Calcium-sensing receptor-mediated macrophage polarization improves myocardial remodeling in spontaneously hypertensive rats.

Chronic inflammation is a key element in the progression of essential hypertension (EH). Calcium plays a key role in inflammation, so its receptor, the calcium-sensing receptor (CaSR), is an essential mediator of the inflammatory process. Compelling evidence suggests that CaSR mediates inflammation in tissues and immune cells, where it mediates their activity and chemotaxis. Macrophages (Mφs) play a major role in the inflammatory response process. This study provided convincing evidence that R568, a positive regulator of CaSR, was effective in lowering blood pressure in spontaneously hypertensive rats (SHRs), improving cardiac function by alleviating cardiac hypertrophy and fibrosis. R568 can increase the content of CaSR and M2 macrophages (M2Mφs, exert an anti-inflammatory effect) in myocardial tissue, reduce M1 macrophages (M1Mφs), which have a pro-inflammatory effect in this process. In contrast, NPS2143, a negative state regulator of CaSR, exerted the opposite effect in all of the above experiments. Following this study, R568 increased CaSR content in SHR myocardial tissue, lowered blood pressure, promoted macrophages to M2Mφs and improved myocardial fibrosis, but interestingly, both M1Mφs and M2Mφs were increased in the peritoneal cavity of SHRs, the number of M2Mφs remained lower than M1Mφs. In vitro, R568 increased CaSR content in RAW264.7 cells (a macrophage cell line), regulating intracellular Ca2+ ([Ca2+]i) inhibited NOD-like receptor family protein 3 (NLRP3) inflammasome activation and ultimately prevented its conversion to M1Mφs. The results showed that a decrease in CaSR in hypertensive rats causes further development of hypertension and cardiac damage. EH myocardial remodeling can be improved by CaSR overexpression by suppressing NLRP3 inflammasome activation and macrophage polarization toward M1Mφs and increasing M2Mφs.

Effect of electroacupuncture on behavior and hippocampal inflammatory factors in rats with chronic fatigue syndrome. / ç”µé’ˆå¯¹æ ¢æ€§ç–²åŠ³ç»¼åˆå¾å¤§é¼ è¡Œä¸ºå­¦åŠæµ·é©¬ç‚Žæ€§å› å­çš„å½±å“.

OBJECTIVES: To observe the effect of electroacupuncture (EA) on the changes of behavior and hippocampal inflammatory factors in rats with chronic fatigue syndrome (CFS), so as to explore its possible mechanisms in the treatment of CFS. METHODS: Twenty-seven SD rats were randomly divided into control, model and electroacupuncture (EA) groups (n=9 rats in each group). The CFS model was established by multi-factor compound stress stimulation method. Rats of the EA group received EA (10 Hz) at "Shenting" (GV24) penetrating "Baihui" (GV20), "Dazhui" (GV14) for 15 min, twice a day for 14 days. The general conditions, Morris water maze test, open field test, the exhausted running platform were conducted for determining the rats' locomotor and learning-memory activities. H.E. staining was used to observe the morphological structure of neurons in hippocampal CA1 region. The contents of interleukin (IL)-10, IL-17 and transforming growth factor (TGF) ß1 in hippocampus and serum of rats were detected by ELISA, and the positive expressions of IL-10, IL-17 and TGF-ß1 in hippocampal CA1 region were detected by immunofluorescence staining. RESULTS: Compared with the control group, the score of general condition was increased (P<0.05), the escape latency was prolonged (P<0.05), the number of crossing the original platform was decreased (P<0.05), the numbers of crossing the grid and entering the central area were increased (P<0.05), and the exhaustive treadmill time was shortened (P<0.05) in the model group. The contents of IL-10 in the hippocampus and serum were decreased (P<0.05), while IL-17 and TGF-ß1 contents were increased (P<0.05). The immunofluorescence intensity of IL-10 in the hippocampus was decreased (P<0.05), while the intensity of IL-17 and TGF-ß1 were increased (P<0.05). After treatment, compared with the model group, the score of general condition was decreased (P<0.05), the escape latency was shortened (P<0.05), the number of crossing the original platform was increased (P<0.05), the numbers of crossing the grid and entering the central area were decreased (P<0.05), and the exhaustive treadmill time was prolonged (P<0.05) in the EA group. The contents of IL-10 in the hippocampus and serum were increased (P<0.05), while IL-17 and TGF-ß1 levels were decreased (P<0.05). The immunofluorescence intensity of IL-10 in the hippocampus was increased (P<0.05), while the intensity of IL-17 and TGF-ß1 were decreased (P<0.05). H.E. staining showed that in the model group, the number of neurons in the hippocampus decreased, with disordered arrangement and loose structure, and a small numbers of neuronal nuclei were missing. The degree of tissue damage of the EA group was milder than that of the model group. CONCLUSIONS: EA can alleviate fatigue and spatial learning and memory impairment in CFS rats, which may be related to the regulation of peripheral and central inflammation.

