mice recapitulated the accelerated liver tumorigenesis. Supplementation with Lactobacillus reuteri , which produces tryptophan metabolites, inhibited SREBP2 expression and tumorigenesis in mice with gut flora disequilibrium. Thus, gut flora disequilibrium promotes liver cancer initiation by modulating tryptophan metabolism and up-regulating SREBP2.

This study developed an analysis based on children’s multi-sensory experiences and preferences in urban forest park to make practical suggestions for the design of children’s activity areas. Taking Maofeng Mountain Forest Park in Guangzhou, Guangdong province as a case study, based on a face-to-face survey and online questionnaire survey, this study analyzed children’s multi-sensory landscape preferences in the park and explored the influence of multi-sensory experiences on children’s behavioral experience by establishing a structural equation model. The results reveal that visual, auditory, tactile and olfactory sensations were significantly correlated with children’s behavioral experiences. In terms of landscape preference, children preferred landscapes in blue-green tones, original building materials and challenging entertainment programs. Based on these analysis results, the design recommendations for children’s activity areas in urban forest parks are discussed.

The chromatographic fingerprint of 14 batches of

Programmed death-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) help tumor cells evade immune surveillance, and are regarded as important targets of anti-tumor immunotherapy. Post-translational modification of PD-L1 has potential value in immunosuppression. Here, we identified that ubiquitin-specific protease 8 (USP8) deubiquitinates PD-L1. Pancreatic cancer tissues exhibited significantly increased USP8 levels compared with those in normal tissues. Clinically, the expression of USP8 showed a significant association with the tumor-node-metastasis stage in multiple patient-derived cohorts of pancreatic cancer. Meanwhile, USP8 deficiency could reduce tumor invasion and migration and tumor size in an immunity-dependent manner, and improve anti-tumor immunogenicity. USP8 inhibitor pretreatment led to reduced tumorigenesis and immunocompetent mice with Usp8 knockdown tumors exhibited extended survival. Moreover, USP8 interacted positively with PD-L1 and upregulated its expression by inhibiting the ubiquitination-regulated proteasome degradation pathway in pancreatic cancer. Combination therapy with a USP8 inhibitor and anti-PD-L1 effectively suppressed pancreatic tumor growth by activation of cytotoxic T-cells and the anti-tumor immunity was mainly dependent on the PD-L1 pathway and CD8 + T cells. Our findings highlight the importance of targeting USP8, which can sensitize PD-L1-targeted pancreatic cancer to immunotherapy and might represent a novel therapeutic strategy to treat patients with pancreatic tumors in the future.

BackgroundsIn advanced pancreatic ductal adenocarcinoma (PDAC), immune therapy, including immune checkpoint inhibitors, has limited efficacy, encouraging the study of combination therapy.MethodsTumor necrosis factor receptor 2 (TNFR2) was analyzed via immunohistochemistry, immunofluorescence, western blotting, and ELISAs. The in vitro mechanism that TNFR2 regulates programmed cell death 1 ligand 1 (PD-L1) was investigated using immunofluorescence, immunohistochemistry, flow cytometry, western blotting, and chromatin immunoprecipitation (ChIP). In vivo efficacy and mechanistic studies, using C57BL/6 mice and nude mice with KPC cell-derived subcutaneous and orthotopic tumors, employed antibodies against TNFR2 and PD-L1. Survival curves were constructed for the orthotopic model and a genetically engineered PDAC model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre). Mass cytometry, immunohistochemistry, and flow cytometry analyzed local and systemic alterations in the immunophenotype.ResultsTNFR2 showed high expression and is a prognostic factor in CD8+ T cell-enriched pancreatic cancer. TNFR2 promotes tumorigenesis and progression of pancreatic cancer via dual effect: suppressing cancer immunogenicity and partially accelerating tumor growth. TNFR2 positivity correlated with PD-L1, and in vitro and in vivo, it could regulate the expression of PDL1 at the transcription level via the p65 NF-κB pathway. Combining anti-TNFR2 and PD-L1 antibodies eradicated tumors, prolonged overall survival in pancreatic cancer, and induced strong antitumor immune memory and secondary prevention by reducing the infiltration of Tregs and tumor-associated macrophages and inducing CD8+ T cell activation in the PDAC microenvironment. Finally, the antitumor immune response derived from combination therapy is mainly dependent on CD8+ T cells, partially dependent on CD4+ T cells, and independent of natural killer cells.ConclusionsAnti-TNFR2 and anti-PD-L1 combination therapy eradicated tumors by inhibiting their growth, relieving tumor immunosuppression, and generating robust memory recall.

