Association of the High-Sensitivity C-Reactive Protein-to-Albumin Ratio with Carotid Atherosclerotic Plaque: A Community-Based Cohort Study.

Background: The inflammatory response is a pivotal factor in accelerating the progression of atherosclerosis. The high-sensitivity C-reactive protein-to-albumin ratio (CAR) has emerged as a novel marker of systemic inflammation. However, few studies have shown the CAR to be a promising prognostic marker for carotid atherosclerotic disease. This study aimed to analyse the predictive role of the CAR in carotid atherosclerotic disease. Methods: This community-based cohort study recruited 2003 participants from the Rose asymptomatic IntraCranial Artery Stenosis (RICAS) study who were free of stroke or transient ischemic attack. Carotid atherosclerotic plaques and their stability were identified via carotid ultrasound. Logistic regression models were utilized to investigate the association between CAR and the presence of carotid atherosclerotic plaques. Results: The prevalence of carotid atherosclerotic plaques was 38.79% in this study. After adjusting for clinical risk factors, including sex, age, dyslipidemia, hypertension, diabetes mellitus (DM), and smoking and drinking habits, a high CAR-level was independently associated with carotid plaque (odds ratio [OR] of upper: 1.46, 95% confidence interval [CI]: 1.13-1.90, P = 0.004; P for trend = 0.011). The highest CAR tertile was still significantly associated with carotid plaques among middle-aged (40-64 years) or female participants. Notably, an elevated CAR may be an independent risk factor for vulnerable carotid plaques (OR of upper: 2.06, 95% CI: 1.42-2.98, P < 0.001; P for trend <0.001). Conclusion: A high CAR may be correlated with a high risk of carotid plaques, particularly among mildly aged adults (40-64 years) or females. Importantly, the CAR may be associated with vulnerable carotid plaques, suggesting that the CAR may be a new indicator for stroke prevention.

Proteomic analysis identifies PFKP lactylation in SW480 colon cancer cells.

Aerobic glycolysis is a pivotal hallmark of cancers, including colorectal cancer. Evidence shows glycolytic enzymes are regulated by post-translational modifications (PTMs), thereby affecting the Warburg effect and reprograming cancer metabolism. Lysine lactylation is a PTM reported in 2019 in histones. In this study, we identified protein lactylation in FHC cells and SW480 colon cancer cells through mass spectrometry. Totally, 637 lysine lactylation sites in 444 proteins were identified in FHC and SW480 cells. Lactylated proteins were enriched in the glycolysis pathway, and we identified lactylation sites in phosphofructokinase, platelet (PFKP) lysine 688 and aldolase A (ALDOA) lysine 147. We also showed that PFKP lactylation directly attenuated enzyme activity. Collectively, our study presented a resource to investigate proteome-wide lactylation in SW480 cells and found PFKP lactylation led to activity inhibition, indicating that lactic acid and lactylated PFKP may form a negative feedback pathway in glycolysis and lactic acid production.

Structural insight into the macrocyclic inhibitor TPX-0022 of c-Met and c-Src.

c-Met has been an attractive target of prognostic and therapeutic studies in various cancers. TPX-0022 is a macrocyclic inhibitor of c-Met, c-Src and CSF1R kinases and is currently in phase I/II clinical trials in patients with advanced solid tumors harboring MET gene alterations. In this study, we determined the co-crystal structures of the c-Met/TPX-0022 and c-Src/TPX-0022 complexes to help elucidate the binding mechanism. TPX-0022 binds to the ATP pocket of c-Met and c-Src in a local minimum energy conformation and is stabilized by hydrophobic and hydrogen bond interactions. In addition, TPX-0022 exhibited potent activity against the resistance-relevant c-Met L1195F mutant and moderate activity against the c-Met G1163R, F1200I and Y1230H mutants but weak activity against the c-Met D1228N and Y1230C mutants. Overall, our study reveals the structural mechanism underlying the potency and selectivity of TPX-0022 and the ability to overcome acquire resistance mutations and provides insight into the development of selective c-Met macrocyclic inhibitors.

Effects of advance care planning on end-of-life decisions among community-dwelling elderly people and their relatives: a systematic review and meta-analysis.

