Novel immune classification based on machine learning of pathological images predicts early recurrence of hepatocellular carcinoma.

Introduction: Immune infiltration within the tumor microenvironment (TME) plays a significant role in the onset and progression of hepatocellular carcinoma (HCC). Machine learning applied to pathological images offers a practical means to explore the TME at the cellular level. Our former research employed a transfer learning procedure to adapt a convolutional neural network (CNN) model for cell recognition, which could recognize tumor cells, lymphocytes, and stromal cells autonomously and accurately within the images. This study introduces a novel immune classification system based on the modified CNN model. Method: Patients with HCC from both Beijing Hospital and The Cancer Genome Atlas (TCGA) database were included in this study. Additionally, least absolute shrinkage and selection operator (LASSO) analyses, along with logistic regression, were utilized to develop a prognostic model. We proposed an immune classification based on the percentage of lymphocytes, with a threshold set at the median lymphocyte percentage. Result: Patients were categorized into high or low infiltration subtypes based on whether their lymphocyte percentages were above or below the median, respectively. Patients with different immune infiltration subtypes exhibited varying clinical features and distinct TME characteristics. The low-infiltration subtype showed a higher incidence of hypertension and fatty liver, more advanced tumor stages, downregulated immune-related genes, and higher infiltration of immunosuppressive cells. A reliable prognostic model for predicting early recurrence of HCC based on clinical features and immune classification was established. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves was 0.918 and 0.814 for the training and test sets, respectively. Discussion: In conclusion, we proposed a novel immune classification system based on cell information extracted from pathological slices, provides a novel tool for prognostic evaluation in HCC.

Collagen degradation assessment with an in vitro rotator cuff tendinopathy model using multiparametric ultrashort-TE magnetization transfer (UTE-MT) imaging.

PURPOSE: This study aims to assess ultrashort-TE magnetization transfer (UTE-MT) imaging of collagen degradation using an in vitro model of rotator cuff tendinopathy. METHODS: Thirty-six supraspinatus tendon specimens were divided into three groups and treated with 600 U collagenase (Group 1), 150 U collagenase (Group 2), and phosphate buffer saline (Group 3). UTE-MT imaging was performed to assess changes in macromolecular fraction (MMF), macromolecule transverse relaxation time (T2m), water longitudinal relaxation rate constant (R1m), the magnetization exchange rate from the macromolecular to water pool (Rm0 w) and from water to the macromolecular pool (Rm0 m), and magnetization transfer ratio (MTR) at baseline and following digestion and their differences between groups. Biochemical and histological studies were conducted to determine the extent of collagen degradation. Correlation analyses were performed with MMF, T2m, R1m, Rm0 w, Rm0 m, and MTR, respectively. Univariate and multivariate linear regression analyses were performed to evaluate combinations of UTE-MT parameters to predict collagen degradation. RESULTS: MMF, T2m, R1m, Rm0 m, and MTR decreased after digestion. MMF (r = -0.842, p < 0.001), MTR (r = -0.78, p < 0.001), and Rm0 m (r = -0.662, p < 0.001) were strongly negatively correlated with collagen degradation. The linear regression model of differences in MMF and Rm0 m before and after digestion explained 68.9% of collagen degradation variation in the tendon. The model of postdigestion in MMF and T2m and the model of MTR explained 54.2% and 52.3% of collagen degradation variation, respectively. CONCLUSION: This study highlighted the potential of UTE-MT parameters for evaluation of supraspinatus tendinopathy.

Combined effects of vitamin D deficiency and systemic inflammation on all-cause mortality and cause-specific mortality in older adults.

