Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies.

Despite the success of targeted therapies in cancer treatment, therapy-induced resistance remains a major obstacle to a complete cure. Tumor cells evade treatments and relapse via phenotypic switching driven by intrinsic or induced cell plasticity. Several reversible mechanisms have been proposed to circumvent tumor cell plasticity, including epigenetic modifications, regulation of transcription factors, activation or suppression of key signaling pathways, as well as modification of the tumor environment. Epithelial-to-mesenchymal transition, tumor cell and cancer stem cell formation also serve as roads towards tumor cell plasticity. Corresponding treatment strategies have recently been developed that either target plasticity-related mechanisms or employ combination treatments. In this review, we delineate the formation of tumor cell plasticity and its manipulation of tumor evasion from targeted therapy. We discuss the non-genetic mechanisms of targeted drug-induced tumor cell plasticity in various types of tumors and provide insights into the contribution of tumor cell plasticity to acquired drug resistance. New therapeutic strategies such as inhibition or reversal of tumor cell plasticity are also presented. We also discuss the multitude of clinical trials that are ongoing worldwide with the intention of improving clinical outcomes. These advances provide a direction for developing novel therapeutic strategies and combination therapy regimens that target tumor cell plasticity.

Role of protein phosphorylation in cell signaling, disease, and the intervention therapy.

Protein phosphorylation is an important post-transcriptional modification involving an extremely wide range of intracellular signaling transduction pathways, making it an important therapeutic target for disease intervention. At present, numerous drugs targeting protein phosphorylation have been developed for the treatment of various diseases including malignant tumors, neurological diseases, infectious diseases, and immune diseases. In this review article, we analyzed 303 small-molecule protein phosphorylation kinase inhibitors (PKIs) registered and participated in clinical research obtained in a database named Protein Kinase Inhibitor Database (PKIDB), including 68 drugs approved by the Food and Drug Administration of the United States. Based on previous classifications of kinases, we divided these human protein phosphorylation kinases into eight groups and nearly 50 families, and delineated their main regulatory pathways, upstream and downstream targets. These groups include: protein kinase A, G, and C (AGC) and receptor guanylate cyclase (RGC) group, calmodulin-dependent protein kinase (CaMK) group, CMGC [Cyclin-dependent kinases (CDKs), Mitogen-activated protein kinases (MAPKs), Glycogen synthase kinases (GSKs), and Cdc2-like kinases (CLKs)] group, sterile (STE)-MAPKs group, tyrosine kinases (TK) group, tyrosine kinase-like (TKL) group, atypical group, and other groups. Different groups and families of inhibitors stimulate or inhibit others, forming an intricate molecular signaling regulatory network. This review takes newly developed new PKIs as breakthrough point, aiming to clarify the regulatory network and relationship of each pathway, as well as their roles in disease intervention, and provide a direction for future drug development.

Identification and analysis of microRNA editing events in recurrent bladder cancer based on RNA sequencing: MicroRNA editing level is a potential novel biomarker.

Background: With the continued advancement of RNA-seq (RNA-sequencing), microRNA (miRNA) editing events have been demonstrated to play an important role in different malignancies. However, there is yet no description of the miRNA editing events in recurrent bladder cancer. Objective: To identify and compare miRNA editing events in primary and recurrent bladder cancer, as well as to investigate the potential molecular mechanism and its impact on patient prognosis. Methods: We examined the mRNA and miRNA transcriptomes of 12 recurrent bladder cancer cases and 13 primary bladder cancer cases. The differentially expressed mRNA sequences were analyzed. Furthermore, we identified the differentially expressed genes (DEGs) in recurrent bladder cancer. The Gene Ontology (GO) functional enrichment analyses on DEGs and gene set enrichment analysis were performed. The consensus molecular subtype (CMS) classification of bladder cancer was identified using the Consensus MIBC package in R (4.1.0); miRNA sequences were then further subjected to differentially expressed analysis and pathway enrichment analysis. MiRNA editing events were identified using miRge3.0. miRDB and TargetScanHuman were used to predict the downstream targets of specific differentially edited or expressed miRNAs. The expression levels of miR-154-5p and ADAR were validated by RT-qPCR. Finally, survival and co-expression studies were performed on the TCGA-BLCA cohort. Results: First, the mRNA expression levels in recurrent bladder cancer changed significantly, supporting progression via related molecular signal pathways. Second, significantly altered miRNAs in recurrent bladder cancer were identified, with miR-154-5p showing the highest level of editing in recurrent bladder cancer and may up-regulate the expression levels of downstream targets HS3ST3A1, AQP9, MYLK, and RAB23. The survival analysis results of TCGA data revealed that highly expressed HS3ST3A1 and RAB23 exhibited poor prognosis. In addition, miR-154 editing events were found to be significant to CMS classification. Conclusion: MiRNA editing in recurrent bladder cancer was detected and linked with poor patient prognosis, providing a reference for further uncovering the intricate molecular mechanism in recurrent bladder cancer. Therefore, inhibiting A-to-I editing of miRNA may be a viable target for bladder cancer treatment, allowing current treatment choices to be expanded and individualized.

