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Background: CD2-associated protein (CD2AP) is a podocyte-associated gene and its reduced expression is associated with the development of proteinuria and glomerulosclerosis. However, few studies have focused on the correlation between the expression and prognosis of CD2AP in renal clear cell carcinoma (ccRCC). Therefore, we aimed to assess the regulation of CD2AP expression and prognostic value in ccRCC., Methods: Multiple databases were employed to examine the expression of CD2AP in ccRCC. RT-qPCR, Western Blot and immunohistochemistry were used to validate CD2AP expression in different cell lines and tissue samples. Kaplan-Meier analysis and ROC curve analysis were performed on the predictive prognostic performance of CD2AP. COX regression was used to construct CD2AP-related prognostic models. The TIMER and TISIDB databases were used to analyze the correlation of tumor-infiltrating immune cells with gene expression, mutations, somatic copy number variation, and immune molecules. Mass spectrometry was used to detect methylation status of the promoter CpG site of CD2AP in multiple cells., Results: We found that CD2AP expression was downregulated in ccRCC and its lower expression level was correlation with worse patient prognosis, higher tumor stage and grade and distant metastasis through analysis of databases, ccRCC cell lines and clinical tissue samples. Moreover, database and mass spectrometry techniques identified and validated cg12968598 hypermethylation as one of the key reasons for the downregulation of CD2AP expression. CD2AP expression was also associated with macrophage and neutrophil infiltration., Conclusions: Taken together, our results suggest that CD2AP can be used as a diagnostic and prognostic biomarker in ccRCC patients and that DNA hypermethylation plays an important role in reducing CD2AP expression., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Tomato cultivars with contrasting resistance to pathogens regulate root exudates differentially in response to Ralstonia solanacearum attacks. However, strategies using innate root exudates against infection remain unknown. This study analyzed the innate root exudates of two tomato cultivars and their functions in regulating R. solanacearum infection. The innate root exudates differed between the two cultivars. Astaxanthin released from resistant plants inhibited colonization by R. solanacearum but promoted motility, while neferine released from susceptible plants suppressed motility and colonization. The secretion of astaxanthin in resistant tomatoes promoted the growth of biocontrol fungi in soil and reduced the abundance of pathogenic fungi. Neferine secreted by the susceptible cultivar inhibited the relative abundance of the bacterial-biocontrol-related Bacillus genus, indirectly reducing the soil's immune capacity. This study revealed contrasting strategies using root exudates in resistant and susceptible tomato cultivars to cope with R. solanacearum infection, providing a basis for breeding disease-resistant cultivars.

Sarcopenia is characterized by the loss of muscle mass and function. It is well known that sarcopenia is often associated with aging, while in recent years, sarcopenia comorbid with chronic diseases such as cirrhosis has attracted widespread attention, whose underlying molecular mechanisms remain unclear. Since cirrhosis and sarcopenia are assumed to be closely interrelated in terms of pathogenesis, this review innovatively discussed the role of epigenetic modifications and microecological dysregulation in sarcopenia in the context of liver cirrhosis. Here we illustrated the relationship between sarcopenia and cirrhosis in the aspect of epigenetics, dysbiosis, and the crosstalk between gene modifications and intestinal microecology. Furthermore, the alterations in cirrhosis patients with sarcopenia, such as inflammatory response and oxidative stress, are found to present synergistic effects in the pathways of epigenetics and dysbiosis leading to sarcopenia. This review proposes that microbiome-based therapies are promising to break the vicious cycle between epigenetic modification and dysbiosis, providing strong support for the use of intestinal microecological interventions to prevent sarcopenia in cirrhotic patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xu, Pan, Zhang, Dai and Xu.)

