Macrophage-Derived Nanosponges Adsorb Cytokines and Modulate Macrophage Polarization for Renal Cell Carcinoma Immunotherapy.

Renal cell carcinoma (RCC) is a hot tumor infiltrated by large numbers of CD8+ T cells and is highly sensitive to immunotherapy. However, tumor-associated macrophages (TAMs), mainly M2 macrophages, tend to undermine the efficacy of immunotherapy and promote the progression of RCC. Here, macrophage-derived nanosponges are fabricated by M2 macrophage membrane-coated poly（lactic-co-glycolic acid）（PLGA）, which could chemotaxis to the CXC and CC chemokine subfamily-enriched RCC microenvironment via corresponding membrane chemokine receptors. Subsequently, the nanosponges act like cytokine decoys to adsorb and neutralize broad-spectrum immunosuppressive cytokines such as colony stimulating factor-1(CSF-1), transforming growth factor-ß（TGF-ß）, and Lnterleukin-10（IL-10）, thereby reversing the polarization of M2-TAMs toward the pro-inflammatory M1 phenotype, and enhancing the anti-tumor effect of CD8+ T cells. To further enhance the polarization reprogramming efficiency of TAMs, DSPE-PEG-M2pep is conjugated on the surface of macrophage-derived nanosponges for specific recognition of M2-TAMs, and the toll like receptors 7/8（TLR7/8） agonist, R848, is encapsulated in these nanosponges to induce M1 polarization, which result in significant efficacy against RCC. In addition, these nanosponges exhibit undetectable biotoxicity, making them suitable for clinical applications. In summary, a promising and facile strategy is provided for immunomodulatory therapies, which are expected to be used in the treatment of tumors, autoimmune diseases, and inflammatory diseases.

Characteristics of bacterial community structure in the sediment of Chishui River (China) and the response to environmental factors.

Sediment microorganisms performed an essential function in the biogeochemical cycle of aquatic ecosystems, and their structural composition was closely related to environmental carrying capacity and water quality. In this study, the Chishui River (Renhuai section) was selected as the research area, and the concentrations of environmental factors in the water and sediment were detected. High⁃throughput sequencing was adopted to reveal the characteristics of bacterial community structures in the sediment. In addition, the response of bacteria to environmental factors was explored statistically. Meanwhile, the functional characteristics of bacterial were also analyzed based on the KEGG database. The results showed that the concentration of environmental factors in the water and sediment displayed spatial differences, with the overall trend of midstream > downstream > upstream, which was related to the wastewater discharge from the Moutai town in the midstream directly. Proteobacteria was the most dominant phylum in the sediment, with the relative abundance ranged from 52.06% to 70.53%. The distribution of genus-level bacteria with different metabolic activities varied in the sediment. Upstream was dominated by Massilia, Acinetobacter, and Thermomonas. In the midstream, Acinetobacter, Cloacibacterium and Comamonas were the main genus. Nevertheless, the abundance of Lysobacter, Arenimonas and Thermomonas was higher in the downstream. Redundancy analysis (RDA) showed that total nitrogen (TN) and total phosphorus (TP) were the main environmental factors which affected the structure of bacterial communities in sediment, while total organic carbon (TOC) was the secondary. The bacterial community was primarily associated with six biological pathway categories such as metabolism. Carbohydrate metabolism and amino acid metabolism were the most active functions in the 31 subfunctions. This study could contribute to the understanding of the structural composition and driving forces of bacteria in the sediment, which might benefit for the ecological protection of Chishui River.

New insights into toxicity reduction and pollutants removal during typical treatment of papermaking wastewater.