This study aims to analyze the indoor environment preferences of Chinese urban elderly, to create a living environment that is beneficial to the physical and mental health of Chinese elderly, and to enhance their sense of well-being. Based on an in-depth study of 306 urban elderly’s bedroom indoor environment preference in 21 Chinese provinces, using questionnaire method, this study concludes that: (1) Group characteristics: for urban elderly, the key words for bedroom color and lighting preference are low saturation, bright, warm tones and warm white light; personal characteristics such as the gender, physical condition, and education have a strong correlation with factors in the indoor living environment; (2) Physical environment preferences: gender presents the most significant potential effect on elderly physical environment preferences; (3) Established indicator system: the indicator system includes five main indicators of basic bedroom conditions, bedroom materials, bedroom colors, bedroom physical environment and other soft furnishings, and 22 sub-indicators. This study has some implications for guiding the design of elderly’s apartments and the bedroom environment, as well as effectively using the indoor environment to meet the physiological and psychological needs of the urban elderly.

The Mixed Lineage Leukemia protein 1 (MLL1) plays an essential role in the maintenance of the histone H3 lysine 4 (H3K4) methylation status for gene expression during differentiation and development. The methyltransferase activity of MLL1 is regulated by three conserved core subunits, WDR5, RBBP5 and ASH2L. Here, we determined the structure of human RBBP5 and demonstrated its role in the assembly and regulation of the MLL1 complex. We identified an internal interaction between the WD40 propeller and the C-terminal distal region in RBBP5, which assisted the maintenance of the compact conformation of the MLL1 complex. We also discovered a vertebrate-specific motif in the C-terminal distal region of RBBP5 that contributed to nucleosome recognition and methylation of nucleosomes by the MLL1 complex. Our results provide new insights into functional conservation and evolutionary plasticity of the scaffold protein RBBP5 in the regulation of KMT2-family methyltransferase complexes.

Conidiation capacity and conidial quality are very important for the production and application of mycopesticides. Most filamentous ascomycetous fungi have two distinct patterns of conidiation. Conidiation through microcycle conidiation proceeds to more rapidly achieve a maximum of conidial yield than normal conidiation and hence is of greater merit for exploitation in mass production of fungal insect pathogens, such as Metarhizium acridum. In this study, the mechanism underlying the conidiation pattern shift in M. acridum was explored by characterization of the fungal homeobox gene MaH1. MaH1 was evidently localized to the nuclei of hyphae and transcriptionally expressed at a maximal level when conidiation began. Intriguingly, deletion of MaH1 in M. acridum resulted in a shift of normal conidiation to microcycle conidiation on one-quarter strength Sabouraud's dextrose agar medium, and hence accelerated conidiation and increased conidial yield. In the deletion mutant, moreover, conidia became larger in size and hyphae cells were shorter in length while conidial virulence and stress tolerance were not altered. As revealed by digital gene expression profiling, MaH1 controlled the shift of conidiation patterns by mediating transcription of a set of genes related to hyphal growth, cell differentiation, conidiation, and some important signaling pathways. These findings indicate that MaH1 and its downstream genes can be exploited to increase the conidial yield for more efficient production of mycopesticides.

Urban forest parks play a crucial role in contributing to the urban environment, residential well-being, and social welfare. Visitors’ perception of multi-sensory interactive experiences in urban forest parks is an important source of information for landscape planning. Whilst data elicited from visitors via questionnaires are temporally and spatially restricted, online media provide a public platform for the direct and comprehensive expression of park experiences beyond such restrictions. To look into visitors’ multi-sensory interactive experiences in an urban forest park in China, a total of 7447 reviews of such were collected from four authoritative online platforms using Python, and the ROSTCM tool was used to generate semantic and social networks out of the data set. The results showed that urban forest park visitors’ sensory experiences are dominated by visual and olfactory perceptions, followed by audio-visual and visual-tactile interactions. Among them, visual perception displays the highest degree of specificity and diversity, while tactile and gustatory perceptions are relatively infrequent and singular. The landscapes that affect visitors’ perceptual preferences mainly include floriculture, green vegetation, soundscapes, and sanitation utilities. Moreover, both the fresh air and the agreeable environment have a significant positive impact on visitors’ perceptions. The above findings not only have practical implications for the landscape planning and design of urban forest parks, but also provide theoretical insights into the evaluation of natural landscapes in urban forest parks from the perspective of tourists’ multi-sensory experiences.

p62/SQSTM1 is frequently up-regulated in many cancers including hepatocellular carcinoma. Highly expressed p62 promotes hepato-carcinogenesis by activating many signaling pathways including Nrf2, mTORC1, and NFκB signaling. However, the underlying mechanism for p62 up-regulation in hepatocellular carcinoma remains largely unclear. Herein, we confirmed that p62 was up-regulated in hepatocellular carcinoma and its higher expression was associated with shorter overall survival in patients. The knockdown of p62 in hepatocellular carcinoma cells decreased cell growth in vitro and in vivo. Intriguingly, p62 protein stability could be reduced by its acetylation at lysine 295, which was regulated by deacetylase Sirt1 and acetyltransferase GCN5. Acetylated p62 increased its association with the E3 ligase Keap1, which facilitated its poly-ubiquitination-dependent proteasomal degradation. Moreover, Sirt1 was up-regulated to deacetylate and stabilize p62 in hepatocellular carcinoma. Additionally, Hepatocyte Sirt1 conditional knockout mice developed much fewer liver tumors after Diethynitrosamine treatment, which could be reversed by the re-introduction of exogenous p62. Taken together, Sirt1 deacetylates p62 at lysine 295 to disturb Keap1-mediated p62 poly-ubiquitination, thus up-regulating p62 expression to promote hepato-carcinogenesis. Therefore, targeting Sirt1 or p62 is a reasonable strategy for the treatment of hepatocellular carcinoma.