BACKGROUND: Vitamin D deficiency and systemic inflammation share common pathological mechanisms in muscle loss, cardio-pulmonary function decline, and abnormal metabolism, which are linked to chronic conditions, senescence, and early mortality. However, their combined effect on mortality in older adults has not been well established. This study longitudinal aimed to explore the independent and combined associations of serum 25-hydroxyvitamin D [25(OH)D] and high sensitivity C-reactive protein (hs-CRP) with mortality risk in Chinese community-based older people. METHODS: 3072 older adults (86.07 ± 11.87 years, 54.52% female) from the Chinese Longitudinal Healthy Longevity Survey (2012-2018) were enrolled. Baseline 25(OH)D and hs-CRP levels were collected, and survival information was recorded in the 2014 and 2018 follow-up waves. Cox proportional hazard regressions were conducted to explore the associations between 25(OH)D, hs-CRP, and mortality. Demographic characteristics, health behaviors, and chronic disease biomarkers were adjusted. RESULTS: During 10,622.3 person-years of follow-up (median: 3.51 years), 1321 older adults died, including 448 deaths due to cardiovascular disease (CVD). Increased mortality risk was associated with lower 25(OH)D and higher hs-CRP quantiles, even after adjusting for each other and multiple covariates (all P-trend < 0.05). In combined analyses, the highest all-cause mortality (HR: 2.18, 95% CI: 1.73 ~ 2.56), CVD mortality (HR: 2.30, 95% CI: 1.64 ~ 3.21), and non-CVD mortality (HR: 2.19, 95% CI: 1.79 ~ 2.49) were obtained in participants with both 25(OH)D deficiency (< 50 nmol/L) and high hs-CRP (≥ 3.0 mg/L), respectively. We observed significant additive interactions of 25(OH)D and hs-CRP on all-cause mortality and non-CVD mortality (RERIS>0). CONCLUSIONS: Low 25(OH)D and high hs-CRP, both independently and jointly, increase mortality risk in Chinese community-dwelling older adults. Thus, priority should be given to early detection and appropriate intervention in older individuals with combined vitamin D deficiency and systemic inflammation. Molecular mechanisms of related adverse health effect are worthy of further investigation.

Ginsenoside 20(S)-Rg3 reduces KIF20A expression and promotes CDC25A proteasomal degradation in epithelial ovarian cancer.

Background: Ginsenoside 20(S)-Rg3 shows promising tumor-suppressive effects in ovarian cancer via inhibiting NF-κB signaling. This study aimed to explore the downstream tumor suppressive mechanisms of ginsenoside Rg3 via this signaling pathway. Materials and methods: A systematical screening was applied to examine the expression profile of 41 kinesin family member genes in ovarian cancer. The regulatory effect of ginsenoside Rg3 on KIF20A expression was studied. In addition, we explored interacting proteins of KIF20A and their molecular regulations in ovarian cancer. RNA-seq data from The Cancer Genome Atlas (TCGA) was used for bioinformatic analysis. Epithelial ovarian cancer cell lines SKOV3 and A2780 were used as in vitro and in vivo cell models. Commercial human ovarian cancer tissue arrays were used for immunohistochemistry staining. Results: KIF20A is a biomarker of poor prognosis among the kinesin genes. It promotes ovarian cancer cell growth in vitro and in vivo. Ginsenoside Rg3 can suppress the transcription of KIF20A. GST pull-down and co-immunoprecipitation (IP) assays confirmed that KIF20A physically interacts with BTRC (ß-TrCP1), a substrate recognition subunit for SCFß-TrCP E3 ubiquitin ligase. In vitro ubiquitination and cycloheximide (CHX) chase assays showed that via interacting with BTRC, KIF20A reduces BTRC-mediated CDC25A poly-ubiquitination and enhances its stability. Ginsenoside Rg3 treatment partly abrogates KIF20A overexpression-induced CDC25A upregulation. Conclusion: This study revealed a novel anti-tumor mechanism of ginsenoside Rg3. It can inhibit KIF20A transcription and promote CDC25A proteasomal degradation in epithelial ovarian cancer.

Targeted IFNγ induction by a genetically engineered Salmonella typhimurium is the key to the liver metastasis inhibition in a mouse model of pancreatic neuroendocrine tumor.

