eEF2 in the prefrontal cortex promotes excitatory synaptic transmission and social novelty behavior.

Regulation of mRNA translation is essential for brain development and function. Translation elongation factor eEF2 acts as a molecular hub orchestrating various synaptic signals to protein synthesis control and participates in hippocampus-dependent cognitive functions. However, whether eEF2 regulates other behaviors in different brain regions has been unknown. Here, we construct a line of Eef2 heterozygous (HET) mice, which show a reduction in eEF2 and protein synthesis mainly in excitatory neurons of the prefrontal cortex. The mice also show lower spine density, reduced excitability, and AMPAR-mediated synaptic transmission in pyramidal neurons of the medial prefrontal cortex (mPFC). While HET mice exhibit normal learning and memory, they show defective social behavior and elevated anxiety. Knockdown of Eef2 in excitatory neurons of the mPFC specifically is sufficient to impair social novelty preference. Either chemogenetic activation of excitatory neurons in the mPFC or mPFC local infusion of the AMPAR potentiator PF-4778574 corrects the social novelty deficit of HET mice. Collectively, we identify a novel role for eEF2 in promoting prefrontal AMPAR-mediated synaptic transmission underlying social novelty behavior.

Discovery of a doublecortin-like kinase 1 inhibitor to prevent inflammatory responses in acute lung injury.

Doublecortin-like kinase 1 (DCLK1) is a microtubule-associated protein kinase involved in neurogenesis and human cancer. Recent studies have revealed a novel functional role for DCLK1 in inflammatory signaling, thus positioning it as a novel target kinase for respiratory inflammatory disease treatment. In this study, we designed and synthesized a series of NVP-TAE684-based derivatives as novel anti-inflammatory agents targeting DCLK1. Bio-layer interferometry binding screening and kinase assays of the NVP-TAE684 derivatives led to the discovery of an effective DCLK1 inhibitor (a24), with an IC50 of 179.7 nM. Compound a24 effectively inhibited lipopolysaccharide (LPS)-induced inflammation in macrophages with higher potency than the lead compound. Mechanistically, compound a24 inhibited LPS-induced inflammation by inhibiting DCLK1-mediated IKKß phosphorylation. Furthermore, compound a24 showed in vivo anti-inflammatory activity in an LPS-challenged acute lung injury model. These findings suggest that compound a24 may serve as a novel candidate for the development of DCLK1 inhibitors and a potential therapeutic agent for the treatment of inflammatory diseases.

Anti-inflammatory effects of resveratrol in treating interstitial cystitis/bladder pain syndrome: a multi-faceted approach integrating network pharmacology, molecular docking, and experimental validation.

This study aims to investigate the anti-inflammatory effects of Resveratrol (RES) in the treatment of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) by integrating network pharmacology, molecular docking, and experimental validation. Potential targets of RES were identified using DrugBank and SwissTargetPrediction, while IC/BPS-related targets were obtained from DisGeNET and Genecards. Molecular docking was performed using UCSF Chimera and SwissDock to validate the binding affinity of RES to key targets. Experimental validation involved treating TNF-α induced urothelial cells with RES, followed by assessments using RT-qPCR, ELISA, and Western blotting. A total of 86 drug targets and 211 disease targets were analyzed, leading to the identification of 8 key therapeutic targets for RES in IC/BPS treatment. Molecular docking revealed a strong affinity of RES for ESR2, with notable interactions also observed with SHBG, PTGS2, PPARG, KIT, PI3KCA, and AKT1. In vitro experiments confirmed that RES significantly alleviated the inflammatory response in TNF-α-induced urothelial cells, normalizing the expression levels of ESR2, SHBG, PPARG, and AKT1. RES can modulate critical pathways involving ESR2, SHBG, PPARG, and AKT1, highlighting its potential as a therapeutic agent for IC/BPS. This study provides a theoretical foundation for the clinical application of RES in treating IC/BPS.

