Aspartate Transaminase-to-Albumin Ratio (ATAR), a Novel Prognostic Index, Predicts Outcomes in Patients with Small-Cell Lung Cancer.

BACKGROUND: Small cell lung cancer (SCLC) is characterized by high invasion rates, rapid progression, and poor prognoses. Thus, identifying SCLC patients at high risk of progression and death is critical to improve long-term survival. In this study, the aspartate transaminase-to-albumin ratio (ATAR) was examined as a prognostic factor for SCLC patients. METHODS: We screened 196 SCLC patients from December 2013 to September 2022 at the Sichuan Cancer Hospital. The data was collected from patients' medical information as well as from their blood results during diagnosis. Using the Youden index as a cutoff value, patients were divided into high-risk（> 0.54) and low-risk (≤ 0.54) ATAR groups. We analyzed the prognostic factors for overall survival (OS) using the Kaplan-Meier method, univariate and multivariate analyses, Cox regression, and the C-index. RESULTS: There were 109 (55.6%) smokers among the patients, and the median OS was 17.55 months. The Kaplan-Meier analysis indicated that patients with high-risk ATAR had significantly lower OS (p < 0.0001). A multivariate analysis demonstrated that elevated ATAR is an independent adverse predictor of OS (p < 0.001, HR = 1.907). Our study found that ATAR is an independent predictor of survival outcomes in SCLC, which was superior to ALB, PNI, and SII in predicting outcomes in low-risk and high-risk groups (all p < 0.05). Models combining ATAR with ALB, PNI, and SII showed more powerful prognostic value than their corresponding original models. Moreover, the prognostic indicator ATAR can significantly stratify stage I - II and III - IV SCLC patients (p ＜ 0.05). CONCLUSIONS: Peripheral blood ATAR prognostic index can be used as an independent predictor of SCLC patients before treatment.

The role of imprinting genes' loss of imprints in cancers and their clinical implications.

Genomic imprinting plays an important role in the growth and development of mammals. When the original imprint status of these genes is lost, known as loss of imprinting (LOI), it may affect growth, neurocognitive development, metabolism, and even tumor susceptibility. The LOI of imprint genes has gradually been found not only as an early event in tumorigenesis, but also to be involved in progression. More than 120 imprinted genes had been identified in humans. In this review, we summarized the most studied LOI of two gene clusters and 13 single genes in cancers. We focused on the roles they played, that is, as growth suppressors and anti-apoptosis agents, sustaining proliferative signaling or inducing angiogenesis; the molecular pathways they regulated; and especially their clinical significance. It is notable that 12 combined forms of multi-genes' LOI, 3 of which have already been used as diagnostic models, achieved good sensitivity, specificity, and accuracy. In addition, the methods used for LOI detection in existing research are classified into detection of biallelic expression (BAE), differentially methylated regions (DMRs), methylation, and single-nucleotide polymorphisms (SNPs). These all indicated that the detection of imprinting genes' LOI has potential clinical significance in cancer diagnosis, treatment, and prognosis.

Metabolomics Analysis and Diagnosis of Lung Cancer: Insights from Diverse Sample Types.

Lung cancer is a highly fatal disease that poses a significant global health burden. The absence of characteristic clinical symptoms frequently results in the diagnosis of most patients at advanced stages of lung cancer. Although low-dose computed tomography (LDCT) screening has become increasingly prevalent in clinical practice, its high rate of false positives continues to present a significant challenge. In addition to LDCT screening, tumor biomarker detection represents a critical approach for early diagnosis of lung cancer; unfortunately, no tumor marker with optimal sensitivity and specificity is currently available. Metabolomics has recently emerged as a promising field for developing novel tumor biomarkers. In this paper, we introduce metabolic pathways, instrument platforms, and a wide variety of sample types for lung cancer metabolomics. Specifically, we explore the strengths, limitations, and distinguishing features of various sample types employed in lung cancer metabolomics research. Additionally, we present the latest advances in lung cancer metabolomics research that utilize diverse sample types. We summarize and enumerate research studies that have investigated lung cancer metabolomics using different metabolomic sample types. Finally, we provide a perspective on the future of metabolomics research in lung cancer. Our discussion of the potential of metabolomics in developing new tumor biomarkers may inspire further study and innovation in this dynamic field.

