Background The processes of prostate cancer (PCa) invasion and metastasis are facilitated by proteolytic cascade involving multiple proteases, such as matrix metalloproteinases, serine proteases and cysteine proteases including cathepsin K (CatK). CatK is predominantly secreted by osteoclasts and specifically degrades collagen I leading to bone destruction. PCa and breast cancer preferentially metastasize to the bone. Importantly, CatK expression level is greater in PCa bone metastatic sites compared to primary tumor and normal prostate tissues. However, the underlying mechanism of CatK during PCa metastases into the bone remains to be elucidated. We investigated the functional role of CatK during the PCa establishment and growth process in the murine bone. Methods CatK mRNA expression was validated by RT-PCR, protein expression by immunoblotting in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Its protein production was measured using ELISA assay. The effect of both knockdowns via siRNA and CatK inhibitor was compared in regard to PCa cell invasion. We further studied the dose-dependent CatK inhibitor effect on conditioned media-induced bone resorption. In setting up an animal model, C4-2B cells were injected into the tibiae of SCID mice. The animals treated with either vehicle or CatK inhibitor for 8 weeks at the time of tumor cell injection (tumor establishment model; protocol I) or 4 weeks after tumor cell injection (tumor progression model; protocol II) were applied to histological and histomorphometric analyses. Results We confirmed CatK expression in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Furthermore, we observed the inhibitory effects of a selective CatK inhibitor on PCa cell invasion. The CatK inhibitor dose-dependently inhibited PCa-conditioned media-induced bone resorption. Upon injection of C4-2B cells into the tibiae of SCID mice, the selective CatK inhibitor significantly prevented the tumor establishment in protocol I, and reduced the tumor growth in bone in protocol II. It also decreased serum PSA levels in both animal models. The inhibitory effects of the CatK inhibitor were enhanced in combination with zoledronic acid (ZA). Conclusion The selective CatK inhibitor may prevent the establishment and progression of PCa in bone, thus making it a novel therapeutic approach for advanced PCa.
Radiochemotherapy (RCT) is a powerful treatment for cervical cancer, which affects not only malignant cells but also the immune and stromal compartments of the tumor. Understanding the remodeling of the local ecosystem induced by RCT would provide valuable insights into improving treatment strategies for cervical cancer. In this study, we applied single-cell RNA-sequencing to paired pre- and post-RCT tumor biopsies from patients with cervical cancer and adjacent normal cervical tissues. We found that the residual population of epithelial cells post-RCT showed upregulated expression of MHC class II genes. Moreover, RCT led to the accumulation of monocytic myeloid-derived suppressor cells with increased pro-inflammatory features and CD16+ NK cells with a higher cytotoxic gene expression signature. However, subclusters of T cells showed no significant increase in the expression of cytotoxic features post-RCT. These results reveal the complex responses of the tumor ecosystem to RCT, providing evidence of activation of innate immunity and MHC-II upregulation in cervical cancer.
This study aimed to investigate the proximate and phytochemicals present in seeds of 24 mung bean (Vigna radiate L.) genotypes from four provinces of China for estimating their nutritional and antioxidant properties. Proximate analysis of mung bean genotypes revealed that starch, protein, fat, ash and water-soluble polysaccharide ranged from 39.54–60.66, 17.36–24.89, 4.24–12.18, 2.78–3.53 and 1.99–2.96 g/100 g respectively. The five principal fatty acids detected in mung beans were stearic acid, palmitic acid, linoleic acid, oleic acid, and linolenic acid. The contents of insoluble-bound phenolic compounds, soluble phenolic compounds, and flavonoids ranged from 0.78 to 1.5 mg GAE g− 1, 1.78 to 4.10 mg GAE g− 1, and 1.25 to 3.52 mg RE g− 1, respectively. The black seed coat mung bean genotype M13 (Suheilv 1) exhibited highest flavonoid and phenolic contents which showed strong antioxidant activity. Two flavonoids (vitexin and isovitexin) and four phenolic acids (caffeic, syringic acid, p-coumaric, and ferulic acids) were identified by HPLC. Vitexin and isovitexin were the major phenolic compounds in all mung bean genotypes. The content of soluble phenolic compounds had positive correlation with DPPH (r2 = 0.713) and ABTS (r2 = 0.665) radical scavenging activities. Principal component analysis indicated that the first two principal components could reflect most details on mung bean with a cumulative contribution rate of 66.1%. Twenty-four mung bean genotypes were classified into four groups based on their phenolic compounds contents and antioxidant activities. The present study highlights the importance of these mung bean genotypes as a source of nature antioxidant ingredient for the development of functional foods or a source of health promoting food. Graphical Abstract
The intratumor heterogeneity of human papillomavirus (HPV)‐related cervical cancer remains poorly defined. We performed single‐cell RNA sequencing on 18 046 individual cells derived from two HPV‐related cervical adenosquamous carcinoma samples to analyze the transcriptional heterogeneity of both epithelial and immune constituents, identifying seven epithelial (Epi1‐7) and 11 immune subclusters. Based on expression of known cervical cancer markers, Epi1‐2 primarily displayed features of adenocarcinoma, whereas Epi3‐6 were instead characterized by features of squamous carcinoma. Our analyses also revealed that hypoxia and Kirsten rat sarcoma viral oncogene signaling were highly represented within Epi1; metabolic pathways mediating glycolysis and oxidative phosphorylation were enriched in Epi2‐4; while Epi5 was enriched in p53 pathway components and features of epithelial–mesenchymal transition. Moreover, CD8+FGFBP2+ T cells and FGFBP2+ natural killer cells were found to display high levels of cytotoxic effectors (GZMA, GZMB, GNLY, and PRF1) and low levels of inhibitory markers (PDCD1, TIGIT, and CTLA4), such that tumor infiltration by these populations was positively associated with survival in a cohort of n = 165 patients with HPV‐related cervical cancer from The Cancer Genome Atlas database (p = 0.017 and 0.014, respectively). These results shed new light on the intratumor heterogeneity of HPV‐related cervical adenosquamous carcinoma, which will help to refine diagnostic and treatment approaches.
At present, most vascular intervention surgical robots (VISRs) cannot achieve effective force feedback and lack regulation of the clamping force of the guidewire. In this paper, a VISR based on force feedback and clamping force regulation is proposed. It is a master–slave system consisting of a master manipulator that is flexible enough and a slave wire feeder that can deliver the guidewire. Accurate force feedback is established to ensure the safety of the operation, and the clamping force of the guidewire can be regulated in real time. Based on the dynamic analysis of the mechanism, the control scheme of the system is designed. The two-dimensional fuzzy PID (Proportion Integration Differentiation) controller is equipped with on-line tuning parameters and anti-interference capabilities. The sine and step signals are selected to carry out simulation analysis on the controller. The performance of the designed VISR was verified by a force feedback experiment, a clamping force regulation experiment and a vascular model experiment.
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