Background: Liver metastasis is one of the primary causes of death for the patients with pancreatic neuroendocrine tumors (PNETs). However, no curative therapy has been developed so far. Methods: The anti-tumor efficacy of a genetically engineered tumor-targeting Salmonella typhimurium YB1 was evaluated on a non-functional INR1G9 liver metastasis model. Differential inflammatory factors were screened by Cytometric Bead Array. Antibody depletion assay and liver-targeted AAV2/8 expression vector were used for functional evaluation of the differential inflammatory factors. Results: We demonstrated that YB1 showed significant anti-tumor efficacy as a monotherapy. Since YB1 cannot infect INR1G9 cells, its anti-tumor effect was possibly due to the modulation of the tumor immune microenvironment. Two inflammatory factors IFNγ and CCL2 were elevated in the liver after YB1 administration, but only IFNγ was found to be responsible for the anti-tumor effect. Liver-targeted expression of IFNγ caused the activation of macrophages and NK cells, and reproduced the therapeutic effect of YB1 on liver metastasis. Conclusion: We demonstrated that YB1 may exhibit anti-tumor effect mainly based on IFNγ induction. Targeted IFNγ therapy can replace YB1 for treating liver metastasis of PNETs.

Characteristics and clustering analysis of peripheral blood lymphocyte subsets in children with systemic lupus erythematosus complicated with clinical infection.

OBJECTIVES: Clinical infection is a common complication in children with systemic lupus erythematosus (SLE). However, few studies have investigated immune alterations in children with SLE complicated with clinical infection. We assessed lymphocyte subsets in children with SLE to explore the possibility of clinical infection. METHODS: We retrospectively analyzed the proportion of peripheral lymphocyte subsets in 140 children with SLE. Children with SLE were classified into different clusters according to the proportion of peripheral blood lymphocyte subsets: (CD3 + /CD4 + T cell, CD3 + /CD8 + T cell, CD3 + /CD4 + /CD8 + T cell, CD3 + /CD4-/CD8- T cell, CD19 + B cell, and CD3-/CD16 + /CD56 + NK cell). Differences in the proportion of lymphoid subsets, infection rates, and systemic lupus erythematosus disease activity index (SLEDAI) scores were compared between clusters. In addition, we grouped the subjects according to the presence or absence of infection. Proportions of lymphoid subsets, demographic variables, clinical presentation, and other laboratory variables were compared between the infected and uninfected groups. Finally, the diagnostic ability of lymphocyte subset ratios to distinguish secondary infection in children with SLE was predicted using an ROC curve. RESULTS: Cluster C2 had a higher proportion of B cells than Cluster C1, while Cluster C1 had a lower proportion of NK cells, CD3 + T cells, CD3 + /CD4 + T cells, CD3 + /CD8 + T cells, and CD3 + /CD4-/CD8- T cells. Infection rates and SLEDAI scores were higher in Cluster C2 than in Cluster C1. The infected children had a higher proportion of B cells and a lower proportion of CD3 + T cells, CD3 + /CD4 + T cells, CD3 + /CD8 + T cells, and CD3 + /CD4-/CD8- T cells. There were no significant differences in lymphoid subsets between children in Cluster C2 and the infected groups. The area under the ROC curve of B lymphocytes in predicting SLE children with infection was 0.842. The area under the ROC curve was 0.855 when a combination of B cells, NK cells, CD4 + T cells, and CD8 + T cells was used to predict the outcome of coinfection. CONCLUSIONS: A high percentage of B cells and a low percentage of CD3 + T cells, CD3 + /CD4 + T cells, CD3 + /CD8 + T cells, CD3 + /CD4 + /CD8 + T cells, and CD3 + /CD4-/CD8- T cells may be associated with infection in children with SLE. B cells was used to predict the outcome of coinfection in children with SLE. Key Points • A high percentage of B cells and a low percentage of CD3 + T cells, CD3 + /CD4 + T cells, CD3 + /CD8 + T cells, CD3 + /CD4 + /CD8 + T cells, and CD3 + /CD4-/CD8- T cells may be associated with infection in children with SLE • B cells was used to predict the outcome of coinfection in children with SLE.