Expression Significance of Estrogen Receptor ER-α36 in Breast Cancer Treated by Chemotherapy: A Meta-Analysis.

Estrogen receptor (ER) is a molecular marker and target for diagnosing and treating breast cancer (BC). ER-α36, a novel estrogen receptor subtype, involved in the proliferation, differentiation, metastasis, and invasion of tumor cells. It is closely linked to the progression of various cancers. Therefore, studying ER is of high significance in treating BC. In this study, we will investigate the changes in the expression level of ER-α36 in patients with BC treated by chemotherapy through meta-analysis, so as to evaluate the clinical value of ER-α36 in the prognosis of BC treated by chemotherapy. English databases such as PubMed, Web of Science, Embase, and The Cochrane Library were searched to retrieve the articles published from the establishment of the database to April 2023. The keywords included chemotherapy, neoadjuvant chemotherapy, breast cancer, estrogen receptor alpha, and ER-α36. Five suitable studies, encompassing 636 patients, were ultimately selected. The meta-analysis results revealed that, following the chemotherapy, the analysis of ER-α36 positive cases yielded an Odds Ratio (OR) of 0.42, a 95% confidence interval (CI) of 0.28-0.64 (Z = 4.00, P < 0.0001). Additionally, the analysis of cases exhibiting remission in BC demonstrated an OR of 2.22 (95% CI = 1.40-3.50, Z = 3.40, P = 0.0007). Compared to patients receiving single chemotherapy agents or those untreated with chemotherapy, the combined use of multiple chemotherapy drugs can significantly reduce the levels of ER-α36 in BC patients, enhancing the remission rate of BC. ER-α36 can serve as a critical indicator for assessing the prognosis of BC following chemotherapy.

FBXW7 in breast cancer: mechanism of action and therapeutic potential.

Breast cancer is one of the frequent tumors that seriously endanger the physical and mental well-being in women. F-box and WD repeat domain-containing 7 (FBXW7) is a neoplastic repressor. Serving as a substrate recognition element for ubiquitin ligase, FBXW7 participates in the ubiquitin-proteasome system and is typically in charge of the ubiquitination and destruction of crucial oncogenic proteins, further performing a paramount role in cell differentiation, apoptosis and metabolic processes. Low levels of FBXW7 cause abnormal stability of pertinent substrates, mutations and/or deletions in the FBXW7 gene have been reported to correlate with breast cancer malignant progression and chemoresistance. Given the lack of an effective solution to breast cancer's clinical drug resistance dilemma, elucidating FBXW7's mechanism of action could provide a theoretical basis for targeted drug exploration. Therefore, in this review, we focused on FBXW7's role in a range of breast cancer malignant behaviors and summarized the pertinent cellular targets, signaling pathways, as well as the mechanisms regulating FBXW7 expression. We also proposed novel perspectives for the exploitation of alternative therapies and specific tumor markers for breast cancer by therapeutic strategies aiming at FBXW7.

Research progress on the role of PDGF/PDGFR in type 2 diabetes.

Platelet-derived growth factors (PDGFs) are basic proteins stored in the α granules of platelets. PDGFs and their receptors (PDGFRs) are widely expressed in platelets, fibroblasts, vascular endothelial cells, platelets, pericytes, smooth muscle cells and tumor cells. The activation of PDGFR plays a number of critical roles in physiological functions and diseases, including normal embryonic development, cellular differentiation, and responses to tissue damage. In recent years, emerging experimental evidence has shown that activation of the PDGF/PDGFR pathway is involved in the development of diabetes and its complications, such as atherosclerosis, diabetic foot ulcers, diabetic nephropathy, and retinopathy. Research on targeting PDGF/PDGFR as a treatment has also made great progress. In this mini-review, we summarized the role of PDGF in diabetes, as well as the research progress on targeted diabetes therapy, which provides a new strategy for the treatment of type 2 diabetes.