Targeting HNRNPU to overcome cisplatin resistance in bladder cancer.

PURPOSE: The overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC. EXPERIMENTAL DESIGN: The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity. RESULTS: Significant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1). CONCLUSIONS: Our study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer.

[Study on positive reaction of foot three yin-meridians in patients with typeâ ¢ chronic prostatitis based on meridian diagnosis].

OBJECTIVE: To explore the relationship between typeⅢ chronic prostatitis and the positive reaction of foot three yin-meridians based on meridian diagnosis. METHODS: Using the traditional meridian diagnosis combined with tenderness meter detection, the positive reaction rate of meridians and acupoints of crural foot three yin-meridians and tenderness pain threshold of standard acupoint location were compared in the typeⅢ chronic prostatitis patients (prostatitis group, 32 cases) and healthy subjects (health group, 30 cases). RESULTS: The positive reaction rate of the spleen meridian was higher than those in the kidney meridian and the liver meridian in the prostatitis group (P<0.001). The positive reaction rates of the spleen meridian, the kidney meridian and the liver meridian and the total positive reaction rate of foot three yin-meridians in the prostatitis group were higher than those in the health group (P<0.001). In the prostatitis group, the positive reaction rates of Sanyinjiao (SP 6), Yinlingquan (SP 9), Taixi (KI 3), Ligou (LR 5), Diji (SP 8), Ququan (LR 8), Shangqiu (SP 5) and Zhongfeng (LR 4) were higher than those in the health group (P<0.001), the tenderness pain threshold of acupoints of crural foot three yin-meridians was lower than the health group (P<0.001). The positive reaction rate of the spleen meridian was positively correlated with the pain score and the total score of National Institute of Health chronic prostatitis symptom index (NIH-CPSI), and the positive reaction rate of the kidney meridian was positively correlated with age and international prostate symptom score (IPSS) in the prostatitis group. CONCLUSION: The positive reactions of foot three yin-meridians, especially the spleen meridian, are closely related to the pathological state of typeⅢ chronic prostatitis, pain and urination symptom are significantly correlated with the spleen meridian and the kidney meridian respectively.

[Analysis on specific effect of acupoints at the upper arms in treatment of scrofula and goiter].

Through analyzing the indication distribution of the different acupoints located at the upper limbs recorded in Science of Acupoints and Science of Meridians and Acupoints, the industry planning teaching materials of traditional Chinese medicine, it is discovered that the acupoints located at the upper arms are commonly selected for the treatment of scrofula and goiter, while the acupoints below the elbow at the hand meridians and those at the lower limbs of the foot meridians which running through the neck, do not have the similar indications. Based on a further analysis on the literature at ancient and modern times, it is believed that the acupoints located on the lateral side of the upper arms, especially those at the large intestine meridian of hand-yangming perhaps have the specific effect in treatment of scrofula and goiter.

[Automatic houses detection with color aerial images based on image segmentation].

In order to achieve housing automatic detection from high-resolution aerial imagery, the present paper utilized the color information and spectral characteristics of the roofing material, with the image segmentation theory, to study the housing automatic detection method. Firstly, This method proposed in this paper converts the RGB color space to HIS color space, uses the characteristics of each component of the HIS color space and the spectral characteristics of the roofing material for image segmentation to isolate red tiled roofs and gray cement roof areas, and gets the initial segmentation housing areas by using the marked watershed algorithm. Then, region growing is conducted in the hue component with the seed segment sample by calculating the average hue in the marked region. Finally through the elimination of small spots and rectangular fitting process to obtain a clear outline of the housing area. Compared with the traditional pixel-based region segmentation algorithm, the improved method proposed in this paper based on segment growing is in a one-dimensional color space to reduce the computation without human intervention, and can cater to the geometry information of the neighborhood pixels so that the speed and accuracy of the algorithm has been significantly improved. A case study was conducted to apply the method proposed in this paper to high resolution aerial images, and the experimental results demonstrate that this method has a high precision and rational robustness.