Investigation of ENO2 as a promising novel marker for the progression of colorectal cancer with microsatellite instability-high.

BACKGROUND: Microsatellite instability-high (MSI-H) has emerged as a significant biological characteristic of colorectal cancer (CRC). Studies reported that MSI-H CRC generally had a better prognosis than microsatellite stable (MSS)/microsatellite instability-low (MSI-L) CRC, but some MSI-H CRC patients exhibited distinctive molecular characteristics and experienced a less favorable prognosis. In this study, our objective was to explore the metabolic transcript-related subtypes of MSI-H CRC and identify a biomarker for predicting survival outcomes. METHODS: Single-cell RNA sequencing (scRNA-seq) data of MSI-H CRC patients were obtained from the Gene Expression Omnibus (GEO) database. By utilizing the copy number variation (CNV) score, a malignant cell subpopulation was identified at the single-cell level. The metabolic landscape of various cell types was examined using metabolic pathway gene sets. Subsequently, functional experiments were conducted to investigate the biological significance of the hub gene in MSI-H CRC. Finally, the predictive potential of the hub gene was assessed using a nomogram. RESULTS: This study revealed a malignant tumor cell subpopulation from the single-cell RNA sequencing (scRNA-seq) data. MSI-H CRC was clustered into two subtypes based on the expression profiles of metabolism-related genes, and ENO2 was identified as a hub gene. Functional experiments with ENO2 knockdown and overexpression demonstrated its role in promoting CRC cell migration, invasion, glycolysis, and epithelial-mesenchymal transition (EMT) in vitro. High expression of ENO2 in MSI-H CRC patients was associated with worse clinical outcomes, including increased tumor invasion depth (p = 0.007) and greater likelihood of perineural invasion (p = 0.015). Furthermore, the nomogram and calibration curves based on ENO2 showed potential prognosis predictive performance. CONCLUSION: Our findings suggest that ENO2 serves as a novel prognostic biomarker and is associated with the progression of MSI-H CRC.

Elesclomol Loaded Copper Oxide Nanoplatform Triggers Cuproptosis to Enhance Antitumor Immunotherapy.

The induction of cuproptosis, a recently identified form of copper-dependent immunogenic cell death, is a promising approach for antitumor therapy. However, sufficient accumulation of intracellular copper ions (Cu2+) in tumor cells is essential for inducing cuproptosis. Herein, an intelligent cuproptosis-inducing nanosystem is constructed by encapsulating copper oxide (CuO) nanoparticles with the copper ionophore elesclomol (ES). After uptake by tumor cells, ES@CuO is degraded to release Cu2+ and ES to synergistically trigger cuproptosis, thereby significantly inhibiting the tumor growth of murine B16 melanoma cells. Moreover, ES@CuO further promoted cuproptosis-mediated immune responses and reprogrammed the immunosuppressive tumor microenvironment by increasing the number of tumor-infiltrating lymphocytes and secreted inflammatory cytokines. Additionally, combining ES@CuO with programmed cell death-1 (PD-1) immunotherapy substantially increased the antitumor efficacy in murine melanoma. Overall, the findings of this study can lead to the use of a novel strategy for cuproptosis-mediated antitumor therapy, which may enhance the efficacy of immune checkpoint inhibitor therapy.

Prognostic factors and survival prediction in hepatocellular carcinoma: development and validation of a novel nomogram based on the SEER database.

Background: Current staging systems for hepatocellular carcinoma (HCC) still have limitations in clinical practice. Our study aimed to explore the prognostic factors and develop a new nomogram to predict the cancer-specific survival (CSS) for patients with HCC. Methods: A total of 6,166 HCC patients were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were randomly grouped into the training cohort (70%) and validation cohort (30%). Multivariate Cox analysis was used to identify prognostics factors for CSS of patients, then we incorporated these variables and presented a new nomogram to predict 2- and 5-year CSS. The performance of the nomogram was assessed with respect to its calibration, concordance index (C-index), area under the receiver operating characteristic (ROC) curve (AUC), and decision curve analysis (DCA). Results: Multivariate Cox analysis revealed that American Joint Committee on Cancer (AJCC) stage, race, grade, surgery, chemotherapy, radiation, tumor size, bone metastasis (BM), and alpha-fetoprotein (AFP) were independently associated with CSS. The prediction nomogram which contained these predictors showed good performance, with a C-index of 0.802 [95% confidence interval (CI), 0.792-0.812] in the training cohort and 0.801 (95% CI, 0.787-0.815) in the validation cohort. The calibration curves demonstrated good agreement between the actual observation and the nomogram prediction. Furthermore, the nomogram showed improved discriminative capacity (AUC, 0.873 and 0.875 for 2- and 5-year CSS in validation set) compared to the 7th tumor-node-metastasis (TNM) staging system (AUC, 0.735 and 0.717). The DCA also indicated good application of the nomogram. Conclusions: This study presents a novel nomogram that incorporates the important prognostic factors of HCC, which can be conveniently used to accurately predict the 2- and 5-year CSS of patients with HCC, thus assisting individualized clinical decision making.