BACKGROUND: Currently, more and more older people are inevitably facing the final stages of life and their need for end-of-life care is becoming more prominent. It is therefore important to understand in advance what older people expect from their approaching end-of-life care and attention. We conducted a meta-analysis to explore the influence of advance care planning (ACP) on end-of-life decision-making among older adults living in community settings and their family members. METHODS: We searched databases including PubMed, Embase, Cochrane Library, and Web of Science through 10 August 2022, to locate randomized controlled trials (RCTs) that investigated the effects of ACP on the end-of-life decision-making of community-dwelling elderly individuals and their family members. Studies we obtained from the databases were screened based on specific inclusion and exclusion criteria. The software Stata 15.0 was used for combining and analyzing data. RESULTS: A total of 8 RCTs were eligible for meta-analysis. They involved 1,292 community-dwelling elderly people. The meta-analysis results revealed the incidence of the following items among participants after the intervention of the ACP: cardiopulmonary resuscitation (CPR) [rate =26%, 95% confidence interval (CI): 11-41%], life-sustaining treatment (rate =12%, 95% CI: 6-18%), gastric gavage (rate =34%, 95% CI: 18-50%), mechanical ventilation (rate =34%, 95% CI: 14-54%), death at home (rate =7%, 95% CI: 3-12%), and death in hospital (rate =6%, 95% CI: 3-10%). The systematic review protocol was prespecified and registered in the international prospective register of systematic reviews (PROSPERO; CRD42022348900). CONCLUSIONS: According to current research, ACP is a promising treatment that can improve the end of life of elderly people living in the community and their families. However, considering the heterogeneity of the included studies, multi-center RCTs with high quality and larger sample sizes need to be conducted to confirm our conclusions.

Lactylation-Related Gene Signature Effectively Predicts Prognosis and Treatment Responsiveness in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor associated with high morbidity and mortality. Therefore, it is of great importance to develop effective prognostic models and guide clinical treatment in HCC. Protein lactylation is found in HCC tumors and is associated with HCC progression. METHODS: The expression levels of lactylation-related genes were identified from the TCGA database. A lactylation-related gene signature was constructed using LASSO regression. The prognostic value of the model was assessed and further validated in the ICGC cohort, with the patients split into two groups based on risk score. Glycolysis and immune pathways, treatment responsiveness, and the mutation of signature genes were analyzed. The correlation between PKM2 expression and the clinical characteristics was investigated. RESULTS: Sixteen prognostic differentially expressed lactylation-related genes were identified. An 8-gene signature was constructed and validated. Patients with higher risk scores had poorer clinical outcomes. The two groups were different in immune cell abundance. The high-risk group patients were more sensitive to most chemical drugs and sorafenib, while the low-risk group patients were more sensitive to some targeted drugs such as lapatinib and FH535. Moreover, the low-risk group had a higher TIDE score and was more sensitive to immunotherapy. PKM2 expression correlated with clinical characteristics and immune cell abundance in the HCC samples. CONCLUSIONS: The lactylation-related model exhibited robust predictive efficiency in HCC. The glycolysis pathway was enriched in the HCC tumor samples. A low-risk score indicated better treatment response to most targeted drugs and immunotherapy. The lactylation-related gene signature could be used as a biomarker for the effective clinical treatment of HCC.

Suberoylanilide Hydroxamic Acid (SAHA) Treatment Reveals Crosstalk Among Proteome, Phosphoproteome, and Acetylome in Nasopharyngeal Carcinoma Cells.

Suberoylanilide hydroxamic acid (SAHA), a famous histone deacetylase (HDAC) inhibitor, has been utilized in clinical treatment for cutaneous T-cell lymphoma. Previously, the mechanisms underlying SAHA anti-tumor activity mainly focused on acetylome. However, the characteristics of SAHA in terms of other protein posttranslational modifications (PTMs) and the crosstalk between various modifications are poorly understood. Our previous work revealed that SAHA had anti-tumor activity in nasopharyngeal carcinoma (NPC) cells as well. Here, we reported the profiles of global proteome, acetylome, and phosphoproteome of 5-8 F cells upon SAHA induction and the crosstalk between these data sets. Overall, we detected and quantified 6,491 proteins, 2,456 phosphorylated proteins, and 228 acetylated proteins in response to SAHA treatment in 5-8 F cells. In addition, we identified 46 proteins exhibiting both acetylation and phosphorylation, such as WSTF and LMNA. With the aid of intensive bioinformatics analyses, multiple cellular processes and signaling pathways involved in tumorigenesis were clustered, including glycolysis, EGFR signaling, and Myc signaling pathways. Taken together, this study highlighted the interconnectivity of acetylation and phosphorylation signaling networks and suggested that SAHA-mediated HDAC inhibition may alter both acetylation and phosphorylation of viral proteins. Subsequently, cellular signaling pathways were reprogrammed and contributed to anti-tumor effects of SAHA in NPC cells.

pH indicator-based sensor array in combination with hyperspectral imaging for intelligent evaluation of withering degree during processing of black tea.