An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase.

The main proteinase (Mpro) of SARS-CoV-2 plays a critical role in cleaving viral polyproteins into functional proteins required for viral replication and assembly, making it a prime drug target for COVID-19. It is well known that noncompetitive inhibition offers potential therapeutic options for treating COVID-19, which can effectively reduce the likelihood of cross-reactivity with other proteins and increase the selectivity of the drug. Therefore, the discovery of allosteric sites of Mpro has both scientific and practical significance. In this study, we explored the binding characteristics and inhibiting process of Mpro activity by two recently reported allosteric inhibitors, pelitinib and AT7519 which were obtained by the X-ray screening experiments, to probe the allosteric mechanism via molecular dynamic (MD) simulations. We found that pelitinib and AT7519 can stably bind to Mpro far from the active site. The binding affinity is estimated to be -24.37 ± 4.14 and - 26.96 ± 4.05 kcal/mol for pelitinib and AT7519, respectively, which is considerably stable compared with orthosteric drugs. Furthermore, the strong binding caused clear changes in the catalytic site of Mpro, thus decreasing the substrate accessibility. The community network analysis also validated that pelitinib and AT7519 strengthened intra- and inter-domain communication of Mpro dimer, resulting in a rigid Mpro, which could negatively impact substrate binding. In summary, our findings provide the detailed working mechanism for the two experimentally observed allosteric sites of Mpro. These allosteric sites greatly enhance the 'druggability' of Mpro and represent attractive targets for the development of new Mpro inhibitors.

Use of statins and risks of ovarian, uterine, and cervical diseases: a cohort study in the UK Biobank.

PURPOSE: To examine the associations between use of statins and risks of various ovarian, uterine, and cervical diseases, including ovarian cancer, endometrial cancer, cervical cancer, ovarian cyst, polycystic ovarian syndrome, endometriosis, endometrial hyperplasia, endometrial polyp, and cervical polyp. METHODS: We conducted a cohort study among female participants in the UK Biobank. Information on the use of statins was collected through verbal interview. Outcome information was obtained by linking to national cancer registry data and hospital inpatient data. We used Cox proportional hazards regression to examine the associations. RESULTS: A total of 180,855 female participants (18,403 statin users and 162,452 non-users) were included. Use of statins was significantly associated with increased risks of cervical cancer (adjusted hazard ratio (HR), 1.55; 95% confidence interval (95% CI), 1.05-2.30) and polycystic ovarian syndrome (adjusted HR, 4.39; 95% CI, 1.68-11.49). However, we observed no significant association between use of statins and risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial hyperplasia, endometrial polyp, or cervical polyp. CONCLUSION: Our findings suggest that use of statins is associated with increased risks of cervical cancer and polycystic ovarian syndrome, but is not associated with increased or decreased risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial polyp, or cervical polyp.

Unveiling the impact of tertiary lymphoid structures on immunotherapeutic responses of clear cell renal cell carcinoma.

Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that form under pathological conditions. However, the predictive value of TLS in clear cell renal cell carcinoma (ccRCC) for immunotherapies remains unclear. We comprehensively assessed the implications for prognosis and immunological responses of the TLS spatial and maturation heterogeneity in 655 ccRCC patients. A higher proportion of early-TLS was found in peritumoral TLS, while intratumoral TLS mainly comprised secondary follicle-like TLS (SFL-TLS), indicating markedly better survival. Notably, presence of TLS, especially intratumoral TLS and SFL-TLS, significantly correlated with better survival and objective reflection rate for ccRCC patients receiving anti-Programmed Cell Death Protein-1 (PD-1)/Programmed Cell Death-Ligand-1 (PD-L1) immunotherapies. In peritumoral TLS cluster, primary follicle-like TLS, the proportion of tumor-associated macrophages, and Treg infiltration in the peritumoral regions increased prominently, suggesting an immunosuppressive tumor microenvironment. Interestingly, spatial transcriptome annotation and multispectral fluorescence showed that an abundance of mature plasma cells within mature TLS has the capacity to produce IgA and IgG, which demonstrate significantly higher objective response rates and a superior prognosis for ccRCC patients subjected to immunotherapy. In conclusion, this study revealed the implications of TLS spatial and maturation heterogeneity on the immunological status and clinical responses, allowing the improvement of precise immunotherapies of ccRCC.