Prevalence and Antimicrobial Resistance of Ureaplasma urealyticum and Mycoplasma hominis in Patients with Genital Tract Infection in Jiangsu, China.

BACKGROUND: The aim of this study was to investigate the infection and antimicrobial resistance of Ureaplasma urealyticum (U. urealyticum) and Mycoplasma hominis (M. hominis) in patients with genital tract diseases in Jiangsu, China. METHODS: A total of 3,321 patients suspected with genital tract infectious diseases were enrolled in this study from September 2017 to September 2020. The Mycoplasma detection and antimicrobial susceptibility were tested using the commercially available Mycoplasma kit. RESULTS: Among the 3,321 specimens tested, 1,503 (45.3%) were positive for Mycoplasmas, and the proportion of mono-infection of U. urealyticum is highest (79.5%). The overall infection rate has been increasing in the past 3 years. The positive rate in females (68.7%) was higher than in males (25.0%), and the main infection age group was 20 - 39 (81.2%). Besides, U. urealyticum and M. hominis displayed relative lower resistance rates to gatifloxacin, josamycin, minocycline, and doxycycline (6.0%, 6.5%, 3.1%, and 3.2%, respectively). However, the antimicrobial resistance rates to azithromycin, clindamycin, roxithromycin, sparfloxacin, and ofloxacin were relatively high (45.4%, 42.1%, 34.9, 36.0, and 65.5%, respectively). Antimicrobial resistance of U. urealyticum and M. hominis to these 14 drugs have been changing in the past 3 years. CONCLUSIONS: In total, these preliminary data showed the prevalence and antimicrobial resistance status of U. urealyticum and M. hominis in patients suspected with genital tract infectious diseases, which has use for reference on both prevention and treatment of diseases caused by them.

Relationships Between Obstructive Sleep Apnea and Cardiovascular Disease: A Bibliometric Analysis (2010-2021).

BACKGROUND Obstructive sleep apnea (OSA) is a common disease that can lead to intermittent hypoxia, increased sympathetic overdrive, and excessive oxidative stress, and eventually lead to cardiovascular/cerebrovascular diseases and metabolic disorders. The prevalence of OSA is reported to be higher in people with certain cardiovascular diseases (CVD). Therefore, the relationship between OSA and CVD has been gradually favored by researchers. MATERIAL AND METHODS Data were downloaded from the Web of Science Core Collection database. Citespace was used to remove duplicated data and construct knowledge visual maps. RESULTS A total of 7047 publications were obtained. The USA was the largest contributor as well as an important player in the cooperation network between nations. The leading institution was the Mayo Clinic. Our study ultimately identified the top 5 hotspots and 4 research frontiers in this field. Top 5 hotspots were: the specific types of obstructive sleep apnea-related cardiovascular and metabolic co-morbidities, the curative effects of CPAP on these co-morbidities, the specific mechanisms of co-morbidities, the importance of polysomnography on OSA and its co-morbidities with CVD, and the prevalence of OSA and its co-morbidities with CVD in particular populations. The top 4 frontiers were: the relationship between OSA and resistant hypertension, the molecular mechanisms of OSA and its co-morbidities with CVD, specific medications and treatment guidelines for the co-morbidities, and the mainstream research methods in this field. CONCLUSIONS This study provides insight and valuable information for researchers and helps to identify new perspectives concerning potential collaborators and cooperative institutions, hot topics, and research frontiers in this field.

Use of bailing capsules (cordyceps sinensis) in the treatment of chronic kidney disease: a meta-analysis and network pharmacology.