Model for Predicting Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma and Discussion of Prophylaxis Measures.

OBJECTIVE: Relapse of the central nervous system (CNS) is a rare but fatal complication in diffuse large B-cell lymphoma (DLBCL). The purpose of this study is to learn how to identify high-risk patients and take effective preventive measures. METHODS: We retrospectively analyzed 1,290 adult patients with DLBCL at Peking University Cancer Hospital and Shanxi Bethune Hospital between 2010 and 2020. RESULTS: There were 55 patients with CNS relapse who had a median follow-up of 5 years. The risk of CNS relapse was 1.58% in the low-risk group, 5.66% in the moderate-risk group, and 11.67% in the high-risk group based on CNS International Prognostic Index (CNS-IPI). We found that CNS-IPI and testicular involvement were risk factors for CNS relapse, with OR 1.913 (95% CI: 1.036∼3.531; P = 0.038) versus. OR 3.526 (95% CI: 1.335∼9.313; P = 0.011), respectively. Intrathecal MTX and/or cytarabine prophylaxis was used in 166 patients (13.94%), intravenous (IV) high-dose methotrexate (HD-MTX) prophylaxis in 8 patients (0.67%), and intrathecal plus intravenous prophylaxis in 15 patients (1.26%). There was no significant difference in CNS relapse risk between IT, HD-MTX, and no prophylaxis recipients (12.7% vs. 0% vs. 23.6%, respectively, P = 0.170). The risk of CNS relapse was similar whether or not patients accepted prophylaxis (5-year risk 4.1% vs. 2.2%, P = 0.140). CONCLUSIONS: Central nervous system (CNS) relapse is associated with high risk CNS-IPI and testicular involvement. Therefore, it is necessary to pursue novel prophylactic strategies for CNS relapse.

Corrigendum: DDX5 and DDX17-multifaceted proteins in the regulation of tumorigenesis and tumor progression.

[This corrects the article DOI: 10.3389/fonc.2022.943032.].

Impact of age-friendly living environment and intrinsic capacity on functional ability in older adults: a cross-sectional study.

BACKGROUND: The World Health Organization (WHO) has proposed healthy aging framework, supposing that intrinsic capacity (IC), environment and their interaction may have influence on functional ability (FA). It was still unclear how the IC level and age-friendly living environment impact on FA. This study aims to confirm the relationship between the IC level and age-friendly living environment with FA, especially in older adults with low IC. METHODS: Four hundred eighty-five community-dwelling residents aged ≥ 60 years were enrolled. IC constructed by locomotion, cognition, psychological, vitality, and sensory domains was assessed using full assessment tools recommended by WHO. Age-friendly living environment was measured with 12 questions adapted from the spatial indicators framework of age-friendly cities. FA was assessed using activities of daily living (ADL) and one question about mobile payment ability. Multivariate logistic regression was used to explore the association between IC, environment and FA. The influence of the environment on electronic payment and ADL under the IC layer was assessed. RESULTS: Of 485 respondents, 89 (18.4%) had ADL impairment, and 166 (34.2%) had mobile payment function impairment. Limited IC (odds ratio [OR] = 0.783, 95% confidence interval [CI] = 0.621-0.988) and poor environment (OR = 0.839, 95% CI = 0.733-0.960) were associated with mobile payment ability impairment. Our results suggested that a supportive age-friendly living environment influenced FA was more prominent in older adults with poor IC (OR = 0.650, 95% CI = 0.491-0.861). CONCLUSIONS: Our results confirmed IC and the environment had an impact on mobile payment ability. The relationship between environment and FA showed differences according to IC level. These findings suggest that an age-friendly living environment is important to maintain and enhance elders' FA, especially in those with poor IC.

Contrast-enhanced ultrasound liver imaging reporting and data system v2017: patient outcomes after treatment for early-stage hepatocellular carcinoma nodules with category 3-5 and category M.