Identification and validation of molecular subtype and prognostic signature for lung adenocarcinoma based on neutrophil extracellular traps.

Background: Neutrophil Extracellular Traps (NETs) are fibrous networks made of DNA-histone complexes and proteins protruded from activated neutrophils. Accumulating evidences have highlighted the vital role of NETs in tumor progression and diffusion. However, limited systematic studies regarding the role of NETs in LUAD have been performed. Methods: Differentially expressed NETs-related genes and their mutation landscape were identified with TCGA database. Consensus clustering analysis was performed to determine the NETs-related subtypes of LUAD. LASSO algorithm was employed to construct a prognostic signature. Moreover, GSE30219 and GSE31210 were used as independent validation. We also constructed a lncRNA-miRNA-mRNA regulatory axis with several miRNA and lncRNA databases. Results: Consensus clustering identified two NETs-related clusters in LUAD. High NETs score was correlated with a favorable overall survival, abundant immune cell infiltration, and high activity of immune response signal pathways. Six NET-related genes (G0S2, KCNJ15, S100A12, AKT2, CTSG, and HMGB1) with significant prognostic value were screened to develop a prognostic signature. LUAD patients with low-risk had a significantly favorable overall survival both in the training set and validation set. Moreover, NETs-related risk score and clinical stage could act as an independent prognostic factor for LUAD patients. Significant correlation was obtained between risk score and tumor immune microenvironment. We also identified lncRNA BCYRN1/miR-3664-5p/CTSG regulatory axis that may be involved in the progression of LUAD. Conclusion: We developed two molecular subtypes and a prognostic signature for LUAD based on NETs-related genes. This stratification could provide more evidences for estimating the prognosis and immunotherapy of LAUD patients.

Factors influencing platelet isolation: a prospective multicenter study from Western China.

Tumor-educated platelets (TEPs) have been widely reported to have promising application potential; nonetheless, platelet isolation from peripheral blood is an important but neglected step in TEPs research for platelet-based liquid biopsy. In this article, we discussed some common influence factors for platelet isolation. To investigate the factors involved in platelet isolation, a prospective multicenter study was conducted on healthy Han Chinese adults (18 to 79 years of age). A total of 208 individuals were included in the final statistical analysis out of the 226 healthy volunteers who were prospectively enrolled from four hospitals. The primary study metric was the platelet recovery rate (PRR). The similar pattern was observed in the four hospitals, The PRR at room temperature (23°C±2°C) was slightly higher than the PRR at cold temperature (4°C±2°C). Moreover, the PRR gradually decreased as the storage time increased. The PRR for samples within 2 hours of storage is significantly higher than for samples beyond 2 hours (p < .05). Additionally, PRR was also affected by the equipment used in different centers. This study confirmed several factors that influence platelet isolation. In our study, we indicated that platelet isolation should be performed within two hours of peripheral blood draw and held at room temperature until isolation, and that centrifuge models should be fixed during the extraction process, which will further improve the research progress of platelet-based liquid biopsy in cancer.

What is the context? Globally, cancer is one of the leading cause of premature death. Early screening is important for cancer diagnosis and treatment and can even significantly lower cancer mortalityGlobally, cancer is one of the leading cause of premature death. Early screening is important for cancer diagnosis and treatment and can even significantly lower cancer mortalityFor the liquid biopsy, isolation is an important step. Early studies have explored the influencing factors of exosome, circulating tumor cells (CTCs), and other components extraction in liquid biopsy.Despite platelet also being an excellent source of liquid biopsy, few studies have explored the factors that influence platelet isolation.Considering the importance of platelet isolation in tumor-based platelet liquid biopsy, our aim is to optimize platelet isolation conditions as much as possible to obtain a high platelet recovery rate.What is new? In this study, we conducted a prospective multicenter study ofhealthy adults from four centers, combining whole blood with platelet-richplasma to investigate factors influencing platelet recovery rate (PRR) during platelet isolation.In our study, we indicated that platelet isolation should be performed within two hours at room temperature, and that centrifuge models should be fixed during the extraction process, which will further improve the research progress of platelet-based liquid biopsy in cancer.What is the impact? In future platelet-related studies, we should fix the sample storage temperature, storage time and centrifuge model in the process of platelet extraction, so as to reduce the variables affecting platelet extraction as much as possible and ensure the stable recovery rate of platelet extraction.