Papermaking wastewater contained various of toxic and hazardous pollutants that pose significant threats to both the ecosystem and human health. Despite these risks, limited research has addressed the detoxification efficiency and mechanism involved in the typical process treatment of papermaking wastewater. In this study, the acute toxicity of papermaking wastewater after different treatment processes was assessed using luminousbacteria, zebrafish and Daphnia magna (D. magna). Meanwhile, the pollution parament of the corresponding wastewater were measured, and the transformation of organic pollutant in the wastewater was identified by three-dimensional fluorescence and other techniques. Finally, the possible mechanism of toxicity variation in different treatment processes were explored in combination with correlation analyses. The results showed that raw papermaking wastewater displayed high acute toxicity to luminousbacteria, and exhibited slight acute toxicity and acute toxicity effect to zebrafish and D. magna, respectively. After physical and biochemical processes, not only the toxicity of the wastewater to zebrafish and D. magna was completely eliminated, but also the inhibitory effect on luminousbacteria was significantly reduced (TU value decreased from 11.07 to 1.66). Among them, the order of detoxification efficiency on luminousbacteria was air flotation > hydrolysis acidification > IC > aerobic process. Correlation analyses revealed a direct link between the reduced of Total Organic Carbon (TOC) and Chemical Oxygen Demand (COD) and the detoxification efficiency of the different processes on the wastewater. In particular, the removal of benzene-containing aromatic pollutant correlated positively with decreased toxicity. However, the Fenton process, despite lowering TOC and COD, increased of the acute toxicity of the luminousbacteria (TU value increased from 1.66 to 2.33). This may result from the transformation generation of organic pollutant and oxidant residues during the Fenton process. Hence, oxidation technologies such as the Fenton process, as a deep treatment process, should be more concerned about the ecological risks that may be caused while focusing on their effectiveness in removing pollutant.

Endosialin in Cancer: Expression Patterns, Mechanistic Insights, and Therapeutic Approaches.

Endosialin, also known as tumor endothelial marker 1 (TEM1) or CD248, is a single transmembrane glycoprotein with a C-type lectin-like domain. Endosialin is mainly expressed in the stroma, especially in cancer-associated fibroblasts and pericytes, in most solid tumors. Endosialin is also expressed in tumor cells of most sarcomas. Endosialin can promote tumor progression through different mechanisms, such as promoting tumor cell proliferation, adhesion and migration, stimulating tumor angiogenesis, and inducing an immunosuppressive tumor microenvironment. Thus, it is considered an ideal target for cancer treatment. Several endosialin-targeted antibodies and therapeutic strategies have been developed and have shown preliminary antitumor effects. Here, we reviewed the endosialin expression pattern in different cancer types, discussed the mechanisms by which endosialin promotes tumor progression, and summarized current therapeutic strategies targeting endosialin.

Fine root decomposition in forest ecosystems: an ecological perspective.

Fine root decomposition is a physio-biochemical activity that is critical to the global carbon cycle (C) in forest ecosystems. It is crucial to investigate the mechanisms and factors that control fine root decomposition in forest ecosystems to understand their system-level carbon balance. This process can be influenced by several abiotic (e.g., mean annual temperature, mean annual precipitation, site elevation, stand age, salinity, soil pH) and biotic (e.g., microorganism, substrate quality) variables. Comparing decomposition rates within sites reveals positive impacts of nitrogen and phosphorus concentrations and negative effects of lignin concentration. Nevertheless, estimating the actual fine root breakdown is difficult due to inadequate methods, anthropogenic activities, and the impact of climate change. Herein, we propose that how fine root substrate and soil physiochemical characteristics interact with soil microorganisms to influence fine root decomposition. This review summarized the elements that influence this process, as well as the research methods used to investigate it. There is also need to study the influence of annual and seasonal changes affecting fine root decomposition. This cumulative evidence will provide information on temporal and spatial dynamics of forest ecosystems, and will determine how logging and reforestation affect fine root decomposition.

Biomimetic Macrophage Membrane-Camouflaged Nanoparticles Induce Ferroptosis by Promoting Mitochondrial Damage in Glioblastoma.