PF-04449913 Inhibits Proliferation and Metastasis of Colorectal Cancer Cells by Down-regulating MMP9 Expression through the ERK/p65 Pathway.

INTRODUCTION: Colorectal cancer remains a life-threatening malignancy with increasing morbidity and mortality worldwide. Therefore, new and effective anti-colorectal cancer therapeutics are urgently needed. METHOD: In this study, we have studied the anti-tumor properties and potential mechanisms of PF-04449913. Colorectal cancer cell viability was reduced by PF-04449913 in a dose-dependent manner. The migration and invasion ability of malignant colon cells were attenuated by the drug, as demonstrated by the Transwell test. Moreover, PF-04449913 repressed the phosphorylation levels of ERK and other proteins, and the expression levels of MMP9. The anti-tumor effects of the drug in vivo were demonstrated in BALB/c-nude mice models, and PF-04449913 inhibited the malignant phenotype of colorectal cancer cells, including reduction of tumor size and promotion of apoptosis. At the molecular level, PF-04449913 induced a significant decrease in ERK and p65 protein phosphorylation levels and inhibited MMP9 protein expression. RESULTS: Both in vivo and in vitro results showed PF-04449913 to demonstrate antitumor effects, which have been proposed to be mediated through blockade of the ERK/p65 signaling pathway, and subsequent repression of MMP9 expression. CONCLUSION: Our study provides a new perspective on the potential clinical application of PF-04449913 in the treatment of colorectal cancer.

Pretreatment with a modified St. Thomas' solution in patients with severe upper limb injuries: Four case reports.

BACKGROUND: This study aims to describe the application of a modified St. Thomas' solution in patients with severe limb injuries. CASE SUMMARY: Four patients who sustained a high-energy trauma and underwent complete upper limb amputation were pretreated with a modified St. Thomas' solution before upper limb replantation. After the perfusion solution stopped flowing from the blood vessel, the amputated upper limb amputation was replanted. The patients were instructed to perform functional rehabilitation training after the operation. All 4 patients were followed up for 5 years. All the severed upper limbs survived. Routine re-examination after the operation showed that the function of the affected limb was restored. All the patients were satisfied with the sensory and functional recovery of the affected limb. CONCLUSION: The modified St. Thomas' solution can effectively improve the success rate of limb salvage surgery and the recovery of limb function in patients with a severe limb injury.

The effect of metabolic syndrome on postoperative complications and long-term survival of patients with colorectal cancer.

Background: Metabolic syndrome (MetS) is associated with poor prognosis in many cancers. However, the relationship between metabolic syndrome and overall survival (OS) in patients with colorectal cancer (CRC) remains unclear. We aimed to comprehensively analyze whether MetS could affect postoperative complications and long-term survival in patients with CRC. Methods: We included patients who underwent CRC resection at our center between January 2016 and December 2018. Bias was reduced through propensity score matching analysis. Patients with CRC were divided into the MetS and non-MetS groups based on whether they had MetS. Univariate and multivariate analyses were used to identify risk factors affecting OS. Results: We included 268 patients; among them, 120 were included for further analysis after propensity score matching. There were no significant between-group differences in the clinicopathological features after matching. Compared with the non-MetS group, the MetS group had a shorter OS (P = 0.027); however, there was no significant between-group difference in postoperative complications. Multivariate analysis revealed that MetS (hazard ratio [HR] = 1.997, P = 0.042), tumor-node-metastasis stage (HR = 2.422, P = 0.003), and intestinal obstruction (HR = 2.761, P = 0.010) were independent risk factors for OS. Conclusions: MetS affects the long-term survival of patients with CRC without affecting postoperative complications.