OBJECTIVE: To evaluate correlation between contrast-enhanced ultrasonography Liver Imaging Reporting and Data System (CEUS LI-RADS; v. 2017) categories (LR 3-5 vs LR-M) and outcomes in patients with early-stage hepatocellular carcinoma (HCC) after initial therapy. METHODS: In this retrospective study, 272 patients with high risks for HCC and solitary clinically or pathologically confirmed HCC were identified between January 2010 and December 2015. Patients were initially treated by resection and radiofrequency ablation (RFA) according to the Barcelona Clinic Liver Cancer staging system and were followed up until December 31, 2018. Recurrence-free survival (RFS) and overall survival (OS) were compared between nodules assigned as LR 3-5 or LR M according to CEUS LI-RADS v. 2017 by using the Kaplan-Meier curve, log-rank test, and Cox proportional hazard model. RESULTS: Early washout is the key determinating whether a nodule is classed as LR-M. Treatment procedures and LI-RADS category showed an independent correlation with OS and RFS (p < 0.05). LR 3-5 category were more correlated with better OS (88.6 months and 74.2 months, respectively; p = 0.017) compared with LR-M. Surgical resection demonstrated longer OS and RFS than RFA in LR-M patients and longer OS in LR 3-5 patients (p < 0.05). Besides, there was no significantly difference in OS and RFS between two categories in resection (p > 0.05), while for patients treated with RFA, LR 3-5 patients showed significant longer OS and RFS than LR-M patients (p < 0.05). CONCLUSION: Patients with HCC assigned as LR-M showed worse RFS and OS and surgical resection tended to be a more effective treatment for these patients. ADVANCES IN KNOWLEDGE: Putting forward a theory that CEUS LI-RADS categories could independently predict the outcome for patients with solitary HCC at early-stage after initial treatment.

Thermal conductivity and mechanical properties of graphite/Mg composite with a super-nano CaCO3 interfacial layer.

Incorporating graphite/graphene into a Mg alloy matrix is a promising approach for developing lightweight heat dissipation materials. However, carbon material is inherently incompatible with Mg because of their distinctly different surface characteristics, resulting in the challenge of composite fabricating and interface controlling. Herein, a new strategy of in situ interfacial modification was proposed to achieve excellent thermal conductivity and mechanical properties in graphite/Mg composites. A super-nano CaCO3 interfacial layer was reported in this paper. The detailed interfacial structure, reaction thermodynamics and kinetics, and interface strengthening mechanisms were analyzed and discussed. Several preferential epitaxial relationships of the Mg/CaCO3 interface were revealed, which are conducive to minimize the interfacial energy, stabilize and strengthen the interface. Moreover, strong ionic bond of graphite/CaCO3 interface was demonstrated. The strong chemical interface bonding of graphite-Mg via in situ interface modification facilitates both the interfacial cohesion and interfacial thermal conduction, which endows the graphite/Mg composites with superior strength-thermal conductivity synergy.

HNRNPD is a prognostic biomarker in non-small cell lung cancer and affects tumor growth and metastasis via the PI3K-AKT pathway.

Heterogeneous nuclear ribonucleoprotein D (HNRNPD) can regulate expression of key proteins in various cancers. However, the prognostic predictive value and biology function of HNRNPD in non-small cell lung cancer (NSCLC) is unknown. First, we used the TCGA and GEO datasets to determine that HNRNPD predicts the prognosis of NSCLC patients. Following that, we knocked down HNRNPD in NSCLC cell lines in vitro and validated its biological function using CCK-8, transwell assays, wound healing tests, and Western blotting. Finally, we constructed tissue microarrays (TMAs) from 174 NSCLC patients and verified our findings using immunohistochemistry staining for HNRNPD from public databases. In both the public datasets, NSCLC tissues with elevated HNRNPD expression had shorter overall survival (OS). In addition, HNRNPD knockdown NSCLC cell lines showed significantly reduced proliferation, invasion, and metastatic capacity via the PI3K-AKT pathway. Finally, elevated HNRNPD expression in NSCLC TMAs was linked to a poorer prognosis and decreased PD-L1 expression levels. HNRNPD is associated with a poorer prognosis in NSCLC and affects tumor growth and metastasis via the PI3K-AKT pathway.