Background: Various inherited traits contribute to the overall risk of venous thromboembolism (VTE). In addition, the epidemiology of thrombophilia in the East-Asian VTE population remains unclear; thus, we aimed to assess the proportion of hereditary thrombophilia via a meta-analysis., Methods: Publications from PubMed, EMBASE, web of science, and Cochrane before December 30, 2022, were searched. Studies from Japan, Korea, China, Hong Kong, Taiwan, Singapore, Thailand, Vietnam, Myanmar, and Cambodia were included. Congenital thrombophilia was described as diseases including protein C (PC) deficiency, protein S (PS) deficiency, antithrombin (AT) deficiency, factor (F)V Leiden (FVL), and prothrombin G20210A mutations. Studies were selected by 2 reviewers for methodological quality analysis. A random-effects model was used for the meta-analysis, assuming that estimated effects in the different studies are not identical., Results: Forty-four studies involving 6453 patients from 7 counties/regions were included in the meta-analysis. The prevalence of PC, PS, and AT deficiencies were 7.1%, 8.3%, and 3.8%, respectively. Among 2924 patients from 22 studies, 5 patients were carriers of FVL mutation. Among 2196 patients from 10 studies, 2 patients were carriers of prothrombin G20210A mutation in a Thailand study., Conclusion: The prevalence of PC, PS, and AT deficiencies was relatively high, while a much lower prevalence of FVL and prothrombin G20210A mutations were identified in East-Asian patients with VTE. Our data stress the relative higher prevalence of PC, PS, and AT deficiencies for thrombophilia in the East-Asian VTE population., (© 2023 The Author(s).)

Fecal calprotectin (FC) levels correlate with the disease activity of inflammatory bowel diseases (IBD); however, the utility of FC in predicting IBD relapse remains to be determined. We aim to evaluate the efficacy of fecal calprotectin in predicting the relapse of inflammatory bowel disease. We searched Pubmed (MEDLINE), Embase, Web of Science, and the Cochrane library databases up to 7 July 2021. Our study estimated the pooled sensitivity and specificity, summary receiver operating characteristic (SROC) curve, and the optimal cut-off value for predicting IBD relapse using a multiple threshold model. A total of 24 prospective studies were included in the meta-analysis. The optimal FC cut-off value was 152 μg/g. The pooled sensitivity and specificity of FC was 0.720 (0.528 to 0.856) and 0.740 (0.618 to 0.834), respectively. FC is a useful, non-invasive, and inexpensive biomarker for the early prediction of IBD relapse. An FC value of 152 μg/g is an ideal threshold to identify patients with a high relapse probability., Competing Interests: The authors declare no conflict of interest.

Background: Recently studies have identified a critical role for interferon regulatory factor (IRF) in modulating tumour immune microenvironment (TME) infiltration and tumorigenesis., Methods: Based on IRF1-9 expression profiles, we classified all ccRCC samples into three molecular subtypes (clusters A-C) and characterized the prognosis and immune infiltration of these clusters. IRFscore constructed by principal component analysis was performed to quantify IRF-related subtypes in individual patients., Results: We proved that IRFscore predicted multiple patient characteristics, with high IRFscore group having poorer prognosis, suppressed TME, increased T-cell exhaustion, increased TMB and greater sensitivity to anti- PD-1/CTLA-4 therapies. Furthermore, analysis of metastatic ccRCC (mccRCC) molecular subtypes and drug sensitivity proved that low IRFscore was more sensitive to targeted therapies. Moreover, IRFscore grouping can be well matched to the immunological and molecular typing of ccRCC. qRT-PCR showed differential expression of IRFs in different cell lines., Conclusions: Evaluating IRF-related molecular subtypes in individual ccRCC patients not only facilitates our understanding of tumour immune infiltration, but also provides more effective clinical ideas for personalised treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Chen, Yang, Zhang, Shao and Xu.)

Recently, studies have revealed the prognostic value of 5-methylcytosine (m5C) in clear cell renal cell carcinoma (ccRCC). However, the role of m5C methylation in ccRCC immune infiltration and the immunotherapeutic response remains unknown. Based on the mRNA expressions of 14 m5C regulators, we evaluated the m5C modification patterns of 530 tumor samples from the TCGA-ccRCC database. We used the principal component analysis (PCA) algorithm to construct individual patient m5Cscores to facilitate individual analysis of m5C modification patterns in ccRCC patients. We finally defined three different m5C modification patterns. Different clinical features and immune heterogeneity existed among the three patterns, and their immune infiltration characteristics could correspond to different immune phenotypes, including the immune-inflamed, immune-excluded, and immune-desert phenotype. We designed the m5Cscore calculated by the PCA algorithm to measure individual patients' m5C modification patterns. The low m5Cscore group presented with a positive prognosis, increased TMB, and immune activation. Additionally, low m5Cscore patients showed an increased response to immune checkpoint inhibitors. We further the value of the m5Cscore in predicting OS verified in four other tumor cohorts. Our findings revealed that m5C methylation modifications are essential in regulating ccRCC immune infiltration. Assessing single ccRCC patients' m5C modification patterns can fully improve our comprehension of tumor immune characteristics and be used to provide effective personalized immunotherapy strategies for clinical use.