The Bailing Capsule is a commonly used traditional Chinese medicine for the treatment of chronic kidney disease (CKD). However, its therapeutic effects and pharmacological mechanisms have not been fully explored. In this study, we integrated meta-analysis and network pharmacology to provide scientific evidence for the efficacy and pharmacological mechanism of Bailing Capsule in treating CKD. We conducted searches for randomized controlled studies matching the topic in PubMed, the Cochrane Library, Embase, Web of Science, and the Wanfang Database, and screened them according to predefined inclusion and exclusion criteria. Dates from the included studies were extracted for meta-analysis, including renal function indicators, such as 24-h urinary protein (24UP), blood urea nitrogen (BUN), and serum creatinine (Scr), as well as inflammatory indicators like high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Network pharmacology was employed to extract biological information, including active drug ingredients and potential targets of the drugs and diseases, for network construction and gene enrichment. Our findings indicated that 24UP, BUN, and Scr in the treatment group containing Bailing Capsule were lower than those in the control group. In terms of inflammatory indicators, hs-CRP, IL-6, and TNF-α, the treatment group containing Bailing Capsule also exhibited lower levels than the control group. Based on network pharmacology analysis, we identified 190 common targets of Bailing Capsule and CKD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested that the pharmacological mechanism of Bailing Capsule might be related to immune response, inflammatory response, vascular endothelial damage, cell proliferation, and fibrosis. This demonstrates that Bailing Capsule can exert therapeutic effects through multiple targets and pathways, providing a theoretical basis for its use.

Associations between serum testosterone levels and overactive bladder in women: a cross-sectional research of NHANES 2011 to 2016.

PURPOSE: Androgen receptors are expressed in the pelvic floor and lower urinary tract. However, the association between serum testosterone and overactive bladder (OAB) in women remains unclear. This study aimed to investigate their association in a nationally representative population. METHODS: In this cross-sectional study, we collected data on female participants older than 20 years with serum total testosterone measurements and OAB questionnaires from the 2011-2016 National Health and Nutrition Examination Survey (NHANES). Survey-weighted logistic regression models were used to analyze the relationship between testosterone and OAB in women. RESULTS: Data on 4991 women was analyzed in this study, of whom 25.9% had OAB symptoms. Women with lower serum testosterone had an increased frequency of urge urinary incontinence and nocturia compared to participants with enough testosterone. The multivariate logistic models showed that those women with a testosterone level less than 18.5 ng/dL had significantly higher odds of OAB compared to those with a testosterone level greater than 18.5 ng/dL [OR 95% CI = 1.271 (1.073-1.505), P = 0.0076]. Separate interaction analyses revealed no significant effect of age, BMI, diabetes, education, alcohol use and menopause on the association between serum testosterone and OAB. Sensitivity analyses demonstrated that additional variables (depression, stroke and stress urinary incontinence) had no significant effect on this relationship. CONCLUSIONS: Low serum testosterone is associated with an increased likelihood of OAB in women. This supports the potential therapeutic role of testosterone supplementation in women with OAB. Given the direct and indirect effects of testosterone on the pelvic floor and lower urinary tract, a potential mechanism for this relationship can be further explored in translational studies.

Associations Between Serum Estrogen Levels and Urinary Incontinence in Women: A Cross-sectional Analysis of NHANES 2013 to 2016.

OBJECTIVE: To explore the relationship between serum estrogen levels and urinary incontinence in a nationally representative female population. MATERIALS AND METHODS: We included women who had serum estradiol measurements and self-reported urinary incontinence problems in the 2013-2016 National Health and Nutrition Examination Survey cycles. A weighted multivariable logistic regression model was used to determine the association between urinary incontinence and serum estrogen levels after adjusting for age, race, Body Mass Index, diabetes, venipuncture, hypertension, poverty-to-income ratio, smoking, marital status, alcohol use, education, and menopause. RESULT: A total of 4114 individuals were ultimately included in our study. Of these women, 1200 (29.17%) complained of urge urinary incontinence (UUI), 1674 (40.69%) complained of stress urinary incontinence (SUI), 730 (17.74%) complained of mixed urinary incontinence (MUI). Women in the lowest quartile of serum estrogen were more likely to complain of UUI compared to those in the highest quartile (OR=1.885; 95% CI=1.042-3.412, P = .039). No association was noted between serum estrogen levels and SUI or MUI. CONCLUSION: Our study shows a significant association between low serum estrogen level and the increased likelihood of UUI in women. Further research is required to validate our findings, elucidate the physiological mechanisms that underlie them, and assess potential therapeutic implications.