The increasing understanding of ferroptosis has indicated its role and therapeutic potential in cancer; however, this knowledge has yet to be translated into effective therapies. Glioblastoma (GBM) patients face a bleak prognosis and encounter challenges due to the limited treatment options available. In this study, we conducted a genome-wide CRISPR-Cas9 screening in the presence of a ferroptosis inducer (RSL3) to identify the key driver genes involved in ferroptosis. We identified ALOX15, a key lipoxygenase (LOX), as an essential driver of ferroptosis. Small activating RNA (saRNA) was used to mediate the expression of ALOX15 promoted ferroptosis in GBM cells. We then coated saALOX15-loaded mesoporous polydopamine (MPDA) with Angiopep-2-modified macrophage membranes (MMs) to reduce the clearance by the mononuclear phagocyte system (MPS) and increase the ability of the complex to cross the blood-brain barrier (BBB) during specific targeted therapy of orthotopic GBM. These generated hybrid nanoparticles (NPs) induced ferroptosis by mediating mitochondrial dysfunction and rendering mitochondrial morphology abnormal. In vivo, the modified MM enabled the NPs to target GBM cells, exert a marked inhibitory effect on GBM progression, and promote GBM radiosensitivity. Our results reveal ALOX15 to be a promising therapeutic target in GBM and suggest a biomimetic strategy that depends on the biological properties of MMs to enhance the in vivo performance of NPs for treating GBM.

[IgG78-DM1 inhibits pulmonary fibrosis by targeting and killing CD248-positive myofibroblasts in mice].

Objective To investigate the therapeutic effect of targeting and killing CD248-positive myofibroblasts on bleomycin-induced pulmonary fibrosis in mice. Methods IgG78-DM1, an antibody-maytansine 1 (DM1) conjugate targeting CD248, was prepared. The drug conjugation efficiency was measured and calculated by UV spectrophotometer, and the identification of IgG78-DM1 was performed through SDS-PAGE and Western blot analysis. In vitro, the binding activity of IgG78-DM1 on CD248-positive myofibroblasts was detected by flow cytometry and the cytotoxicity of IgG78-DM1 to CD248-positive myofibroblasts was evaluated by CCK-8 assay. In vivo, C57BL/6 male mice were randomly divided into control group, idiopathic pulmonary fibrosis group, human IgG-DM1 (hIgG-DM1) control group, and IgG78-DM1 treatment group. Then, the mouse models with pulmonary fibrosis induced by bleomycin were constructed. Two weeks later, the animal models were intravenously injected with IgG78-DM1. After the treatment of two weeks, lung tissues were collected for Masson staining and Sirius Red staining to evaluate the degree of pulmonary fibrosis. Real-time fluorescence quantitative PCR was used to measure the expression levels of CD248, as well as markers of fibroblastic activation including alpha-smooth muscle actin (α-SMA) and type I collagen alpha 1 (COL1A1). The safety of IgG78-DM1 was preliminarily assessed by conducting liver and kidney function tests. Results IgG78-DM1 was successfully prepared, and its drug conjugation ratio was 3.2. The antibody structure remained stable after conjugation, allowing effective binding and cytotoxicity against CD248-positive myofibroblasts. After treatment with IgG78-DM1, the degree of pulmonary fibrosis in mice significantly reduced, accompanied by the decrease of the expression of CD248, α-SMA, and COL1A1. The liver and kidney function of the mice remained at normal levels compared to the normal control group. Conclusion IgG78-DM1 effectively inhibits pulmonary fibrosis in mice by targeting and killing CD248-positive myofibroblasts. The safety of this strategy is preliminarily assessed.

A Prostate-Specific Membrane Antigen PET-Based Approach for Improved Diagnosis of Prostate Cancer in Gleason Grade Group 1: A Multicenter Retrospective Study.