Microplastics (MPs) pollution has been recognized as a threat to sustainable fisheries due to the risks of MPs contamination in the process of feed production and susceptibility of fish to ingest MPs from the aquatic environment. In this study, we applied comprehensive approaches to investigate the impacts of polyethylene microplastics (PE-MPs) on juvenile genetically improved farmed tilapia (GIFT, Oreochromis niloticus) through 9-week dietary exposure based on growth performance, gut microbiota, liver metabolism, and gene expressions in brain and liver tissues. Dietary exposure to two kinds of PE-MPs with different median size (27 μm and 63 μm, respectively) concentration-dependently decreased weight gain (WG), while increased feed conversion ratio (FCR) and hepatosomatic index (HSI) of the tilapia. Dietary administration of PE-MPs also significantly reduced the activities of intestinal protease and amylase. PE-MPs particles of the larger size groups (63 μm) were mainly detected in feces, but those of the smaller ones (27 μm) tended to be accumulated in intestine. PE-MPs ingestion resulted in the alteration of gut microbiota composition, with Fusobacteria, Verrucomicrobia and Firmicutes as the overrepresented bacterial taxa. Metabolomic assays of liver samples in fish fed the diets containing 8 % of PE-MPs revealed the particle size-specific variations in composition of differential metabolites and metabolism pathways such as amino acid and glycerophospholipid metabolism. Gene expressions of brain and liver samples were analyzed by RNA-seq. Photoperiodism and circadian rhythm were the representative biological processes enriched for the differentially expressed genes (DEGs) identified from the brain. Citrate cycle (TCA cycle) was the most enriched pathway revealed by a joint transcriptomic and metabolic pathway analysis for the liver, followed by propanoate and pyruvate metabolism. Furthermore, an integration analysis of the gut microbiome and liver transcriptome data identified significant associations between several pathogenic bacteria taxa and immune pathways. Our findings demonstrated that the sizes and concentrations of PE-MPs are critically related to their toxic impacts on microbiota community, metabolism, gene expressions and thus fish growth., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: As the most common renal malignancy, kidney renal clear cell carcinoma (KIRC) has a high prevalence and death rate as well as a poor response to treatment. Developing an efficient prognostic model is essential for accurately predicting the outcome and therapeutic benefit of KIRC patients., Methods: Gene expression profiles of podocyte-associated genes (PAGs) were obtained from The Cancer Genome Atlas and GEO datasets. Cox regression and Lasso regression analyses were then used for filtering prognosis-associated PAGs. Risk score (RS) was computed from these genetic characteristics. Kaplan-Meier analysis and receiver operating characteristic (ROC) curves were applied for ascertaining the prognostic value. Stratified analysis was used to sufficiently validate model performance. Concordance index was used to compare the predictive ability of different models. Immuno-infiltration analysis and immunophenoscore were utilized for the prediction of patient reaction to immune checkpoint inhibitors (ICIs)., Results: WT1, ANLN, CUBN, OSGEP, and RHOA were significantly associated with KIRC prognosis. Prognostic analysis indicated that high-RS patients have a significantly poorer outcome. Cox regression analysis demonstrated a potential for RS to be an independent prognostic factor. Pathway enrichment results indicated a lower enrichment of cancer-related biological pathways in the low-RS subgroup. Immune infiltration analysis and IPS demonstrated greater responsiveness to ICIs in the high RS group., Conclusions: This podocyte-associated KIRC prognostic model can effectively predict KIRC prognosis and immunotherapy response, which may help to provide clinicians with more effective treatment strategies., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Good's syndrome (GS) is often accompanied by recurrent respiratory infections and chronic diarrhea. The main purpose was to evaluate the peripheral immune status of a GS patient after thymoma resection. Twenty healthy volunteers were recruited as healthy controls (HCs). Flow cytometry was applied to determine the proportions of circuiting CD4 + T cells, CD8 + T cells, γδ T cells, and regulatory T (Treg) cells in our GS patient. We also examined the proliferation capability of ex vivo CD4 + T cells and detected the levels of cytokines interferon- (IFN-) γ and interleukin-17A secreted by ex vivo immune cells from this GS patient. Compared with healthy control subjects, this GS patient had fewer B cells, an inverted ratio of CD4 + /CD8 + cells, and more Treg cells in his peripheral blood. Additionally, the patient's V δ 2 T cell levels were significantly decreased despite having a normal percentage of γδ T cells. Ex vivo peripheral CD4 + T cells from the patient showed insufficient proliferation and division potential as well as excessive expression of PD-1. Moreover, IFN- γ was predominantly derived from CD8 + T cells in this GS patient, rather than from CD4 + T cells and γδ T cells. This GS patient had impaired T and B cell immunological alternations and cytokine disruptions after thymectomy. Detailed research should focus on therapies that can adjust the immune status in such patients for a better outcome.