Exploration of the link between gut microbiota and purinergic signalling.

Growing evidence reveals that microorganisms in the gut are linked to metabolic health and disease risk in human beings to a considerable extent. The focus of research at this stage must tend to focus on cause-and-effect studies. In addition to being a component of DNA and RNA, purine metabolites can be involved in purine signalling in the body as chemical messengers. Abnormalities in purinergic signalling may lead to neuropathy, rheumatic immune diseases, inflammation, tumors, and a wide range of other diseases. It has proved that gut microbes are involved in purinergic signalling. The relationship between these gut-derived purinergic signalling molecules and host metabolism may be one of the important clues to our understanding of the mechanisms by which the microbiota affects host metabolism.

Crosstalk between Methylation and ncRNAs in Breast Cancer: Therapeutic and Diagnostic Implications.

Breast cancer, as a highly heterogeneous malignant tumor, is one of the primary causes of death among females worldwide. The etiology of breast cancer involves aberrant epigenetic mechanisms and abnormal expression of certain non-coding RNA (ncRNAs). DNA methylation, N6-methyladenosine(m6A), and histone methylation are widely explored epigenetic regulation types in breast cancer. ncRNAs are a group of unique RNA transcripts, mainly including microRNA (miRNAs), long non-coding RNA (lncRNAs), circular RNA (circRNAs), small interfering RNA (siRNAs), piwi-interacting RNA (piRNAs), etc. Different types of methylation and ncRNAs mutually regulate and interact to form intricate networks to mediate precisely breast cancer genesis. In this review, we elaborate on the crosstalk between major methylation modifications and ncRNAs and discuss the role of their interaction in promoting breast cancer oncogenesis. This review can provide novel insights into establishing a new diagnostic marker system on methylation patterns of ncRNAs and therapeutic perspectives of combining ncRNA oligonucleotides and phytochemical drugs for breast cancer therapy.

Comprehensive Analysis of the Molecular Characteristics and Prognosis value of AT II-associated Genes in Non-small Cell Lung Cancer.

Alveolar type II (AT II) is a key structure of the distal lung epithelium and essential to maintain normal lung homeostasis. Dedifferentiation of AT II cells is significantly correlated with lung tumor progression. However, the potential molecular mechanism and clinical significance of AT II-associated genes for lung cancer has not yet been fully elucidated. In this study, we comprehensively analyzed the gene expression, prognosis value, genetic alteration, and immune cell infiltration of eight AT II-associated genes (AQP4, SFTPB, SFTPC, SFTPD, CLDN18, FOXA2, NKX2-1, and PGC) in Nonsmall Cell Lung Cancer (NSCLC). The results have shown that the expression of eight genes were remarkably reduced in cancer tissues and observably relating to clinical cancer stages. Survival analysis of the eight genes revealed that low-expression of CLDN18, FOXA2, NKX2-1, PGC, SFTPB, SFTPC, and SFTPD were significantly related to a reduced progression-free survival (FP), and low CLDN18, FOXA2, and SFTPD mRNA expression led to a short postprogression survival (PPS). Meanwhile, the alteration of 8 AT II-associated genes covered 273 out of 1053 NSCLC samples (26%). Additionally, the expression level of eight genes were significantly correlated with the infiltration of diverse immune cells, including six types of CD4+T cells, macrophages, neutrophils, B cells, CD8+ T cells, and dendritic cells. In summary, this study provided clues of the values of eight AT II-associated genes as clinical biomarkers and therapeutic targets in NSCLC and might provide some new inspirations to assist the design of new immunotherapies.

Clinlabomics: leveraging clinical laboratory data by data mining strategies.