Preliminary clinical study of personalized neoantigen vaccine therapy for microsatellite stability (MSS)-advanced colorectal cancer.

Immunotherapy based on immune checkpoint inhibitors (ICIs) has provided revolutionary results in treating various cancers. However, its efficacy in colorectal cancer (CRC), especially in microsatellite stability-CRC, is limited. This study aimed to observe the efficacy of personalized neoantigen vaccine in treating MSS-CRC patients with recurrence or metastasis after surgery and chemotherapy. Candidate neoantigens were analyzed from whole-exome and RNA sequencing of tumor tissues. The safety and immune response were assessed through adverse events and ELISpot. The clinical response was evaluated by progression-free survival (PFS), imaging examination, clinical tumor marker detection, circulating tumor DNA (ctDNA) sequencing. Changes in health-related quality of life were measured by the FACT-C scale. A total of six MSS-CRC patients with recurrence or metastasis after surgery and chemotherapy were administered with personalized neoantigen vaccines. Neoantigen-specific immune response was observed in 66.67% of the vaccinated patients. Four patients remained progression-free up to the completion of clinical trial. They also had a significantly longer progression-free survival time than the other two patients without neoantigen-specific immune response (19 vs. 11 months). Changes in health-related quality of life improved for almost all patients after the vaccine treatment. Our results shown that personalized neoantigen vaccine therapy is likely to be a safe, feasible and effective strategy for MSS-CRC patients with postoperative recurrence or metastasis.

Construction of a metabolism-related gene prognostic model to predict survival of pancreatic cancer patients.

Pancreatic cancer (PC) is one of the most fatal malignant tumors, and is commonly diagnosed at an advanced stage with no effective therapy. Metabolism-related genes (MRGs) and immune-related genes (IRGs) play considerable roles in the tumor microenvironment. Therefore, an effective prediction model based on MRGs and IRGs could aid in the prognosis of PC. In this study, differential expression analysis was performed to gain 25 intersectional genes from 857 differentially expressed MRGs (DEMRGs), and 1353 differentially expressed IRGs, from The Cancer Genome Atlas database of PC. Cox and Lasso regression were applied and a five-DEMRGs prognostic model constructed. Survival analysis, ROC values, risk curve and validation analysis showed that the model could independently predict PC prognosis. In addition, the correlation analysis suggested that the five-DEMRGs prognostic model could reflect the status of the immune microenvironment, including Tregs, M1 macrophages and Mast cell resting. Therefore, our study provides new underlying predictive biomarkers and associated immunotherapy targets.

Human cytomegalovirus-induced immune regulation is correlated with poor prognosis in patients with colorectal cancer.

Evidence suggests that human cytomegalovirus (HCMV) infection may be implicated in the progression of colorectal cancer (CRC). However, the correlation between HCMV infection and survival outcomes in patients with CRC remains unclear. Here, we constructed a flow algorithm to identify HCMV sequences based on the RNA-seq data of patients with CRC derived from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The patients' clinical information matrix was used to calculate the Euclidean distance to filter out suitable patients not infected with HCMV, combined with patients' survival outcomes, to reveal how HCMV infection is involved in CRC progression. HCMV infection is widespread in patients with CRC, and the prevalence of HCMV infection ranges from 10 to 36% in four independent CRC datasets, with infection being concentrated in carcinoma tissue rather than in normal tissue. In addition, HCMV-positive patients had a poor survival prognosis, with three HCMV genes, UL82, UL42, and UL117, associated with poor patient survival outcomes. Most importantly, we suppose that the regulation of immune function by HCMV may be key to the poor prognosis of patients with CRC. We found that HCMV infection was associated with poor prognosis in CRC patients and identified three prognosis-associated HCMV genes. The regulation of immune function caused by HCMV infection was the key factor, while HCMV-positive patients with CRC mostly presented with a state of immunosuppression. This may provide new ideas for the personalized treatment of patients with CRC, especially with respect to immunotherapy.

Correction: Ciclopirox activates PERK-dependent endoplasmic reticulum stress to drive cell death in colorectal cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Ciclopirox activates PERK-dependent endoplasmic reticulum stress to drive cell death in colorectal cancer.