Chemotherapy is commonly used to treat early-stage invasive and advanced-stage breast cancer either before or after surgery. Increasing evidence from clinical analysis and in vitro studies has shown that ER-positive breast cancer cells are insensitive to chemotherapy. Complete understanding of how ERα mediates drug resistance is prerequisite to improvement of the chemotherapeutic efficacy. Over-expression of P-glycoprotein (P-gp) encoded by MDR1 gene is one of the major causes of drug resistance. The association between ERα and MDR1 in breast cancer is still unclear and the limited reports are conflict. This study systematically explored intrinsic link between ERα and the P-gp over-expression in paclitaxel-resistant ERα(+) breast cancer cell lines and mouse model in molecular details. Our data showed that ERα activated the MDR1 transcription in MCF-7/PTX breast cancer cells by binding to ERE1/2 and interacting with Sp1 that bridged to the downstream CG-rich element within the MDR1 promoter. Knockdown of MDR1 restrained the effect of ERα in MCF-7 cells and sensitized the cells to paclitaxel. Treatment of ICI 182,780 that selectively suppressed ERα significantly decreased the MDR1 expression and increased the sensitivity of drug resistant breast cancer cells and xenograft tumors to paclitaxel. Our data strongly demonstrated that ERα was able to increase drug resistance of breast cancer cells through activating MDR1 transcription. This novel mechanism provides new insight to how the ERα signaling regulates response of ERα(+) breast tumors to chemotherapy, which may be exploited for developing novel therapeutic strategies for breast cancer in the future., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Obstructive sleep apnea syndrome (OSAS) is an important risk factor for cardiovascular diseases. Chronic intermittent hypoxia (CIH) is considered to be one of the most important causes of cardiovascular diseases in OSA patients. This repeated hypoxia and reoxygenation cycle is similar to hypoxia-reperfusion injury, which initiates oxidative stress. In this study, we observed cardiocytes injury induced by CIH and the effect of N-acetylcysteine (NAC)., Methods: Thirty ICR mice were randomly assigned to 3 groups: control, CIH and NAC (CIH + NAC) groups. Malondialdehyde (MDA) and superoxide dismutase (SOD) of cardiocyte homogenates were measured. Serum lipids were measured by an instrument method. Serum cardiac troponin I (cTnI) was detected by enzyme-linked immunosorbent assays (ELISA). Myocardium pathological sections were observed., Results: (1) The SOD activity and MDA concentration of cardiocyte homogenates in the CIH group were significantly higher than in other groups (P < 0.005). The MDA concentration of the NAC group was lower than that of the control group (P < 0.01). (2) The serum cTnI concentration of the CIH and NAC groups was significantly higher than that of the control group (P < 0.01). (3) Serum triglyceride levels in the NAC group were lower than in the other groups (P < 0.01), while there were no significant differences in low density lipoprotein and high density lipoprotein among the three groups. (4) The degeneration of myocardium, transverse striation blurred, and fabric effusion were observed in tissue sections in the CIH and NAC groups. However, normal tissue was found in the control group., Conclusion: The oxidative stress induced by CIH can injure cardiocytes and the injury effect can be partially inhibited by NAC.