Serum glycoprotein non-metastatic melanoma protein B (GPNMB) level as a potential biomarker for diabetes mellitus-related cataract: A cross-sectional study.

Background: Diabetes mellitus (DM), a metabolic disease that has attracted significant research and clinical attention over the years, can affect the eye structure and induce cataract in patients diagnosed with DM. Recent studies have indicated the relationship between glycoprotein non-metastatic melanoma protein B (GPNMB) and DM and DM-related renal dysfunction. However, the role of circulating GPNMB in DM-associated cataract is still unknown. In this study, we explored the potential of serum GPNMB as a biomarker for DM and DM-associated cataract. Methods: A total of 406 subjects were enrolled, including 60 and 346 subjects with and without DM, respectively. The presence of cataract was evaluated and serum GPNMB levels were measured using a commercial enzyme-linked immunosorbent assay kit. Results: Serum GPNMB levels were higher in diabetic individuals and subjects with cataract than in those without DM or cataract. Subjects in the highest GPNMB tertile group were more likely to have metabolic disorder, cataract, and DM. Analysis performed in subjects with DM elucidated the correlation between serum GPNMB levels and cataract. Receiver operating characteristic (ROC) curve analysis also indicated that GPNMB could be used to diagnose DM and cataract. Multivariable logistic regression analysis illustrated that GPNMB levels were independently associated with DM and cataract. DM was also found to be an independent risk factor for cataract. Further surveys revealed the combination of serum GPNMB levels and presence of DM was associated with a more precise identification of cataract than either factor alone. Conclusions: Increased circulating GPNMB levels are associated with DM and cataract and can be used as a biomarker of DM-associated cataract.

Phosphorus limitation induced by nitrogen addition changed soil microbial community structure in a subtropical Pinus taiwanensis forest.

Soil microorganisms play an important role in the biogeochemical cycles of terrestrial ecosystems. How-ever, it is still unclear how the amount and duration of nitrogen (N) addition affect soil microbial community structure and whether there is a correlation between the changes in microbial community structure and their nutrient limi-tation status. In this study, we conducted an N addition experiment in a subtropical Pinus taiwanensis forest to simulate N deposition with three treatments: control (CK, 0 kg N·hm-2·a-1), low N (LN, 40 kg N·hm-2·a-1), and high N (HN, 80 kg N·hm-2·a-1). Basic soil physicochemical properties, phospholipid fatty acids content, and carbon (C), N and phosphorus (P) acquisition enzyme activities were measured after one and three years of N addition. The relative nutrient limitation status of soil microorganisms was analyzed using ecological enzyme stoichiometry. The results showed that one-year N addition did not affect soil microbial community structure. Three-year LN treatment significantly increased the contents of Gram-positive bacteria (G+), Gram-negative bacteria (G-), actinomycetes (ACT), and total phospholipid fatty acids (TPLFA), whereas three-year HN treatment did not significantly affect soil microbial community, indicating that bacteria and ACT might be more sensitive to N addition. Nitrogen addition exacerbated soil C and P limitation. Phosphorus limitation was the optimal explanatory factor for the changes in soil microbial community structure. It suggested that P limitation induced by N addition might be more beneficial for the growth of certain oligotrophic bacteria (e.g. G+) and the microorganisms participating in the P cycling (e.g. ACT), with consequences on soil microbial community structure of subtropical Pinus taiwanensis forest.

Peripheral blood lymphocyte subsets in children with nephrotic syndrome: a retrospective analysis.