The preoperative Gleason grade group (GG) from transrectal ultrasound-guided prostate biopsy is crucial for treatment decisions but may underestimate the postoperative GG and miss clinically significant prostate cancer (csPCa), particularly in patients with biopsy GG1. In such patients, an SUVmax of at least 12 has 100% specificity for detecting csPCa. In patients with an SUVmax of less than 12, we aimed to develop a model to improve the diagnostic accuracy of csPCa. Methods: The study retrospectively included 56 prostate cancer patients with transrectal ultrasound-guided biopsy GG1 and an SUVmax of less than 12 from 2 tertiary hospitals. All [68Ga]Ga-PSMA-HBED-CC PET scans were centrally reviewed in Xijing Hospital. A deep learning model was used to evaluate the overlap of SUVmax (size scale, 3 cm) and the level of Gleason pattern (size scale, 500 µm). A diagnostic model was developed using the PRIMARY score and SUVmax, and its discriminative performance and clinical utility were compared with other methods. The 5-fold cross-validation (repeated 1,000 times) was used for internal validation. Results: In patients with GG1 and an SUVmax of less than 12, significant prostate-specific membrane antigen (PSMA) histochemical score (H-score) H-score overlap occurred among benign gland, Gleason pattern 3, and Gleason pattern 4 lesions, causing SUVmax overlap between csPCa and non-csPCa. The model of 10 × PRIMARY score + 2 × SUVmax exhibited a higher area under the curve (AUC, 0.8359; 95% CI, 0.7233-0.9484) than that found using only the SUVmax (AUC, 0.7353; P = 0.048) or PRIMARY score (AUC, 0.7257; P = 0.009) for the cohort and a higher AUC (0.8364; 95% CI, 0.7114-0.9614) than that found using only the Prostate Imaging Reporting and Data System (PI-RADS) score of 5-4 versus 3-1 (AUC, 0.7036; P = 0.149) and the PI-RADS score of 5-3 versus 2-1 (AUC, 0.6373; P = 0.014) for a subgroup. The model reduced the misdiagnosis of the PI-RADS score of 5-4 versus 3-1 by 78.57% (11/14) and the PI-RADS score of 5-3 versus 2-1 by 77.78% (14/18). The internal validation showed that the mean 5-fold cross-validated AUC was 0.8357 (95% CI, 0.8357-0.8358). Conclusion: We preliminarily suggest that the model of 10 × PRIMARY score + 2 × SUVmax may enhance the diagnostic accuracy of csPCa in patients with biopsy GG1 and an SUVmax of less than 12 by maximizing PSMA information use, reducing the misdiagnosis of the PI-RADS score, and thereby aiding in making appropriate treatment decisions.

CD248 promotes migration and metastasis of osteosarcoma through ITGB1-mediated FAK-paxillin pathway activation.

BACKGROUND: Osteosarcoma (OS) is the most common malignant bone tumor with a high incidence in children and adolescents. Frequent tumor metastasis and high postoperative recurrence are the most common challenges in OS. However, detailed mechanism is largely unknown. METHODS: We examined the expression of CD248 in OS tissue microarrays by immunohistochemistry (IHC) staining. We studied the biological function of CD248 in cell proliferation, invasion and migration of OS cells by CCK8 assay, transwell and wound healing assay. We also studied its function in the metastasis of OS in vivo. At last, we explored the potential mechanism how CD248 promotes OS metastasis by using RNA-seq, western blot, immunofluorescence staining and co-immunoprecipitation using CD248 knockdown OS cells. RESULTS: CD248 was highly expressed in OS tissues and its high expression was correlated with pulmonary metastasis of OS. Knockdown of CD248 in OS cells significantly inhibited cell migration, invasion and metastasis, while had no obvious effect on cell proliferation. Lung metastasis in nude mice was significantly inhibited when CD248 was knocked down. Mechanistically, we found that CD248 could promote the interaction between ITGB1 and extracellular matrix (ECM) proteins like CYR61 and FN, which activated the FAK-paxillin pathway to promote the formation of focal adhesion and metastasis of OS. CONCLUSION: Our data showed that high CD248 expression is correlated with the metastatic potential of OS. CD248 may promote migration and metastasis through enhancing the interaction between ITGB1 and certain ECM proteins. Therefore, CD248 is a potential marker for diagnosis and effective target for the treatment of metastatic OS.

Single-cell analysis reveals the COL11A1+ fibroblasts are cancer-specific fibroblasts that promote tumor progression.