Cohort profile: the China surgery and anesthesia cohort (CSAC).

The China Surgery and Anaesthesia Cohort (CSAC) study was launched in July 2020 and is an ongoing prospective cohort study recruiting patients aged 40-65 years who underwent elective surgeries with general anaesthesia across four medical centres in China. The general objective of the CSAC study is to improve our understanding of the complex interaction between environmental and genetic components as well as to determine their effects on a wide range of interested surgery/anaesthesia-related outcomes. To achieve this goal, we collected enriched phenotypic data, e.g., sociodemographic characteristics, lifestyle factors, perioperative neuropsychological changes, anaesthesia- and surgery-related complications, and medical conditions, at recruitment, as well as through both active (at 1, 3, 7 days and 1, 3, 6, 12 months after surgery) and passive (for more than 1 year after surgery) follow-up assessments. We also obtained omics data from blood samples. In addition, COVID-19-related information was collected from all participants since January 2023, immediately after COVID-19 restrictions were eased in China. As of July 18, 2023, 12,766 participants (mean age = 52.40 years, 57.93% were female) completed baseline data collection (response rate = 94.68%), among which approximately 70% donated blood and hair samples. The follow-up rates within 12 months after surgery were > 92%. Our initial analyses have demonstrated the incidence of and risk factors for chronic postsurgical pain (CPSP) and postoperative cognitive dysfunction (POCD) among middle-aged Chinese individuals, which may prompt further mechanistic exploration and facilitate the development of effective interventions for preventing those conditions. Additional studies, such as genome-wide association analyses for identifying the genetic determinants of CPSP and POCD, are ongoing, and their findings will be released in the future.

Preoperative psychological symptoms and chronic postsurgical pain: analysis of the prospective China Surgery and Anaesthesia Cohort study.

BACKGROUND: Both preoperative psychological symptoms and chronic postsurgical pain (CPSP) are prevalent conditions and major concerns among surgery patients, with inconclusive associations. METHODS: Based on the China Surgery and Anaesthesia Cohort (CSAC), we recruited 8350 surgery patients (40-65 yr old) from two medical centres between July 2020 and March 2023. Patients with preoperative psychological symptoms (i.e. anxiety, depression, stress reaction, and poor sleep quality) were identified using corresponding well-established scales. We then examined the associations of individual preoperative psychological symptoms and major patterns of preoperative psychological symptoms (identified by k-means clustering analysis) with CPSP, and different pain trajectories within 3 months. Lastly, mediation analyses were conducted to elucidate the mediating role of surgery/anaesthesia-related factors and the presence of 1-month postoperative psychological symptoms on the studied associations. RESULTS: We included 1302 (1302/8350, 15.6%) CPSP patients. When analysed separately, all studied preoperative psychological symptoms were associated with increased CPSP risk, with the most pronounced odds ratio noted for anxiety (1.52, 95% confidence interval [CI] 1.23-1.86). Compared with patients clustered in the minor symptom group, excess risk of CPSP and experiencing an increasing pain trajectory was increased among patients with preoperative psychological symptoms featured by sleep disturbances (odds ratio=1.46, 95% CI 1.25-1.70 for CPSP and 1.58, 95% CI 1.20-2.08 for increasing pain trajectory) and multiple psychological symptoms (1.84 [95% CI 1.48-2.28] and 4.34 [95% CI 3.20-5.88]). Mediation analyses revealed acute/subacute postsurgical pain and psychological symptoms existing 1 month after surgery as notable mediators of the observed associations. CONCLUSIONS: The presence of preoperative psychological symptoms might individually or jointly increase the risk of chronic postsurgical pain or experiencing deterioration in pain trajectory. Interventions for managing acute/subacute postsurgical pain and psychological symptoms at 1 month after surgery might help reduce such risk. CLINICAL TRIAL REGISTRATION: ChiCTR2000034039.