Ciclopirox (CPX) modulates multiple cellular pathways involved in the growth of a variety of tumor cell types. However, the effects of CPX on colorectal cancer (CRC) and the underlying mechanisms for its antitumor activity remain unclear. Herein, we report that CPX exhibited strong antitumorigenic properties in CRC by inducing cell cycle arrest, repressing cell migration, and invasion by affecting N-cadherin, Snail, E-cadherin, MMP-2, and MMP-9 expression, and disruption of cellular bioenergetics contributed to CPX-associated inhibition of cell growth, migration, and invasion. Interestingly, CPX-induced reactive oxygen species (ROS) production and impaired mitochondrial respiration, whereas the capacity of glycolysis was increased. CPX (20 mg/kg, intraperitoneally) substantially inhibited CRC xenograft growth in vivo. Mechanistic studies revealed that the antitumor activity of CPX relies on apoptosis induced by ROS-mediated endoplasmic reticulum (ER) stress in both 5-FU-sensitive and -resistant CRC cells. Our data reveal a novel mechanism for CPX through the disruption of cellular bioenergetics and activating protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent ER stress to drive cell death and overcome drug resistance in CRC, indicating that CPX could potentially be a novel chemotherapeutic for the treatment of CRC.

RKI-1447 suppresses colorectal carcinoma cell growth via disrupting cellular bioenergetics and mitochondrial dynamics.

Accumulated evidence suggested the importance of the Rho/Rho-kinase (ROCK) signaling pathway in cancer proliferation and invasion. However, its role in colorectal carcinoma (CRC) is not well understood. This study evaluated the effect of ROCK signaling pathway on CRC behavior on the basis of a novel Rho/ROCK inhibitor RKI-1447. Here, we found RKI-1447 could drastically suppress HCT-8 and HCT-116 cell growth and promoted apoptosis. Our in vitro data indicated suppressed cytoskeletal dynamics induced by RKI-1447 inhibition on mitochondrial respiration, which was evidenced by basal and maximal respiration rates, and ATP production. Simultaneously, cellular basal and maximal glycolytic rates, and glycolytic capacity were also reduced in response to RKI-1447. Moreover, RKI-1447 caused excessive reactive oxygen species generation and membrane depolarization as well as activated ER-stress. We also demonstrated CHOP is essential for RKI-1447 induced cell apoptosis. Finally, we proved inhibition of ROCK by RKI-1447 could effectively inhibit CRC growth in vivo. Taken together, this study demonstrated that inhibition of ROCK signaling pathway by RKI-1447 could suppress CRC via cytoskeleton associated mitochondrial dysfunction and cellular bioenergetics disruption. Our data suggest RKI-1447 may be an attractive antitumor drug candidate for the treatment of CRC.

Controlling Nutritional Status (CONUT) Score Is A Predictor Of Post-Operative Outcomes In Elderly Gastric Cancer Patients Undergoing Curative Gastrectomy: A Prospective Study.

PURPOSE: The Controlling Nutritional Status (CONUT) score is a recently developed measure that is calculated using the serum albumin level, total cholesterol level, and lymphocyte counts. The aim of this study was to examine whether the CONUT score can predict post-operative outcomes in elderly patients undergoing curative gastrectomy. PATIENTS AND METHODS: Pre-operative CONUT scores were evaluated from August 2014 to September 2016 in 357 gastric cancer patients who were scheduled to undergo curative gastrectomy. The patients were divided into three groups according to pre-operative CONUT scores: normal, light, moderate, and severe. We then calculated the association between the patient's CONUT score and post-operative complications. RESULTS: CONUT scores were statistically associated with age (P = 0.015), body mass index (P < 0.001), pre-operative hemoglobin level (P < 0.001), tumor-node-metastasis stage (P < 0.001), surgical method (P = 0.036), and post-operative complications (P < 0.001). Multivariate analysis showed that age and the CONUT score were independent predictors of post-operative complications and 1-year survival. CONCLUSION: CONUT scores can be used to predict post-operative complications and 1-year survival in elderly gastric cancer patients undergoing curative gastrectomy. They can also be used to classify the nutritional status of patients, which can be helpful for pre-and post-operative nutritional management.