Discovery of LC-MI-3: A Potent and Orally Bioavailable Degrader of Interleukin-1 Receptor-Associated Kinase 4 for the Treatment of Inflammatory Diseases.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target in inflammation-related diseases. However, the inhibition of IRAK4 kinase activity may lead to moderate anti-inflammatory efficacy owing to the dual role of IRAK4 as an active kinase and a scaffolding protein. Herein, we report the design, synthesis, and biological evaluation of an efficient and selective IRAK4 proteolysis-targeting chimeric molecule that eliminates IRAK4 scaffolding functions. The most potent compound, LC-MI-3, effectively degraded cellular IRAK4, with a half-maximal degradation concentration of 47.3 nM. LC-MI-3 effectively inhibited the activation of downstream nuclear factor-κB signaling and exerted more potent pharmacological effects than traditional kinase inhibitors. Furthermore, LC-MI-3 exerted significant therapeutic effects in lipopolysaccharide- and Escherichia coli-induced acute and chronic inflammatory skin models compared with kinase inhibitors in vivo. Therefore, LC-MI-3 is a candidate IRAK4 degrader in alternative targeting strategies and advanced drug development.

Measurements of peri-prostatic adipose tissue by MRI predict bone metastasis in patients with newly diagnosed prostate cancer.

Objectives: To investigate the role of MRI measurements of peri-prostatic adipose tissue (PPAT) in predicting bone metastasis (BM) in patients with newly diagnosed prostate cancer (PCa). Methods: We performed a retrospective study on 156 patients newly diagnosed with PCa by prostate biopsy between October 2010 and November 2022. Clinicopathologic characteristics were collected. Measurements including PPAT volume and prostate volume were calculated by MRI, and the normalized PPAT (PPAT volume/prostate volume) was computed. Independent predictors of BM were determined by univariate and multivariate logistic regression analysis, and a new nomogram was developed based on the predictors. Receiver operating characteristic (ROC) curves were used to estimate predictive performance. Results: PPAT and normalized PPAT were associated with BM (P<0.001). Normalized PPAT positively correlated with clinical T stage(cT), clinical N stage(cN), and Grading Groups(P<0.05). The results of ROC curves indicated that PPAT and normalized PPAT had promising predictive value for BM with the AUC of 0.684 and 0.775 respectively. Univariate and multivariate analysis revealed that high normalized PPAT, cN, and alkaline phosphatase(ALP) were independently predictors of BM. The nomogram was developed and the concordance index(C-index) was 0.856. Conclusions: Normalized PPAT is an independent predictor for BM among with cN, and ALP. Normalized PPAT may help predict BM in patients with newly diagnosed prostate cancer, thus providing adjunctive information for BM risk stratification and bone scan selection.

Intrathecal umbilical cord mesenchymal stem cells injection alleviates neuroinflammation and oxidative stress in the cyclophosphamide-induced interstitial cystitis rats through the Sirt1/Nrf2/HO-1 pathway.