BACKGROUND: Nephrotic syndrome (NS) in children is widely believed to be associated with severe changes in the immune system. Based on lymphocyte subset analysis, we examined the pathogenesis of immune deficiencies in children with NS with varying steroid sensitivity. METHODS: Our study utilized flow cytometry to retrospectively analyze the ratios of lymphocyte subsets in 204 children with nephrotic syndrome and 19 healthy children. RESULTS: Compared with healthy children, the ratio of CD4 + /CD8 + in onset and remission was decreased in SRNS group (p < 0.05), and CD19 + B lymphocytes were increased in onset (p < 0.05). Compared with onset, the proportion of CD19 + B lymphocytes decreased in SRNS, while the proportion of CD19 + B lymphocytes increased in SDNS, p < (0.01). The ratio of CD8 + T/CD19 + B in onset in SDNS group was significantly higher than that in SSNS and SRNS groups (p < 0.01) and healthy control group (p < 0.05). Compared with onset, the ratio of CD8 + T/CD19 + B in SDNS group decreased significantly (p < 0.01), while the ratio of CD8 + T/CD19 + B in SRNS group increased significantly (p < 0.01). The proportion of CD56 + CD16 + NK cells was significantly reduced in children with INS (p < 0.01). CONCLUSION: CD8 + T lymphocytes may be involved in the mechanism of lymphocyte subsets disorder during onset of SDNS, while CD19 + B lymphocytes may be involved in the mechanism of lymphocyte subsets disorder during relapse of SDNS. The CD8 + T/CD19 + B ratio may predict the degree of frequent recurrence. There is a certain degree of lymphoid subsets disorder in children with NS.

8-oxo-dGTP curbs tumor development via S phase arrest and AIF-mediated apoptosis.

Oxidative stress can attack precursor nucleotides, resulting in nucleic acid damage in cells. It remains unclear how 8-oxo-dGTP and 8-oxoGTP, oxidized forms of dGTP and GTP, respectively, could affect DNA or RNA oxidation levels and tumor development. To address this, we intravenously administered 8-oxo-dGTP and 8-oxoGTP to wild-type and MTH1-knockout mice. 8-oxoGTP administration increased frequency of tumor incidence, which is more prominent in MTH1-knockout mice. However, 8-oxo-dGTP treatment rather reduced tumor development regardless of the mouse genotype. The tumor suppressive effects of 8-oxo-dGTP were further confirmed using xenograft and C57/6J-ApcMin/Nju mouse models. Mechanistically, 8-oxo-dGTP increased the 8-oxo-dG contents in DNA and DNA strand breakage, induced cell cycle arrest in S phase and apoptosis mediated by AIF, eventually leading to reduced tumor incidence. These results suggest distinct roles of 8-oxo-dGTP and 8-oxoGTP in tumor development.

Delphinidin induces autophagic flux blockage and apoptosis by inhibiting both multidrug resistance gene 1 and DEAD-box helicase 17 expressions in liver cancer cells.

OBJECTIVES: To investigate the function and regulatory mechanisms of delphinidin in the treatment of hepatocellular carcinoma. METHODS: HepG2 and HuH-7 cells were treated with different concentrations of delphinidin. Cell viability was analysed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The cell autophagy and autophagic flux were analysed by LC3b-green fluorescent protein (GFP)-Adv and LC3b-GFP-monomeric red fluorescent protein-Adv transfected HepG2 and HuH-7 cells, respectively. Cell apoptosis was analysed by Hoechst33342 staining, terminal deoxynucleotidyl transferase dUTP nick end labeling staining and DNA laddering. Cell autophagy, apoptosis and survival related protein expressions were detected by Western blotting. KEY FINDINGS: After treatment with different concentrations of delphinidin, the cell survival rate was significantly decreased. Delphinidin could block the autophagic flux, resulting in a significant increase in autophagosomes, and led to an increase in cell apoptosis. The combined application of delphinidin and cisplatin could promote the antitumour effect and reduce the dose of cisplatin in tumour cells. Further mechanism studies reveal that delphinidin could inhibit the multidrug resistance gene 1 (MDR1) and the tumour-promoting transcription cofactor DEAD-box helicase 17 (DDX17) expression in tumour cells. Overexpression of DDX17 could reverse delphinidin's antitumor function in tumour cells. CONCLUSIONS: Delphinidin has a strong anti-tumour effect by inducing tumour cell autophagic flux blockage and apoptosis by inhibiting of both MDR1 and DDX17 expression.