The recent global focus on big data in medicine has been associated with the rise of artificial intelligence (AI) in diagnosis and decision-making following recent advances in computer technology. Up to now, AI has been applied to various aspects of medicine, including disease diagnosis, surveillance, treatment, predicting future risk, targeted interventions and understanding of the disease. There have been plenty of successful examples in medicine of using big data, such as radiology and pathology, ophthalmology cardiology and surgery. Combining medicine and AI has become a powerful tool to change health care, and even to change the nature of disease screening in clinical diagnosis. As all we know, clinical laboratories produce large amounts of testing data every day and the clinical laboratory data combined with AI may establish a new diagnosis and treatment has attracted wide attention. At present, a new concept of radiomics has been created for imaging data combined with AI, but a new definition of clinical laboratory data combined with AI has lacked so that many studies in this field cannot be accurately classified. Therefore, we propose a new concept of clinical laboratory omics (Clinlabomics) by combining clinical laboratory medicine and AI. Clinlabomics can use high-throughput methods to extract large amounts of feature data from blood, body fluids, secretions, excreta, and cast clinical laboratory test data. Then using the data statistics, machine learning, and other methods to read more undiscovered information. In this review, we have summarized the application of clinical laboratory data combined with AI in medical fields. Undeniable, the application of Clinlabomics is a method that can assist many fields of medicine but still requires further validation in a multi-center environment and laboratory.

A new classifier constructed with platelet features for malignant and benign pulmonary nodules based on prospective real-world data.

Objectives: As the pulmonary nodules were hard to be discriminated as benignancy or malignancy only based on imageology, a prospective and observational real-world research was devoted to develop and validate a predictive model for managing the diagnostic challenge. Methods: This study started in 2018, and a predictive model was constructed using eXtreme Gradient Boosting (XGBoost) based on computed tomographic, clinical, and platelet data of all the eligible patients. And the model was evaluated and compared with other common models using ROC curves, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and net benefit (NB). Subsequently, the model was validated in an external cohort. Results: The development group included 419 participants, while there were 62 participants in the external validation cohort. The most accurate XGBoost model called SCHC model including age, platelet counts in platelet rich plasma samples (pPLT), plateletcrit in platelet rich plasma samples (pPCT), nodule size, and plateletcrit in whole blood samples (bPCT). In the development group, the SCHC model performed well in whole group and subgroups. Compared with VA, MC, BU model, the SCHC model had a significant improvement in reclassification as assessed by the NRI and IDI, and could bring the patients more benefits. For the external validation, the model performed not as well. The algorithm of SCHC, VA, MC, and BU model were first integrated using a web tool (http://i.uestc.edu.cn/SCHC). Conclusions: In this study, a platelet feature-based model could facilitate the discrimination of early-stage malignancy from benignancy patients, to ensure accurate diagnosis and optimal management. This research also indicated that common laboratory results also had the potential in diagnosing cancers.

Selection and Validation of Reference Genes for Pan-Cancer in Platelets Based on RNA-Sequence Data.

Many studies in recent years have demonstrated that some messenger RNA (mRNA) in platelets can be used as biomarkers for the diagnosis of pan-cancer. The quantitative real-time polymerase chain reaction (RT-qPCR) molecular technique is most commonly used to determine mRNA expression changes in platelets. Accurate and reliable relative RT-qPCR is highly dependent on reliable reference genes. However, there is no study to validate the reference gene in platelets for pan-cancer. Given that the expression of some commonly used reference genes is altered in certain conditions, selecting and verifying the most suitable reference gene for pan-cancer in platelets is necessary to diagnose early stage cancer. This study performed bioinformatics and functional analysis from the RNA-seq of platelets data set (GSE68086). We generated 95 candidate reference genes after the primary bioinformatics step. Seven reference genes (YWHAZ, GNAS, GAPDH, OAZ1, PTMA, B2M, and ACTB) were screened out among the 95 candidate reference genes from the data set of the platelets' transcriptome of pan-cancer and 73 commonly known reference genes. These candidate reference genes were verified by another platelets expression data set (GSE89843). Then, we used RT-qPCR to confirm the expression levels of these seven genes in pan-cancer patients and healthy individuals. These RT-qPCR results were analyzed using the internal stability analysis software programs (the comparative Delta CT method, geNorm, NormFinder, and BestKeeper) to rank the candidate genes in the order of decreasing stability. By contrast, the GAPDH gene was stably and constitutively expressed at high levels in all the tested samples. Therefore, GAPDH was recommended as the most suitable reference gene for platelet transcript analysis. In conclusion, our result may play an essential part in establishing a molecular diagnostic platform based on the platelets to diagnose pan-cancer.