Withering is one of the most critical steps in the processing of black tea. The degree of withering affects the aroma quality of the finished tea. In this study, we used a pH indicator-based colorimetric sensor array in combination with hyperspectral imaging to intelligently evaluate the withering degree. After analyzing the difference between images taken before and after the reaction of pH indicators with withered leaves, six pH indicators were selected to build a sensor array. Then, the hyperspectral image of each pH indicator was obtained at wavelengths between 400 and 1000 nm. Nonlinear support vector machine (SVM) and least-squares (LS) SVM models were established to determine the degree of withering. Results revealed that the spectral information from single pH indicator failed to accurately evaluate the withering degree. The LS-SVM model achieved satisfactory discriminant results with the low-level data fusion of six pH indicators followed by principal component analysis for dimensionality reduction. The optimal model yielded accuracies of 93.75% and 90.00% for the calibration and prediction sets, respectively. The results indicated that colorimetric sensor array in combination with hyperspectral imaging can effectively determine the withering degree, thus providing a novel method for the intelligent processing of food and tea.

Structure-based design of a dual-warhead covalent inhibitor of FGFR4.

The fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling pathways play critical roles in a variety of cancers, such as hepatocellular carcinoma (HCC). FGFR4 is recognized as a promising target to treat HCC. Currently, all FGFR covalent inhibitors target one of the two cysteines (Cys477 and Cys552). Here, we designed and synthesized a dual-warhead covalent FGFR4 inhibitor, CXF-009, targeting Cys477 and Cys552 of FGFR4. We report the cocrystal structure of FGFR4 with CXF-009, which exhibits a dual-warhead covalent binding mode. CXF-009 exhibited stronger selectivity for FGFR4 than FGFR1-3 and other kinases. CXF-009 can also potently inhibit the single cystine mutants, FGFR4(C477A) and FGFR4(C552A), of FGFR4. In summary, our study provides a dual-warhead covalent FGFR4 inhibitor that can covalently target two cysteines of FGFR4. CXF-009, to our knowledge, is the first reported inhibitor that forms dual-warhead covalent bonds with two cysteine residues in FGFR4. CXF-009 also has the potential to overcome drug induced resistant FGFR4 mutations and might serve as a lead compound for future anticancer drug discovery.

Coupling of Cell Surface Biotinylation and SILAC-Based Quantitative Proteomics Identified Myoferlin as a Potential Therapeutic Target for Nasopharyngeal Carcinoma Metastasis.

Distant metastasis is a major cause of treatment failure in nasopharyngeal carcinoma (NPC) patients. Cell surface proteins represent attractive targets for cancer diagnosis or therapy. However, the cell surface proteins associated with NPC metastasis are poorly understood. To identify potential therapeutic targets for NPC metastasis, we isolated cell surface proteins from two isogenic NPC cell lines, 6-10B (low metastatic) and 5-8F (highly metastatic), through cell surface biotinylation. Stable isotope labeling by amino acids in cell culture (SILAC) based proteomics was applied to comprehensively characterize the cell surface proteins related with the metastatic phenotype. We identified 294 differentially expressed cell surface proteins, including the most upregulated protein myoferlin (MYOF), two receptor tyrosine kinases(RTKs) epidermal growth factor receptor (EGFR) and ephrin type-A receptor 2 (EPHA2) and several integrin family molecules. These differentially expressed proteins are enriched in multiple biological pathways such as the FAK-PI3K-mTOR pathway, focal adhesions, and integrin-mediated cell adhesion. The knockdown of MYOF effectively suppresses the proliferation, migration and invasion of NPC cells. Immunohistochemistry analysis also showed that MYOF is associated with NPC metastasis. We experimentally confirmed, for the first time, that MYOF can interact with EGFR and EPHA2. Moreover, MYOF knockdown could influence not only EGFR activity and its downstream epithelial-mesenchymal transition (EMT), but also EPHA2 ligand-independent activity. These findings suggest that MYOF might be an attractive potential therapeutic target that has double effects of simultaneously influencing EGFR and EPHA2 signaling pathway. In conclusion, this is the first study to profile the cell surface proteins associated with NPC metastasis and provide valuable resource for future researches.

Nanomaterials for cancer therapy: current progress and perspectives.

Cancer is a disease with complex pathological process. Current chemotherapy faces problems such as lack of specificity, cytotoxicity, induction of multi-drug resistance and stem-like cells growth. Nanomaterials are materials in the nanorange 1-100 nm which possess unique optical, magnetic, and electrical properties. Nanomaterials used in cancer therapy can be classified into several main categories. Targeting cancer cells, tumor microenvironment, and immune system, these nanomaterials have been modified for a wide range of cancer therapies to overcome toxicity and lack of specificity, enhance drug capacity as well as bioavailability. Although the number of studies has been increasing, the number of approved nano-drugs has not increased much over the years. To better improve clinical translation, further research is needed for targeted drug delivery by nano-carriers to reduce toxicity, enhance permeability and retention effects, and minimize the shielding effect of protein corona. This review summarizes novel nanomaterials fabricated in research and clinical use, discusses current limitations and obstacles that hinder the translation from research to clinical use, and provides suggestions for more efficient adoption of nanomaterials in cancer therapy.