Background: Cancer-associated fibroblasts (CAFs) promote tumor progression through extracellular matrix (ECM) remodeling and extensive communication with other cells in tumor microenvironment. However, most CAF-targeting strategies failed in clinical trials due to the heterogeneity of CAFs. Hence, we aimed to identify the cluster of tumor-promoting CAFs, elucidate their function and determine their specific membrane markers to ensure precise targeting. Methods: We integrated multiple single-cell RNA sequencing (scRNA-seq) datasets across different tumors and adjacent normal tissues to identify the tumor-promoting CAF cluster. We analyzed the origin of these CAFs by pseudotime analysis, and tried to elucidate the function of these CAFs by gene regulatory network analysis and cell-cell communication analysis. We also performed cell-type deconvolution analysis to examine the association between the proportion of these CAFs and patients' prognosis in TCGA cancer cohorts, and validated that through IHC staining in clinical tumor tissues. In addition, we analyzed the membrane molecules in different fibroblast clusters, trying to identify the membrane molecules that were specifically expressed on these CAFs. Results: We found that COL11A1+ fibroblasts specifically exist in tumor tissues but not in normal tissues and named them cancer-specific fibroblasts (CSFs). We revealed that these CSFs were transformed from normal fibroblasts. CSFs represented a more activated CAF cluster and may promote tumor progression through the regulation on ECM remodeling and antitumor immune responses. High CSF proportion was associated with poor prognosis in bladder cancer (BCa) and lung adenocarcinoma (LUAD), and IHC staining of COL11A1 confirmed their specific expression in tumor stroma in clinical BCa samples. We also identified that CSFs specifically express the membrane molecules LRRC15, ITGA11, SPHK1 and FAP, which could distinguish CSFs from other fibroblasts. Conclusion: We identified that CSFs is a tumor specific cluster of fibroblasts, which are in active state, may promote tumor progression through the regulation on ECM remodeling and antitumor immune responses. Membrane molecules LRRC15, ITGA11, SPHK1 and FAP could be used as therapeutic targets for CSF-targeting cancer treatment.

VIM­AS1 promotes proliferation and drives enzalutamide resistance in prostate cancer via IGF2BP2­mediated HMGCS1 mRNA stabilization.

VIM­AS1, a cancer­specific long non­coding RNA, has been recognized as a pivotal regulator in multiple types of cancer. However, the role of VIM­AS1 in the proliferation and resistance to anti­androgen therapy of LNCaP and C4­2 prostate cancer cells remains to be determined. In the current study, gain­and­loss experiments were used to investigate the effects of VIM­AS on the proliferation and anti­androgen therapy of LNCaP and C4­2 cells. RNA sequencing, RNA pulldown and RNA immunoprecipitation were used to elucidate the underlying mechanism of VIM­AS1 driving prostate progression. It was demonstrated that VIM­AS1 was upregulated in C4­2 cells, an established castration­resistant prostate cancer (CRPC) cell line, compared with in LNCaP cells, an established hormone­sensitive prostate cancer cell line. The present study further demonstrated that VIM­AS1 was positively associated with the clinical stage of prostate cancer. Functionally, overexpression of VIM­AS1 decreased the sensitivity to enzalutamide treatment and enhanced the proliferation of LNCaP cells in vitro, whereas knockdown of VIM­AS1 increased the sensitivity to enzalutamide treatment and reduced the proliferation of C4­2 cells in vitro and in vivo. Mechanistically, 3­hydroxy­3­methylglutaryl­CoA synthase 1 (HMGCS1) was identified as one of the direct downstream targets of VIM­AS1, and VIM­AS1 promoted HMGCS1 expression by enhancing HMGCS1 mRNA stability through a VIM­AS1/insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2)/HMGCS1 RNA­protein complex. Rescue assays indicated that knockdown of HMGCS1 expression ameliorated the increase in proliferation and enzalutamide resistance of prostate cancer cells induced by VIM­AS1 overexpression. Overall, the present study determined the roles and mechanism of the VIM­AS1/IGF2BP2/HMGCS1 axis in regulating proliferation and enzalutamide sensitivity of prostate cancer cells and suggested that VIM­AS1 may serve as a novel therapeutic target for the treatment of patients with CRPC.

Endosialin-positive tumor-derived pericytes promote tumor progression through impeding the infiltration of CD8+ T cells in clear cell renal cell carcinoma.