Effects of 2,2',4'-trihydroxychalcone on the proliferation, metastasis and apoptosis of A549 human lung cancer cells.

The aim of the present study was to evaluate the antitumor effects of 2,2',4'-trihydroxychalcone (7a) on the A549 human lung cancer cell line. A549 cells were treated with different concentrations of 7a for different time periods. Cells without 7a were used as the negative control group. Cell proliferation, invasion, vasculogenic mimicry (VM) formation, heterogeneous adhesion and apoptosis were measured using Cell Counting Kit-8, Transwell invasion, VM, adhesion and flow cytometric assays, respectively. In addition, the expression of related proteins was determined using western blot analysis or ELISA. The present study found that 7a had a significant inhibitory effect on the survival rate of the A549 lung cancer cells but almost no effect on BEAS-2B human lung epithelial cells or human venous endothelial cells. The migration rate, VM length, invasion rate and heterogeneous adhesion number of cells treated with 7a significantly decreased as the concentration increased, while the apoptosis rate increased. Western blot analysis showed that 7a treatment significantly increased the expression levels of E-cadherin, cleaved poly (ADP-ribose) polymerase, Bax and caspase-3 and simultaneously decreased the expression levels of metalloproteinase-2/9, Bcl-2, phosphorylated (p)-PI3K, p-AKT, p-mTOR, vascular endothelial growth factor (VEGF), E-selectin and N-cadherin. At the same time, the ELISA results showed that the level of the pro-angiogenic factor VEGF in the culture media was reduced in the presence of 7a. In addition, 7a could also reduce the nuclear NF-κB protein expression, which could inhibit the gene transcription of tumor apoptosis and metastasis-related proteins. Therefore, 7a may exert inhibitory effects on A549 cells by inhibiting cell proliferation, migration, VM formation and heterogeneous adhesion, as well as by inducing apoptosis through the suppression of the PI3K/AKT/NF-κB signaling pathway; these findings suggested that 7a may be a promising agent for the treatment of lung cancer.

Inhibitory effects of temozolomide on glioma cells is sensitized by RSL3-induced ferroptosis but negatively correlated with expression of ferritin heavy chain 1 and ferritin light chain.

Invasive growth of glioblastoma makes residual tumor unremovable by surgery and leads to disease relapse. Temozolomide is widely used first-line chemotherapy drug to treat glioma patients, but development of temozolomide resistance is almost inevitable. Ferroptosis, an iron-dependent form of non-apoptotic cell death, is found to be related to temozolomide response of gliomas. However, whether inducing ferroptosis could affect invasive growth of glioblastoma cells and which ferroptosis-related regulators were involved in temozolomide resistance are still unclear. In this study, we treated glioblastoma cells with RSL3, a ferroptosis inducer, in vitro (cell lines) and in vivo (subcutaneous and orthotopic animal models). The treated glioblastoma cells with wild-type or mutant IDH1 were subjected to RNA sequencing for transcriptomic profiling. We then analyze data from our RNA sequencing and public TCGA glioma database to identify ferroptosis-related biomarkers for prediction of prognosis and temozolomide resistance in gliomas. Analysis of transcriptome data from RSL3-treated glioblastoma cells suggested that RSL3 could inhibit glioblastoma cell growth and suppress expression of genes involved in cell cycle. RSL3 effectively reduced mobility of glioblastoma cells through downregulation of critical genes involved in epithelial-mesenchymal transition. Moreover, RSL3 in combination with temozolomide showed suppressive efficacy on glioblastoma cell growth, providing a promising therapeutic strategy for glioblastoma treatment. Although temozolomide attenuated invasion of glioblastoma cells with mutant IDH1 more than those with wild-type IDH1, the combination of RSL3 and temozolomide similarly impaired invasive ability of glioblastoma cells in spite of IDH1 status. Finally, we noticed that both ferritin heavy chain 1 and ferritin light chain predicted unfavorable prognosis of glioma patients and were significantly correlated with mRNA levels of methylguanine methyltransferase as well as temozolomide resistance. Altogether, our study provided rationale for combination of RSL3 with temozolomide to suppress glioblastoma cells and revealed ferritin heavy chain 1 and ferritin light chain as biomarkers to predict prognosis and temozolomide resistance of glioma patients.