The purpose of this study is to explore the audio-visual preferences of exercisers in urban forest parks in China and to make practical suggestions for park landscape design. Taking Beigushan Forest Park in Lianyungang City, Jiangsu Province as a case, based on field research and questionnaire survey, this study analyzed the audio-visual preference characteristics of exercisers in the park, revealed the correlation between audio-visual preference and exercisers’ behaviors and individual characteristics, and explored the influence of audio-visual preferences on exercise feelings by establishing a structural equation model. It was found that (1) the forest and its avenue landscape and birdsong are most preferred by exercisers; (2) the audio-visual preferences of people with different exercise forms differ, for example, people who slowly walk, run, and briskly walk have stronger preferences for natural soundscape and visual landscape, while people who use fitness equipment have stronger inclusiveness for human activity sound and prefer public facility-based landscapes. In addition, some individual characteristics such as exercise intensity and exercise frequency significantly affect exercisers’ audio-visual preferences; (3) visual landscape preferences have a greater direct impact on exercise feelings, with natural waterscape having the greatest direct impact, but overall soundscape preferences do not have a high degree of direct impact on exercise feelings, with natural sound still having a strong positive impact. These findings provide a more quantitative basis for the landscape design of urban forest parks from the perspective of exercise behavior.

Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR TKIs) greatly improved clinical outcomes of patients with non-small cell lung cancer (NSCLC). Unfortunately, primary and acquired resistance limits their clinical benefits. To overcome such resistance, new generations of EGFR TKIs have been developed by targeting newly identified mutations in EGFR. However, much less effort has been put into alternative strategies, such as targeting the intrinsic protective responses to EGFR TKIs. In this study, we found that EGFR TKIs, including gefitinib and AZD9291, impaired lysosome-dependent degradation of SQSTM1, thus compromising their anti-cancer efficiency. By accumulating in the lysosome lumen, gefitinib and AZD9291 attenuated lysosomal acidification and impaired autolysosomal degradation of SQSTM1 owing to their intrinsic alkalinity. As a result, SQSTM1 protein was stabilized in response to gefitinib and AZD9291 treatment and conferred EGFR TKI resistance. Depleting SQSTM1 significantly increased the sensitivity of NSCLC cells to gefitinib and AZD9291 both in vitro and in vivo. Furthermore, a chemically modified gefitinib analog lacking alkalinity displayed stronger inhibitory effects on NSCLC cells. Therefore, targeting accumulated SQSTM1 or chemically modified EGFR TKIs may represent new strategies to increase the effectiveness of EGFR targeted therapy.

In this paper, we introduce a new graph operation called subdivision vertex-edge join (denoted by G 1 S ▹ ( G 2 V ∪ G 3 E ) for short), and then the adjacency spectrum, the Laplacian spectrum and the signless Laplacian spectrum of G 1 S ▹ ( G 2 V ∪ G 3 E ) are respectively determined in terms of the corresponding spectra for a regular graph G 1 and two arbitrary graphs G 2 and G 3 . All the above can be viewed as the generalizations of the main results in [X. Liu, Z. Zhang, Bull. Malays. Math. Sci. Soc., 2017:1⁻17]. Furthermore, we also determine the normalized Laplacian spectrum of G 1 S ▹ ( G 2 V ∪ G 3 E ) whenever G i are regular graphs for each index i = 1 , 2 , 3 . As applications, we construct infinitely many pairs of A-cospectral mates, L-cospectral mates, Q-cospectral mates and L -cospectral mates. Finally, we give the number of spanning trees, the (degree-)Kirchhoff index and the Kemeny’s constant of G 1 S ▹ ( G 2 V ∪ G 3 E ) , respectively.

Application of analytic method and Constructing the Smarandachely adjacent vertex distinguishing E-total coloring function, the Smarandachely adjacent vertex distinguishing E-total coloring of two kinds of 3-regular graphs are mainly discussed, and the Smarandachely adjacent vertex distinguishing E-total chromatic number of join graph are obtained. The Smarandachely adjacent vertex distinguishing E-total coloring conjecture is further validated.

The Smarandachely adjacent-vertex total chromatic number of graph $G$ is the smallest positive integer $k$ for which $G$ has a proper total $k$-coloring such that for any pair of adjacent vertices $u,v$, the set of colors appearing at vertex $u$ and its incident edges is not a subset of the set of colors appearing at vertex $v$ and its incident edges. In this paper, a kind of Generalized 3-regular Ring Graph is defined, and the Smarandachely adjacent-vertex total chromatic numbers is discussed by using construct coloring function. Furthermore, the conjecture of Smarandachely adjacent-vertex total coloring of 3-regular graph is checked.