Heterogeneity in tertiary lymphoid structures predicts distinct prognosis and immune microenvironment characterizations of clear cell renal cell carcinoma.

BACKGROUND: Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that develop postnatally in non-lymphoid tissues and are associated with pathological conditions. TLS typically comprise B-cell follicles containing and are encompassed by T- cell zones and dendritic cells. The prognostic and predictive value of TLS in the tumor microenvironment (TME) as potential mediators of antitumor immunity have gained interest. However, the precise relationship between localization and maturation of TLS and the clinical outcome of their presence in clear cell renal cell carcinoma (ccRCC) is yet to be elucidated. METHODS: Immunohistochemistry and multispectral fluorescence were used to evaluate the TLS heterogeneity along with TME cell-infiltrating characterizations. A thorough investigation of the prognostic implications of the TLS heterogeneity in 395 patients with ccRCC from two independent cohorts was conducted. Associations between TLS heterogeneity and immunologic activity were assessed by quantifying the immune cell infiltration. RESULTS: Infiltrated TLS were identified in 34.2% of the ccRCC samples (N=395). These TLS were found to be tumor-proximal, tumor-distal, or both in 37.8%, 74.1%, and 11.9% of the TLS-positive cases, respectively. A higher proportion of early TLS was found in tumor-distal TLS (p=0.016), while tumor-proximal TLS primarily comprised secondary follicle-like structures (p=0.004). In the main study cohort (Fudan University Shanghai Cancer Center, N=290), Kaplan-Meier analyses revealed a significant correlation between the presence of tumor-proximal TLS and improved progression-free survival (PFS, p<0.001) and overall survival (OS, p=0.002). Conversely, the presence of tumor-distal TLS was associated with poor PFS (p=0.02) and OS (p=0.021). These findings were further validated in an external validation set of 105 patients with ccRCC. Notably, the presence of mature TLS (namely secondary follicle-like TLS, with CD23+ germinal center) was significantly associated with better clinical outcomes in patients with ccRCC. Furthermore, novel nomograms incorporating the presence of tumor-proximal TLS demonstrated remarkable predictability for the 8-year outcomes of resected ccRCC (area under the curve >0.80). Additionally, ccRCC samples with tumor-distal TLS enriched with primary follicle-like TLS exhibited higher programmed death-ligand 1 tumor-associated macrophages levels and regulatory T cells infiltration in the tumor-distal region, indicative of a suppressive TME. CONCLUSION: This study for the first time elucidates the impact of TLS localization and maturation heterogeneities on the divergent clinical outcomes of ccRCC. The findings reveal that most TLS in ccRCC are located in the tumor-distal area and are associated with immature, immunosuppressive characterizations. Furthermore, our findings corroborate previous research demonstrating that tumor-proximal TLS were associated with favorable clinical outcomes.

Construction of cuproptosis signature based on bioinformatics and experimental validation in clear cell renal cell carcinoma.

BACKGROUND: Cuproptosis was defined as a novel nonapoptotic cell death pathway and its potential function in clear cell renal cell carcinoma (ccRCC) remains unclear. METHODS: We obtained gene expression profiles, somatic mutation and corresponding clinical information of 881 ccRCC samples from 3 cohorts including the cancer genome atlas cohort, GSE29609 cohort and CheckMate 025 cohort. As described in the latest published article, we enrolled 16 genes as cuproptosis-related genes (CRGs). We explored the expression level, variants and copy number variation of the CRGs. Univariate and multi-variate regression were utilized to assess the prognostic significance of the CRGs. Non-negative matrix factorization was used to identify potential subgroup and gene set variation analysis was used to explore the potential biological functions. CIBERSORT, ESTIMATE algorithm and single sample gene set enrichment analysis were used to evaluate the tumor microenvironment. In vitro experiments including CCK-8, transwell and wound healing assays were utilized to explore the potential biological function of DLAT in ccRCC. RESULTS: We found that except for CDKN2A, the CRGs were positively associated with patients' OS. Cuproptosis cluster, cuproptosis gene cluster and cuproptosis score were established, respectively, and higher cuproptosis score was significantly associated with a worse OS in ccRCC (p < 0.001). The area under the receiver operating characteristic curve of the cuproptosis-related nomogram at 1 year, 3 years, 5 years was 0.858, 0.821 and 0.78, respectively. In addition, we found that the cuproptosis score was positively associated with PDCD1, CTLA4 expression level, thus the cuproptosis score may also reflect the dysfunction of tumor infiltrating immune cells. In vitro experiments indicated that overexpression of DLAT could inhibited the migration and proliferation ability of ccRCC cells. CONCLUSION: Our findings identify a novel cuproptosis-related signature and the cuproptosis characteristics may influence the anti-tumor immunity though complex regulating networks, and thus cuproptosis may play a role in developing novel therapeutic target of ccRCC.