AIMS: Neuroinflammation in the spinal dorsal horn (SDH) region plays an important role in the pathogenesis of interstitial cystitis (IC)/bladder pain syndrome (BPS). Oxidative stress is an important etiological factor for inflammatory diseases. This study aimed to investigate the therapeutic effects of umbilical cord mesenchymal stem cells UMSCs on neuroinflammation and oxidative stress in IC and the underlying mechanisms. MATERIALS AND METHODS: Rats were intraperitoneally injected with cyclophosphamide (50 mg/kg bodyweight) to establish the IC animal model. Additionally, rats were intrathecally injected with a Sirt1-specific agonist (SRT1720; 8 µg/rat) or inhibitor (EX527; 8 µg/rat). Furthermore, rats were intrathecally injected with human UMSCs (hUMSCS; 8 × 105 cells/rat). Rat behavior was examined using the mechanical allodynia test, novel object recognition test, sucrose preference test, and urodynamics analysis. Neuroinflammation and oxidative stress the SDH region were examined using western blotting, immunofluorescence, enzyme-linked immunosorbent assay, and commercial kits. KEY FINDINGS: The Sirt1/Nrf2/HO-1 pathway was downregulated in IC rats. Sirt1 activation and inhibition differentially affected the behavior of IC rats. hUMSCs effectively mitigated the upregulation of oxidative stress, proinflammatory cytokines, and glial activation in the SDH region. Additionally, hUMSCs suppressed mechanical allodynia, dysregulated urodynamics, memory deficits, and depressive-like behavior in IC rats. hUMSCs exerted therapeutic effects through the Sirt1/Nrf2/HO-1 pathway. SIGNIFICANCE: intrathecal hUMSCs injection alleviated behavioral deficits of IC rats by mitigating neuroinflammation and oxidative stress through the Sirt1/Nrf2/HO-1 pathway and can be potentially an effective therapeutic strategy for IC.

Inhibition of SHP2 by the Small Molecule Drug SHP099 Prevents Lipopolysaccharide-Induced Acute Lung Injury in Mice.

Excessive pulmonary inflammation in acute lung injury (ALI) causes high patient mortality. Anti-inflammatory therapy, combined with infection resistance, can help to prevent ALI and save lives. The expression of Src homology-2 domain-containing protein tyrosine phosphatase 2 (SHP2) was found to be significantly higher in macrophages and lung tissues with ALI, and SHP2-associated MAPK pathways were activated by lipopolysaccharide (LPS). The knockdown of the SHP2 gene suppressed the LPS-induced release of inflammatory factors and the phosphorylation of regulators in the NF-κB pathways in macrophages. Our findings showed crosstalk between the LPS-induced inflammatory pathway and the SHP2-associated MAPK pathways. SHP2 inhibition could be a valuable therapeutic approach for inhibiting excessive inflammation in ALI. We discovered that giving SHP099, a specific allosteric inhibitor of SHP2, to mice with ALI and sepsis relieves ALI and significantly increases animal survival. Our study highlights the important role of SHP2 in ALI development and demonstrates the potential application of SHP099 for treating ALI.

Comparison of the predictive value of anthropometric indicators for the risk of benign prostatic hyperplasia in southern China.

This study aimed to compare the predictive value of six selected anthropometric indicators for benign prostatic hyperplasia (BPH). Males over 50 years of age who underwent health examinations at the Health Management Center of the Second Xiangya Hospital, Central South University (Changsha, China) from June to December 2020 were enrolled in this study. The characteristic data were collected, including basic anthropometric indices, lipid parameters, six anthropometric indicators, prostate-specific antigen, and total prostate volume. The odds ratios (ORs) with 95% confidence intervals (95% CIs) for all anthropometric parameters and BPH were calculated using binary logistic regression. To assess the diagnostic capability of each indicator for BPH and identify the appropriate cutoff values, receiver operating characteristic (ROC) curves and the related areas under the curves (AUCs) were utilized. All six indicators had diagnostic value for BPH (all P ≤ 0.001). The visceral adiposity index (VAI; AUC: 0.797, 95% CI: 0.759-0.834) had the highest AUC and therefore the highest diagnostic value. This was followed by the cardiometabolic index (CMI; AUC: 0.792, 95% CI: 0.753-0.831), lipid accumulation product (LAP; AUC: 0.766, 95% CI: 0.723-0.809), waist-to-hip ratio (WHR; AUC: 0.660, 95% CI: 0.609-0.712), waist-to-height ratio (WHtR; AUC: 0.639, 95% CI: 0.587-0.691), and body mass index (BMI; AUC: 0.592, 95% CI: 0.540-0.643). The sensitivity of CMI was the highest (92.1%), and WHtR had the highest specificity of 94.1%. CMI consistently showed the highest OR in the binary logistic regression analysis. BMI, WHtR, WHR, VAI, CMI, and LAP all influence the occurrence of BPH in middle-aged and older men (all P ≤ 0.001), and CMI is the best predictor of BPH.