WW domain binding protein 2 (WBP2) as an oncogene in breast cancer: mechanisms and therapeutic prospects-a narrative review.

Background and Objective: WW domain binding protein 2 (WBP2), considered an emerging breast cancer gene, functions as a binding partner for WW domain proteins. The WBP2 gene is involved in mediating the malignant development and clinical drug resistance of breast cancer, but its potential mechanism remains unclear. Therefore, it is necessary to elucidate the mechanism of WBP2 in breast cancer, which will help to provide new methods for clinical diagnosis and treatment of breast cancer. Methods: The PubMed database was searched using the terms "WW Domain Binding Protein 2" or "WBP2", "breast cancer" or "breast neoplasms" or "human cancer" from January 1997 through August 2022. Through the screening and evaluation of titles and abstracts, about 120 English articles were included in this study. Key Content and Findings: By describing the multiple regulatory functions of WBP2 at the transcriptional, post-transcriptional, and post-translational levels, and summarizing how WBP2 as a key node crosstalks multiple signaling pathways, we reveal the ability of WBP2 to promote breast cancer malignant progression. In different subtypes of breast cancer, the mechanism of WBP2-mediated drug resistance is related to estrogen receptor and epidermal growth factor receptor (EGFR) 2 status, and hormones may be an essential factor in WBP2-mediated drug resistance. In addition, we discuss the application prospects of WBP2 in targeted therapy and immunotherapy and propose therapeutic strategies to overcome drug resistance in breast cancer by jointly targeting WBP2 and its related molecules. This provides a theoretical basis for the innovation of breast cancer targeted drugs. Conclusions: WBP2 is a promising target for breast cancer therapy. Nuclear WBP2, as the main functional form of WBP2 after its activation, is a meaningful indicator for the diagnosis and prediction of breast cancer progression.

G protein coupled estrogen receptor attenuates mechanical stress-mediated apoptosis of chondrocyte in osteoarthritis via suppression of Piezo1.

BACKGROUND: Apoptosis of chondrocyte is involved in osteoarthritis (OA) pathogenesis, and mechanical stress plays a key role in this process by activation of Piezo1. However, the negative regulation of signal conduction mediated by mechanical stress is still unclear. Here, we elucidate that the critical role of G protein coupled estrogen receptor (GPER) in the regulation of mechanical stress-mediated signal transduction and chondrocyte apoptosis. METHODS: The gene expression profile was detected by gene chip upon silencing Piezo1. The expression of GPER in cartilage tissue taken from the clinical patients was detected by RT-PCR and Western blot as well as immunohistochemistry, and the correlation between GPER expression and OA was also investigated. The chondrocytes exposed to mechanical stress were treated with estrogen, G-1, G15, GPER-siRNA and YAP (Yes-associated protein)-siRNA. The cell viability of chondrocytes was measured. The expression of polymerized actin and Piezo1 as well as the subcellular localization of YAP was observed under laser confocal microscope. Western blot confirmed the changes of YAP/ Rho GTPase activating protein 29 (ARHGAP29) /RhoA/LIMK /Cofilin pathway. The knee specimens of osteoarthritis model were stained with safranin and green. OARSI score was used to evaluate the joint lesions. The expressions of GPER and YAP were detected by immunochemistry. RESULTS: Expression profiles of Piezo1- silenced chondrocytes showed that GPER expression was significantly upregulated. Moreover, GPER was negatively correlated with cartilage degeneration during OA pathogenesis. In addition, we uncovered that GPER directly targeted YAP and broadly restrained mechanical stress-triggered actin polymerization. Mechanism studies revealed that GPER inhibited mechanical stress-mediated RhoA/LIMK/cofilin pathway, as well as the actin polymerization, by promoting expression of YAP and ARHGAP29, and the YAP nuclear localization, eventually causing the inhibition of Piezo1. YAP was obviously decreased in degenerated cartilage. Silencing YAP caused significantly increased actin polymerization and activation of Piezo1, and an increase of chondrocyte apoptosis. In addition, intra-articular injection of G-1 to OA rat effectively attenuated cartilage degeneration. CONCLUSION: We propose a novel regulatory mechanism underlying mechanical stress-mediated apoptosis of chondrocyte and elucidate the potential application value of GPER as therapy targets for OA.