Protein Arginine Methyltransferases Refine the Classification of Clear Cell Renal Cell Carcinoma with Distinct Prognosis and Tumor Microenvironment Characteristics.

Background: Clear cell renal cell carcinoma (ccRCC) is an aggressive urological cancer that originates from the proximal tubular epithelium. As one of the most common post-translational modification, protein arginine methylation plays a pivotal role in various cancer-associated biological functions, especially in cancer immunity. Therefore, constructing a protein arginine methylation-related prognostic signature would be beneficial in guiding better personalized clinical management for patients with ccRCC. Methods: Based on the multi-omics profiling of the expression levels of eight protein arginine methyltransferases (PRMTs) in 763 ccRCC samples (from TCGA, CPTAC, EMBL, and ICGC databases), we established a scoring system with machine-learning algorithms to quantify the modification patterns on clinical and immunological characterizations of individual ccRCC patient, which was termed as PRMTScore. Moreover, we utilized two external clinical cohorts receiving immunotherapy (n=302) to validate the reliability of the PRMTScore system. Multiplex immunohistochemistry (mIHC) was performed to characterize the cellular composition of 30 paired ccRCC samples. The proteomic profiling of 232 ccRCC samples obtained from Fudan University Shanghai Cancer Center (FUSCC) was analyzed to validate the protein expression of PRMT5 in ccRCC. Finally, CCK-8, transwell, and wound healing assays were conducted to elucidate the role of PRMT5 in ccRCC in vitro. Results: A total of 763 ccRCC patients with available multi-omics profiling were stratified into two clusters (PRMTCluster A and B) with distinctive prognosis, genomic alterations, tumor microenvironment (TME) characteristics, and fundamental biological mechanisms. Subsequently, protein arginine methylation-related prognostic signature (PRMTScore) was constructed and consisted of SLC16A12, HRH2, F2RL3, and SAA1. The PRMTScore showed remarkable differences in outcomes, immune and stromal fractions, expressions of immune checkpoints, the abundance of immune cells, and immunotherapy response in ccRCC patients. Additionally, preliminary insights unveiled the tumor-suppressive role of PRMT5 in ccRCC, and the signal of PRMT5low significantly predicted aggressive prognosis and the high abundance of PD1+ CD8+ cells in ccRCC. Conclusion: We constructed a PRMTScore system, which showed the potent ability to assess the prognosis, TME characteristics, and immunotherapy response for patients with ccRCC. Moreover, this is the first study to propose that PRMT5 acts as a cancer suppressor in ccRCC.

Retraction Notice to: TNFAIP8 Promotes Cisplatin Chemoresistance in Triple-Negative Breast Cancer by Repressing p53-Mediated miR-205-5p Expression.

[This retracts the article DOI: 10.1016/j.omtn.2020.09.025.].

Postsurgery Subjective Cognitive and Short-Term Memory Impairment Among Middle-Aged Chinese Patients.