BACKGROUND: Immune checkpoint blockade (ICB) therapy can be effective against clear cell renal cell carcinoma (ccRCC), but many patients show no benefit. Tumor-derived pericytes (TDPs) may promote tumor progression by influencing T cells and are an immunotherapy target; however, they may comprise functionally distinct subtypes. We aimed to identify markers of tumor-promoting TDPs and develop TDP-targeting strategies to enhance ICB therapy effectiveness against ccRCC. METHODS: We analyzed the relationship between endosialin (EN) expression and cytotoxic T-lymphocyte (CTL) infiltration in ccRCC tumor samples using flow cytometry and in a ccRCC-bearing mice inhibited for EN via knockout or antibody-mediated blockade. The function of ENhigh TDPs in CTL infiltration and tumor progression was analyzed using RNA-sequencing (RNA-seq) data from ccRCC tissue-derived TDPs and single-cell RNA-seq (scRNA-seq) data from an online database. The role of EN in TDP proliferation and migration and in CTL infiltration was examined in vitro. Finally, we examined the anti-tumor effect of combined anti-EN and anti-programmed death 1 (PD-1) antibodies in ccRCC-bearing mice. RESULTS: High EN expression was associated with low CTL infiltration in ccRCC tissues, and inhibition of EN significantly increased CTL infiltration in ccRCC-bearing mice. RNA-seq and scRNA-seq analyses indicated that high EN expression represented the TDP activation state. EN promoted TDP proliferation and migration and impeded CTL infiltration in vitro. Finally, combined treatment with anti-EN and anti-PD-1 antibodies synergistically enhanced anti-tumor efficacy. CONCLUSION: ENhigh TDPs are in an activated state and inhibit CTL infiltration into ccRCC tissues. Combined treatment with anti-EN and anti-PD-1 antibodies may improve ICB therapy effectiveness against ccRCC.

Single-cell analysis of multiple cancer types reveals differences in endothelial cells between tumors and normal tissues.

Endothelial cells (ECs) play an important role in tumor progression. Currently, the main target of anti-angiogenic therapy is the vascular endothelial growth factor (VEGF) pathway. Some patients do benefit from anti-VEGF/VEGFR therapy; however, a large number of patients do not have response or acquire drug resistance after treatment. Moreover, anti-VEGF/VEGFR therapy may lead to nephrotoxicity and cardiovascular-related side effects due to its action on normal ECs. Therefore, it is necessary to identify targets that are specific to tumor ECs and could be applied to various cancer types. We integrated single-cell RNA sequencing data from six cancer types and constructed a multi-cancer EC atlas to decode the characteristic of tumor ECs. We found that tip-like ECs mainly exist in tumor tissues but barely exist in normal tissues. Tip-like ECs are involved in the promotion of tumor angiogenesis and inhibition on anti-tumor immune responses. Moreover, tumor cells, myeloid cells, and pericytes are the main sources of pro-angiogenic factors. High proportion of tip-like ECs is associated with poor prognosis in multiple cancer types. We also identified that prostate-specific membrane antigen (PSMA) is a specific marker for tip-like ECs in all the cancer types we studied. In summary, we demonstrate that tip-like ECs are the main differential EC subcluster between tumors and normal tissues. Tip-like ECs may promote tumor progression through promoting angiogenesis while inhibiting anti-tumor immune responses. PSMA was a specific marker for tip-like ECs, which could be used as a potential target for the diagnosis and treatment of non-prostate cancers.

Association between long-term exposure to ambient particulate matter and blood pressure, hypertension: an updated systematic review and meta-analysis.

Evidence of more recent studies should be updated to evaluate the effect of long-term exposure to particulate matter (PM) on blood pressure and hypertension.        Studies of long-term effects of PM1, PM2.5 and PM10 on blood pressure (SBP, DBP, MAP), hypertension were searched in Pubmed, Web of Science and Embase before May, 2021. Meta-analysis of 41 studies showed that exposure to PM1, PM2.5 was associated with SBP (1.76 mmHg (95%CI:0.71, 2.80) and 0.63 mmHg (95%CI:0.40, 0.85), per 10 µg/m3 increase in PM), all three air pollutants (PM1, PM2.5, PM10) was associated with DBP (1.16 mmHg (95%CI:0.34, 1.99), 0.31 mmHg (95%CI:0.16, 0.47), 1.17 mmHg (95%CI:0.24, 2.09), respectively. As for hypertension, PM1, PM2.5 and PM10 were all significantly associated with higher risk of hypertension (OR=1.27 (95%CI:1.06, 1.52), 1.15 (95%CI:1.10, 1.20) and 1.11 (95%CI:1.07, 1.16). In conclusion, our study indicated a positive association between long-term exposure to particulate matter and increased blood pressure, hypertension.