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Priming effect (PE) plays an important role in regulating terrestrial soil carbon (C) cycling, but the impact of different C addition modes on the PE in subtropical forest ecosystems with increasing nitrogen (N) deposition is unclear. In this study, we investigated the effects of C addition patterns (single or repeated C addition) on soil PE by adding 13C-labeled glucose for 90 d in an incubation experiment with different levels of N application (0, 20, and 80 kg N·hm-2·a-1). The different patterns of glucose addition significantly increased soil organic C (SOC) mineralization and produced positive PE. Single glucose addition resulted in stronger PE than repeated addition. PE was significantly weakened with increasing N application levels, indicating that N deposition inhibited soil excitation in Phyllostachys edulis forests. The cumulative PE was significantly negatively correlated with ß-N-acetylaminoglucosidase (NAG) and peroxidase (PEO) activities, and was significantly positively correlated with microbial biomass P (MBP) and potential of hydrogen (pH). Our findings indicated that, when acting together on soil, N application and C addition could strongly affect soil C stocks by stimulating the mineralization of native soil organic matter in subtropical forests. The findings further indicated that single C addition model might overestimate the effect of exogenous readily decomposable organic C on PE and ignore the effect of N deposition on PE, which in turn would overestimate the mineralization loss of forest SOC.

Mesencephalic astrocyte-derived neurotrophic factor (MANF): Structure, functions and therapeutic potential.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel evolutionarily conserved protein present in both vertebrate and invertebrate species. MANF shows distinct structural and functional properties than the traditional neurotrophic factors (NTF). MANF is composed of an N-terminal saposin-like lipid-binding domain and a C-terminal SAF-A/B, Acinus and PIAS (SAP) domain connected by a short linker. The two well-described activities of MANF include (1) role as a neurotrophic factor that plays direct neuroprotective effects in the nervous system and (2) cell protective effects in the animal models of non-neuronal diseases, including retinal damage, diabetes mellitus, liver injury, myocardial infarction, nephrotic syndrome, etc. The main objective of the current review is to provide up-to-date insights regarding the structure of MANF, mechanisms regulating its expression and secretion, physiological functions in various tissues and organs, protective effects during aging, and potential clinical applications. Together, this review highlights the importance of MANF in reversing age-related dysfunction and geroprotection.

DDX5 and DDX17-multifaceted proteins in the regulation of tumorigenesis and tumor progression.

DEAD-box (DDX)5 and DDX17, which belong to the DEAD-box RNA helicase family, are nuclear and cytoplasmic shuttle proteins. These proteins are expressed in most tissues and cells and participate in the regulation of normal physiological functions; their abnormal expression is closely related to tumorigenesis and tumor progression. DDX5/DDX17 participate in almost all processes of RNA metabolism, such as the alternative splicing of mRNA, biogenesis of microRNAs (miRNAs) and ribosomes, degradation of mRNA, interaction with long noncoding RNAs (lncRNAs) and coregulation of transcriptional activity. Moreover, different posttranslational modifications, such as phosphorylation, acetylation, ubiquitination, and sumoylation, endow DDX5/DDX17 with different functions in tumorigenesis and tumor progression. Indeed, DDX5 and DDX17 also interact with multiple key tumor-promoting molecules and participate in tumorigenesis and tumor progression signaling pathways. When DDX5/DDX17 expression or their posttranslational modification is dysregulated, the normal cellular signaling network collapses, leading to many pathological states, including tumorigenesis and tumor development. This review mainly discusses the molecular structure features and biological functions of DDX5/DDX17 and their effects on tumorigenesis and tumor progression, as well as their potential clinical application for tumor treatment.