Importance: Perioperative neurocognitive disorder, particularly postoperative cognitive impairment, is common and associated with multiple medical and social adversities, although data from China are lacking. Objective: To examine the incidence, trajectory, and risk factors for subjective cognitive and short-term memory impairment after surgery in the Chinese population. Design, Setting, and Participants: This cohort study used data from the China Surgery and Anesthesia Cohort to assess surgical patients aged 40 to 65 years from 2 medical centers between July 15, 2020, and March 31, 2023, with active follow-up within 1 year after the surgery. Of 11 158 patients who were successfully recruited (response rate, 94.4%), 10 149 participants were eligible and available for analysis. From this population, separate cohorts were constructed for analyzing subjective cognitive impairment (8105 noncardiac and 678 cardiac surgery patients) and short-term memory impairment (5246 noncardiac and 454 cardiac surgery patients). Exposures: Twenty-four potential risk factors regarding comorbidities, preoperative psychological conditions, anesthesia- or surgery-related factors, and postsurgical events were included. Main Outcomes and Measures: Outcomes included subjective cognitive function measured by the 8-Item Informant Interview to Differentiate Aging and Dementia (AD8; scores range from 0 to 8, with higher scores indicating more severe cognitive impairment) and short-term memory measured by the 3-Word Recall Test (TRT; scores range from 0 to 3, with lower scores indicating more severe short-term memory impairment) at 1, 3, 6, and 12 months after noncardiac and cardiac surgery. Generalized linear mixed models were used to identify risk factors associated with the presence of AD8 (score ≥2) or TRT (score <3) abnormality as well as the aggressively deteriorative trajectories of those cognitive measurements. Results: For noncardiac surgery patients, the AD8 analysis included 8105 patients (mean [SD] age, 52.3 [7.1] years; 3378 [41.7%] male), and the TRT analysis included 5246 patients (mean [SD] age, 51.4 [7.0] years; 1969 [37.5%] male). The AD8 abnormality incidence rates after noncardiac surgery increased from 2.2% (175 of 8105) at 7 days to 17.1% (1059 of 6191) at 6 months after surgery, before appearing to decrease. In contrast, the TRT abnormality incidence rates followed a U-shaped pattern, with the most pronounced incidence rates seen at 7 days (38.9% [2040 of 5246]) and 12 months (49.0% [1394 of 2845]). Similar patterns were seen among cardiac surgery patients for the AD8 analysis (678 patients; mean [SD] age, 53.2 [6.3] years; 393 [58.0%] male) and TRT analysis (454 patients; mean [SD] age, 52.4 [6.4] years; 248 [54.6%] male). Among noncardiac surgery patients, the top risk factors for aggressively deteriorative AD8 trajectory and for AD8 abnormality, respectively, after surgery were preoperative sleep disturbances (Pittsburgh Sleep Quality Index ≥16 vs 0-5: odds ratios [ORs], 4.04 [95% CI, 2.20-7.40] and 4.54 [95% CI, 2.40-8.59]), intensive care unit stay of 2 days or longer (ORs, 2.43 [95% CI, 1.26-4.67] and 3.07 [95% CI, 1.67-5.65]), and preoperative depressive symptoms (ORs, 1.76 [95% CI, 1.38-2.24] and 2.23 [95% CI, 1.79-2.77]). Analyses for TRT abnormality and trajectory, as well as the analyses conducted among cardiac surgery patients, found fewer associated factors. Conclusions and Relevance: This cohort study of middle-aged Chinese surgery patients found subjective cognitive and short-term memory impairment within 12 months after both cardiac and noncardiac surgery, with multiple identified risk factors, underscoring the potential of preoperative psychological interventions and optimized perioperative management for postoperative cognitive impairment prevention.

Proteogenomics of different urothelial bladder cancer stages reveals distinct molecular features for papillary cancer and carcinoma in situ.

The progression of urothelial bladder cancer (UC) is a complicated multi-step process. We perform a comprehensive multi-omics analysis of 448 samples from 190 UC patients, covering the whole spectrum of disease stages and grades. Proteogenomic integration analysis indicates the mutations of HRAS regulated mTOR signaling to form urothelial papilloma rather than papillary urothelial cancer (PUC). DNA damage is a key signaling pathway in the progression of carcinoma in situ (CIS) and related to APOBEC signature. Glucolipid metabolism increase and lower immune cell infiltration are associated with PUC compared to CIS. Proteomic analysis distinguishes the origins of invasive tumors (PUC-derived and CIS-derived), related to distinct clinical prognosis and molecular features. Additionally, loss of RBPMS, associated with CIS-derived tumors, is validated to increase the activity of AP-1 and promote metastasis. This study reveals the characteristics of two distinct branches (PUC and CIS) of UC progression and may eventually benefit clinical practice.

Plasma proteomic profiling discovers molecular features associated with upper tract urothelial carcinoma.

Upper tract urothelial carcinoma (UTUC) is often diagnosed late and exhibits poor prognosis. Limited data are available on potential non-invasive biomarkers for disease monitoring. Here, we investigate the proteomic profile of plasma in 362 UTUC patients and 239 healthy controls. We present an integrated tissue-plasma proteomic approach to infer the signature proteins for identifying patients with muscle-invasive UTUC. We discover a protein panel that reflects lymph node metastasis, which is of interest in identifying UTUC patients with high risk and poor prognosis. We also identify a ten-protein classifier and establish a progression clock predicting progression-free survival of UTUC patients. Finally, we further validate the signature proteins by parallel reaction monitoring assay in an independent cohort. Collectively, this study portrays the plasma proteomic landscape of a UTUC cohort and provides a valuable resource for further biological and diagnostic research in UTUC.