Establishment and validation of a polygene prognostic model for clear cell renal cell carcinoma.

Purpose: To establish an effective prognostic model for patients with clear cell renal cell carcinoma (ccRCC). Methods: We identified four hub differentially expressed genes (DEGs) in Gene Expression Omnibus (GEO) database and verified them in the Cancer Gene Atlas (TCGA), STRING, UALCAN, TIMER, and Gene Expression Profiling Interactive Analysis (GEPIA) databases. We then used TCGA and International Cancer Genome Consortium (ICGC) to identify tumor pathway molecules highly correlated with hub DEGs. And by further LASSO and Cox regression analysis, we successfully identified five genes as prognostic factors. Results: We successfully identified a risk prediction model consisting of five genes: IGF2BP3, CDKN1A, GSDMB, FABP5, RBMX. We next distributed patients into low-risk and high-risk groups using the median as a cutoff. The low-risk group obviously had better survival than those in the predicted high-risk group. The results showed discrepancies in tumor-associated immune cell infiltration between risk groups. We also combined the risk model with clinical variables to create a nomogram. Conclusion: Our model has a satisfactory predictive effect on the prognosis of ccRCC patients and may provide new ideas for future immune therapy.

The higher levels of self-reported satisfaction, the lower risk of depressive symptoms: Evidence from a nationwide cross-sectional study in China.

Objectives: This study aimed to investigate the associations between several dimensions of self-reported satisfaction and the risk of depressive symptoms among Chinese middle-aged and older adults. Methods: The China Health and Retirement Longitudinal Study (CHARLS) conducted a nationwide cross-sectional study of middle-aged and older adults. Depressive status was evaluated using the 10-item center for epidemiological studies depression scale (CESD-10), and self-reported life, health, marital status, parent-child relationship, and air quality satisfaction were adopted using Likert 5-point evaluation methods. A generalized linear model (GLM) was applied to explore the association between satisfaction and depression risk. Results: A total of 13,978 Chinese people aged over 45 years old were included in this study, and 35.7% of the participants had depressive symptoms. The GLM analysis indicated that all dimensions of satisfaction were negatively associated with the risk of depressive symptoms. For each 1-point increase in life, health, marital status, parent-child relationship, and air quality satisfaction, the incidence of depressive symptoms decreased by 60.8% (odds ratio (OR) = 0.392; 95% confidence interval (CI): 0.370, 0.414), 56.3% (OR = 0.437; 95% CI: 0.418, 0.458), 41.8% (OR = 0.582; 95% CI: 0.555, 0.610), 37.2% (OR = 0.628; 95% CI: 0.596, 0.662), and 25.6% (OR = 0.744; 95% CI: 0.711, 0.778), respectively. Conclusion: Higher satisfaction levels with life, health, marital status, parent-child relationship, and air quality are associated with a lower risk of depressive symptoms among middle-aged and older adults. Given the aging society and the increasing mental health problems of middle-aged and older adults in China, our study provides a comprehensive perspective for depression prevention and mental health improvement.

An enhancer RNA-based risk model for prediction of bladder cancer prognosis.

Background: Bladder cancer patients have a high recurrence and poor survival rates worldwide. Early diagnosis and intervention are the cornerstones for favorable prognosis. However, commonly used predictive tools cannot meet clinical needs because of their insufficient accuracy. Methods: We have developed an enhancer RNA (eRNA)-based signature to improve the prediction for bladder cancer prognosis. First, we analyzed differentially expressed eRNAs in gene expression profiles and clinical data for bladder cancer from The Cancer Genome Atlas database. Then, we constructed a risk model for prognosis of bladder cancer patients, and analyzed the correlation between this model and tumor microenvironment (TME). Finally, regulatory network of downstream genes of eRNA in the model was constructed by WGCNA and enrichment analysis, then Real-time quantitative PCR verified the differentiation of related genes between tumor and adjacent tissue. Results: We first constructed a risk model composed of eight eRNAs, and found the risk model could be an independent risk factor to predict the prognosis of bladder cancer. Then, the log-rank test and time-dependent ROC curve analysis shown the model has a favorable ability to predict prognosis. The eight risk eRNAs may participate in disease progression by regulating cell adhesion and invasion, and up-regulating immune checkpoints to suppress the immunity in TME. mRNA level change in related genes further validated regulatory roles of eRNAs in bladder cancer. In summary, we constructed an eRNA-based risk model and confirmed that the model could predict the prognosis of bladder cancer patients.