Discovery of a potent and selective allosteric inhibitor targeting the SHP2 tunnel site for RTK-driven cancer treatment.

Src homology 2 domain-containing phosphatase 2 (SHP2) is a cytoplasmic protein tyrosine phosphatase (PTP) that regulates signal transduction of receptor tyrosine kinases (RTKs). Abnormal SHP2 activity is associated with tumorigenesis and metastasis. Because SHP2 contains multiple allosteric sites, identifying inhibitors at specific allosteric binding sites remains challenging. Here, we used structure-based virtual screening to directly search for the SHP2 "tunnel site" allosteric inhibitor. A novel hit (70) was identified as the SHP2 allosteric inhibitor with an IC50 of 10.2 µM against full-length SHP2. Derivatization of hit compound 70 using molecular modeling-guided structure-based modification allowed the discovery of an effective and selective SHP2 inhibitor, compound 129, with 122-fold improved potency compared to the hit. Further studies revealed that 129 effectively inhibited signaling in multiple RTK-driven cancers and RTK inhibitor-resistant cancer cells. Remarkably, 129 was orally bioavailable (F = 55%) and significantly inhibited tumor growth in haematological malignancy. Taken together, compound 129 developed in this study may serve as a promising lead or candidate for cancers bearing RTK oncogenic drivers and SHP2-related diseases.

Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer.

Abnormal activation of fibroblast growth factor receptors (FGFRs) results in the development and progression of human cancers. FGFR2 is frequently amplified or mutated in cancers; therefore, it is an attractive target for tumor therapy. Despite the development of several pan-FGFR inhibitors, their long-term therapeutic efficacy is hindered by acquired mutations and low isoform selectivity. Herein, we report the discovery of an efficient and selective FGFR2 proteolysis-targeting chimeric molecule, LC-MB12, that incorporates an essential rigid linker. LC-MB12 preferentially internalizes and degrades membrane-bound FGFR2 among the four FGFR isoforms; this may promote greater clinical benefits. LC-MB12 exhibits superior potency in FGFR signaling suppression and anti-proliferative activity compared to the parental inhibitor. Furthermore, LC-MB12 is orally bioavailable and shows significant antitumor effects in FGFR2-dependent gastric cancer in vivo. Taken together, LC-MB12 is a candidate FGFR2 degrader for alternative FGFR2-targeting strategies and offers a promising starting point for drug development.

Classification of pyroptosis patterns and construction of a novel prognostic model for prostate cancer based on bulk and single-cell RNA sequencing.

Background: Emerging evidence suggests an important role for pyroptosis in tumorigenesis and recurrence, but it remains to be elucidated in prostate cancer (PCa). Considering the low accuracy of common clinical predictors of PCa recurrence, we aimed to develop a novel pyroptosis-related signature to predict the prognosis of PCa patients based on integrative analyses of bulk and single-cell RNA sequencing (RNA-seq) profiling. Methods: The RNA-seq data of PCa patients was downloaded from several online databases. PCa patients were stratified into two Classes by unsupervised clustering. A novel signature was constructed by Cox and the Least Absolute Shrinkage and Selection Operator (LASSO) regression. The Kaplan-Meier curve was employed to evaluate the prognostic value of this signature and the single sample Gene Set Enrichment Analysis (ssGSEA) algorithm was used to analysis tumor-infiltrating immune cells. At single-cell level, we also classified the malignant cells into two Classes and constructed cell developmental trajectories and cell-cell interaction networks. Furthermore, RT-qPCR and immunofluorescence were used to validate the expression of core pyroptosis-related genes. Results: Twelve prognostic pyroptosis-related genes were identified and used to classify PCa patients into two prognostic Classes. We constructed a signature that identified PCa patients with different risks of recurrence and the risk score was proven to be an independent predictor of the recurrence free survival (RFS). Patients in the high-risk group had a significantly lower RFS (P<0.001). The expression of various immune cells differed between the two Classes. At the single-cell level, we classified the malignant cells into two Classes and described the heterogeneity. In addition, we observed that malignant cells may shift from Class1 to Class2 and thus have a worse prognosis. Conclusion: We have constructed a robust pyroptosis-related signature to predict the RFS of PCa patients and described the heterogeneity of prostate cancer cells in terms of pyroptosis.