Recent advances in soybean protein processing technologies: A review of preparation, alterations in the conformational and functional properties.

Currently, growing concerns about sustainable development and health awareness have driven the development of plant-based meat substitutes. Soybean proteins (SPs) are eco-friendly and high-quality food sources with well-balanced amino acids to meet consumer demand. The functionality and physicochemical attributes of SPs can be improved by appropriate processing and modification. With the burgeoning advances of modern processing technologies in the food industry, a multitude of functional foods and ingredients can be manufactured based on SPs. This review mainly highlights the conformational changes of SPs under traditional and emerging processing technologies and the resultant functionality modifications. By elucidating the relationship between processing-induced structural and functional alterations, detailed and systematic insights are provided regarding the exploitation of these techniques to develop different nutritional and functional soybean products. Some popular methods to modify SPs properties are discussed in this paper, including thermal treatment, fermentation, enzyme catalysis, high hydrostatic pressure, high-intensity ultrasound, atmospheric cold plasma, high-moisture extrusion, glycosylation, pulsed ultraviolet light and interaction with polyphenols. Given these processing technologies, it is promising to expand the application market for SPs and boost the advancement of the soybean industry.

Proteogenomics of clear cell renal cell carcinoma response to tyrosine kinase inhibitor.

The tyrosine kinase inhibitor (TKI) Sunitinib is one the therapies approved for advanced renal cell carcinoma. Here, we undertake proteogenomic profiling of 115 tumors from patients with clear cell renal cell carcinoma (ccRCC) undergoing Sunitinib treatment and reveal the molecular basis of differential clinical outcomes with TKI therapy. We find that chromosome 7q gain-induced mTOR signaling activation is associated with poor therapeutic outcomes with Sunitinib treatment, whereas the aristolochic acid signature and VHL mutation synergistically caused enhanced glycolysis is correlated with better prognosis. The proteomic and phosphoproteomic analysis further highlights the responsibility of mTOR signaling for non-response to Sunitinib. Immune landscape characterization reveals diverse tumor microenvironment subsets in ccRCC. Finally, we construct a multi-omics classifier that can detect responder and non-responder patients (receiver operating characteristic-area under the curve, 0.98). Our study highlights associations between ccRCC molecular characteristics and the response to TKI, which can facilitate future improvement of therapeutic responses.

Lifestyle patterns, genetic susceptibility, and risk of valvular heart disease: a prospective cohort study based on the UK Biobank.

AIMS: Genetic and lifestyle factors are both major contributors to valvular heart disease (VHD). However, it is still uncertain whether genetic susceptibility alters the association between lifestyle and VHD. We aimed to investigate the association between lifestyle and VHD in different genetic risk backgrounds. METHODS AND RESULTS: A prospective cohort study was carried out on 499 341 participants without VHD at baseline. The assessment of lifestyle included smoking, alcohol consumption, diet, activity, and sleep. Genetic susceptibility was separately measured by polygenic risk scores (PRSs) and family history of cardiovascular disease (CVD). Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs) between lifestyle and VHD, as well as aortic stenosis (AS). During a median follow-up of 10.8 years, 12 983 incident VHD cases were diagnosed (incidence rate 2.46 per 1000 person-years), including 3527 AS cases (incidence rate 0.66 per 1000 person-years). The risk of VHD and AS decreased with healthier lifestyles (P value for trend <0.001). Compared to individuals with a unhealthy lifestyle, the HRs of VHD in intermediate and healthy lifestyle groups were 0.81 (0.76-0.86) and 0.81 (0.76-0.87). The negative association between healthy lifestyle and VHD events was independent of genetic risk (P for interaction between healthy lifestyle scores and PRSs/family history of CVD was 0.723/0.763). Similar findings were obtained in analyses of AS, and a stronger negative association was found. CONCLUSION: Our study reveals that adherence to a healthy lifestyle is significantly associated with a reduced risk of VHD especially AS, irrespective of genetic susceptibility. SUMMARY: Based on a cohort of around 490 000 participants, the study investigated the association between lifestyle and VHD under different stratifications of genetic risk. The study found that a healthy lifestyle was associated with a lower risk of VHD, particularly AS, independent of genetic risk. Our findings suggest that advance interventions for lifestyle may be an effective way to reduce the global burden of VHD.