Investigating the Multitarget Pharmacological Mechanism of Ursolic Acid Acting on Colon Cancer: A Network Pharmacology Approach.

OBJECTIVE: To explore the mechanisms of ursolic acid for treating colon cancer based on network pharmacology. METHOD: In this study, the potential targets of ursolic acid against colon cancer were predicted and screened through the TCMSP, SYMMAP, Drug Bank, UNI-PROT, and DISGENET databases. The protein interaction (PPI) network was constructed based on the STRING database, and graphs were drawn with the help of Cytoscape software. GO and KEGG enrichment analyses were performed on the targets by using the DAVID database for biological information annotation. RESULTS: Ursolic acid has 113 targets in the treatment of colon cancer. The core targets included interleukin-6 (IL-6), mitogen-activated protein kinase 3 (MAPK3), vascular endothelial growth factor receptor (VEGFA), prostaglandin endoperoxide synthase 2 (PTGS2), caspase-3 (CASP3), mitogen-activated protein kinase 8 (MAPK8), tumor necrosis factor (TNF), cyclin D1 (CCND1), JUN, signal transducer and transcriptional activator 3 (STAT3), and other targets. The first 10 pathways related to colon cancer were screened out. The main signaling pathways included the TNF signaling pathway and the AGE-RAGE signaling pathway in diabetic complications and human colon cancer infections. CONCLUSION: This study revealed that ursolic acid played a multitarget and multichannel antitumor role by inhibiting the proliferation of tumor cells, inducing apoptosis, and enhancing antiangiogenesis.

Tomato protein phosphatase 2C influences the onset of fruit ripening and fruit glossiness.

Abscisic acid (ABA) plays a vital role in coordinating physiological processes during fresh fruit ripening. Binding of ABA to receptors facilitates the interaction and inhibition of type 2C phosphatase (PP2C) co-receptors. However, the exact mechanism of PP2C during fruit ripening is unclear. In this study, we determined the role of the tomato ABA co-receptor type 2C phosphatase SlPP2C3, a negative regulator of ABA signaling and fruit ripening. SlPP2C3 selectively interacted with monomeric ABA receptors and SlSnRK2.8 kinase in both yeast and tobacco epidermal cells. Expression of SlPP2C3 was ABA-inducible, which was negatively correlated with fruit ripening. Tomato plants with suppressed SlPP2C3 expression exhibited enhanced sensitivity to ABA, while plants overexpressing SlPP2C3 were less sensitive to ABA. Importantly, lack of SlPP2C3 expression accelerated the onset of fruit ripening and affected fruit glossiness by altering the outer epidermis structure. There was a significant difference in the expression of cuticle-related genes in the pericarp between wild-type and SlPP2C3-suppressed lines based on RNA sequencing (RNA-seq) analysis. Taken together, our findings demonstrate that SlPP2C3 plays an important role in the regulation of fruit ripening and fruit glossiness in tomato.