Associations of long-term exposure to ambient ozone with hypertension, blood pressure, and the mediation effects of body mass index: A national cross-sectional study of middle-aged and older adults in China.

BACKGROUND: The associations between long-term exposure to ozone (O3) and respiratory diseases are well established. However, its association with cardiovascular disease (CVD) remains controversial. In this study, we examined the associations between O3 and the prevalence of hypertension and blood pressure, and the mediation effects of body mass index (BMI) in Chinese middle-aged and older adults. METHODS: In this national cross-sectional study, we estimated the O3 exposure of 12,028 middle-aged and older adults from 126 county-level cities in China, using satellite-based spatiotemporal models. Generalized linear mixed models were used to evaluate the associations of long-term exposure to O3 with hypertension and blood pressure, including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP). Mediation effect models were applied to examine the mediation effects of BMI among O3-induced hypertension and elevated blood pressure. RESULTS: Each 10 µg/m3 increase in O3 concentration was significantly associated with an increase of 13.7% (95% confidence interval (CI): 4.8%, 23.3%) in the prevalence of hypertension, an increase of 1.128 mmHg (95% CI: 0.248, 2.005), 0.679 mmHg (95% CI: 0.059, 1.298), 0.820 mmHg (95%CI: 0.245, 1.358) in SBP, DBP, and MAP, respectively. Mediation effect models showed that BMI played 40.08%, 37.25%, 39.95%, and 33.51% mediation roles in the effects of long-term exposure to O3 on hypertension, SBP, DBP, and MAP, respectively. CONCLUSIONS: Long-term exposure to O3 can increase the prevalence of hypertension and blood pressure levels of middle-aged and older adults, and an increase of BMI would be an important modification effect for O3-induced hypertension and blood pressure increase.

Antibody-drug conjugates targeting CD248 inhibits liver fibrosis through specific killing on myofibroblasts.

BACKGROUND: Chronic liver injury induces pathological repair, resulting in fibrosis, during which hepatic stellate cells (HSCs) are activated and transform into myofibroblasts. CD248 is mainly expressed on myofibroblasts and was considered as a promising target to treat fibrosis. The primary aim of this study was to generate a CD248 specific antibody-drug conjugate (ADC) and evaluate its therapeutic efficacy for liver fibrosis and its safety in vivo. METHODS: CD248 expression was examined in patients with liver cirrhosis and in mice with CCl4-induced liver fibrosis. The ADC IgG78-DM1, which targets CD248, was prepared and its bioactivity on activated primary HSCs was studied. The anti-fibrotic effects of IgG78-DM1 on liver fibrosis were evaluated in CCl4-induced mice. The reproductive safety and biosafety of IgG78-DM1 were also evaluated in vivo. RESULTS: CD248 expression was upregulated in patients with liver cirrhosis and in CCl4-induced mice, and was mainly expressed on alpha smooth muscle actin (α-SMA)+ myofibroblasts. IgG78-DM1 was successfully generated, which could effectively bind with and kill CD248+ activated HSCs in vitro and inhibit liver fibrosis in vivo. In addition, IgG78-DM1 was demonstrated to have qualified biosafety and reproductive safety in vivo. CONCLUSIONS: Our study demonstrated that CD248 could be an ideal target for myofibroblasts in liver fibrosis, and CD248-targeting IgG78-DM1 had excellent anti-fibrotic effects in mice with liver fibrosis. Our study provided a novel strategy to treat liver fibrosis and expanded the application of ADCs beyond tumors.