Adverse health consequences of undiagnosed hearing loss at middle age: A prospective cohort study with the UK Biobank.

OBJECTIVES: Hearing impairment is common in the middle-aged population but remains largely undiagnosed and untreated. The knowledge about to what extent and how hearing impairment matters for health is currently lacking. Thus, we aimed to comprehensively examine the adverse health consequences as well as the comorbidity patterns of undiagnosed hearing loss. STUDY DESIGN: Based on the prospective cohort of the UK Biobank, we included 14,620 individuals (median age 61 years) with audiometry-determined (i.e., speech-in-noise test) objective hearing loss and 38,479 individuals with subjective hearing loss (i.e., tested negative but with self-reported hearing problems; median age 58 years) at recruitment (2006-2010), together with 29,240 and 38,479 matched unexposed individuals respectively. MAIN OUTCOME MEASURES: Cox regression was used to determine the associations of both hearing-loss exposures with the risk of 499 medical conditions and 14 cause-specific deaths, adjusting for ethnicity, annual household income, smoking and alcohol intake, exposure to working noise, and BMI. Comorbidity patterns following both exposures were visualized by comorbidity modules (i.e., sets of connected diseases) identified in the comorbidity network analyses. RESULTS: During a median follow-up of 9 years, 28 medical conditions and mortality related to nervous system disease showed significant associations with prior objective hearing loss. Subsequently, the comorbidity network identified four comorbidity modules (i.e., neurodegenerative, respiratory, psychiatric, and cardiometabolic diseases), with the most pronounced association noted for the module related to neurodegenerative diseases (meta-hazard ratio [HR] = 2.00, 95%confidence interval [CI] 1.67-2.39). For subjective hearing loss, we found 57 associated medical conditions, which were partitioned into four modules (i.e., diseases related to the digestive, psychiatric, inflammatory, and cardiometabolic systems), with meta-HRs varying from 1.17 to 1.25. CONCLUSIONS: Undiagnosed hearing loss captured by screening could identify individuals with at greater risk of multiple adverse health consequences, highlighting the importance of screening for speech-in-noise hearing impairment in the middle-aged population, for potential early diagnosis and intervention.

Low expression of miR-1929-3p mediates murine cytomegalovirus-induced fibrosis in cardiac fibroblasts via targeting endothelin a receptor/NLRP3 inflammasome pathway.

MicroRNAs are crucial in the development of myocardial remodeling in hypertension. Low miR-1929-3p expression induced by murine cytomegalovirus (MCMV) infection is closely related to hypertensive myocardial remodeling. This study investigated the molecular mechanism of miR-1929-3p-induced myocardial remodeling after MCMV infection. We modeled MCMV-infected mouse cardiac fibroblasts (MMCFs) as the primary cell model. First, MCMV infection reduced the expression of miR-1929-3p and increased the mRNA and protein expression of its target gene endothelin receptor type A (ETAR) in mouse cardiac fibroblasts (MCFs), which demonstrated an internal relationship with myocardial fibrosis (MF) based on high proliferation, phenotypic transformation (α-SMA), and collagen expression in MMCFs. The transfection of the miR-1929-3p mimic downregulated the high expression of ETAR and alleviated these adverse effects in MMCFs. Inversely, these effects were exacerbated by the miR-1929-3p inhibitor. Second, the transfection of endothelin receptor type A over-expressed adenovirus (adETAR) reversed these positive effects of the miR-1929-3p mimic on MF improvement. Third, the transfection of adETAR exhibited a strong inflammatory response in MMCFs with increased expression of NOD-like receptors pyrin domain containing 3 (NLRP3) and increased secretion of interleukin-18. However, we found that the ETAR antagonist BQ123 and the selected NLRP3 inflammasome inhibitor MCC950 effectively eliminated the inflammatory response induced by both MCMV infection and miR-1929-3p inhibitor. Moreover, the MCF supernatant was related to cardiomyocyte hypertrophy. Our findings suggest that MCMV infection promotes MF by inducing the downregulation of miR-1929-3p and the high expression of ETAR, which activates NLRP3 inflammasomes in MCFs.