A Transcription Factor-Based Risk Model for Predicting the Prognosis of Prostate Cancer and Potential Therapeutic Drugs.

BACKGROUND: Prostate cancer (PC) is one of the most critical cancers affecting men's health worldwide. The development of many cancers involves dysregulation or mutations in key transcription factors. This study established a transcription factor-based risk model to predict the prognosis of PC and potential therapeutic drugs. MATERIALS AND METHODS: In this study, RNA-sequencing data were downloaded and analyzed using The Cancer Genome Atlas dataset. A total of 145 genes related to the overall survival rate of PC patients were screened using the univariate Cox analysis. The Kdmist clustering method was used to classify prostate adenocarcinoma (PRAD), thereby determining the cluster related to the transcription factors. The support vector machine-recursive feature elimination method was used to identify genes related to the types of transcription factors and the key genes specifically upregulated or downregulated were screened. These genes were further analyzed using Lasso to establish a model. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for the functional analysis. The TIMER algorithm was used to quantify the abundance of immune cells in PRAD samples. The chemotherapy response of each GBM patient was predicted based on the public pharmacogenomic database, Genomics of Drug Sensitivity in Cancer (GDSC, http://www.cancerrxgene.org). The R package "pRRophetic" was applied to drug sensitivity (IC50) value prediction. RESULTS: We screened 10 genes related to prognosis, including eight low-risk genes and two high-risk genes. The receiver operating characteristic (ROC) curve was 0.946. Patients in the high-risk score group had a poorer prognosis than those in the low-risk score group. The average area under the curve value of the model at different times was higher than 0.8. The risk score was an independent prognostic factor. Compared with the low-risk score group, early growth response-1 (EGR1), CACNA2D1, AC005831.1, SLC52A3, TMEM79, IL20RA, CRACR2A, and FAM189A2 expressions in the high-risk score group were decreased, while AC012181.1 and TRAPPC8 expressions were increased. GO and KEGG analyses showed that prognosis was related to various cancer signaling pathways. The proportion of B_cell, T_cell_CD4, and macrophages in the high-risk score group was significantly higher than that in the low-risk score group. A total of 25 classic immune checkpoint genes were screened out to express abnormally high-risk scores, and there were significant differences. Thirty mutant genes were identified; in the high- and low-risk score groups, SPOP, TP53, and TTN had the highest mutation frequency, and their mutations were mainly missense mutations. A total of 36 potential drug candidates for the treatment of PC were screened and identified. CONCLUSIONS: Ten genes of both high-and low-risk scores were associated with the prognosis of PC. PC prognosis may be related to immune disorders. SPOP, TP53, and TTN may be potential targets for the prognosis of PC.

Dearomatization-rearomatization strategy of tyrosine for peptide/protein modification through thiol-addition reactions.

We have developed a dearomatization-rearomatization strategy for the modification of peptides/proteins through a thiol-Michael addition to the electrophilic cyclohexadienone intermediate that is generated in situ via the oxidation of tyrosine. This strategy enriches the conjugation toolbox and has great potential for applications in medicinal chemistry and chemical biology.