An iron incorporation-induced nickel hydroxide multiphase with a 2D/3D hierarchical sheet-on-sheet structure for electrocatalytic water oxidation.

An Fe-incorporated Ni(OH)2 multiphase with a unique 2D/3D hierarchical sheet-on-sheet structure exhibits superior catalytic activity and durability for water oxidation, which is contributed by synergistic effects, enhanced electron transport and an increased number of exposed active sites.

Nrf2-miR-129-3p-mTOR Axis Controls an miRNA Regulatory Network Involved in HDACi-Induced Autophagy.

Histone deacetylase inhibitors (HDACis) are the recommended treatment for many solid tumors; however, resistance is a major clinical obstacle for their efficacy. High levels of the transcription factor nuclear factor erythroid 2 like-2 (Nrf2) in cancer cells suggest a vital role in chemoresistance, and regulation of autophagy is one mechanism by which Nrf2 mediates chemoresistance. Although the molecular mechanisms underlying this activity are unclear, understanding them may ultimately improve therapeutic outcomes following HDACi treatment. In this study, we found that HDACi treatment increased Nrf2 mRNA and protein levels and enhanced Nrf2 transcriptional activity. Conversely, Nrf2 knockdown or inhibition blocked HDACi-induced autophagy. In addition, a microRNA (miRNA) array identified upregulation of miR-129-3p in response to Nrf2 overexpression. Chromatin immunoprecipitation assays confirmed miR-129-3p to be a direct Nrf2 target. RepTar and RNAhybrid databases indicated mammalian target of rapamycin (mTOR) as a potential miR-129-3p target, which we experimentally confirmed. Finally, Nrf2 inhibition or miR-129-3p in combination with HDACis increased cell death in vitro and in vivo. Collectively, these results demonstrated that Nrf2 regulates mTOR during HDACi-induced autophagy through miRNA-129-3p and inhibition of this pathway could enhance HDACi-mediated cell death.

Morphology and electronic structure modulation induced by fluorine doping in nickel-based heterostructures for robust bifunctional electrocatalysis.

Fabrication of advanced electrocatalysts with high activity and durability is urgently needed to achieve energy conversion and pollution treatment at the same time. Herein, we highlight a fluorine-doped nickel-based heterostructure, in which fluorine doping displays a dual effect in Ni(OH)2 nanosheets/Ni3S2 heteronanorods. On the one hand, fluorine doping can facilitate the formation of Ni(OH)2 nanosheets/Ni3S2 heteronanorods through one-step in situ growth on nickel foams. The unique heterostructure enables good exposure of abundant active sites and highly active heterointerfaces. On the other hand, the uniform incorporation of fluorine can effectively modulate the electron density at the Fermi level of Ni3S2, contributing to the improved electrical conductivity and charge transfer efficiency, further improving the electrocatalytic activity in the oxygen evolution reaction (OER) and urea oxidation reaction (UOR). The optimal heterostructure presents a low overpotential of 360 mV to reach the OER current density of 100 mA cm-2. Finally, this heterostructure also displays a superior UOR anodic peak current of about 322.9 mA cm-2, almost the highest value at the anodic peak compared to the literature.

The silencing of replication protein A1 induced cell apoptosis via regulating Caspase 3.

AIMS: Gastrointestinal cancers are a kind of deadly malignancy afflicting close to a million peoples worldwide. 5-Fluorouracil (5-Fu) is a main chemotherapeutic agent for cancer treatment. However, prolonged exposure of 5-Fu to cancer cells may cause chemoresistance and decrease the therapeutic potential of 5-Fu. MAIN METHODS: Replication protein A (RPA) is a component of the origin recognition complex. In our study, we explored the role of RPA1 in hepatocellular carcinoma cell SMMC-7721, gastric cancer cell SGC-7901 and colorectal cancer HT-29 via lentiviral particles infection. Flow cytometry assay was used to examine the effect of RPA1 on cell proliferation, cell cycle and apoptosis. Western blot was employed to determine the role of RPA1 on Caspase 3 expression. KEY FINDINGS: Immunohistochemstry results showed that RPA1 was highly expressed in colorectal cancer tissues. Only 5-Fu or the knockdown of RPA1 suppressed cell clone formation, induced cell cycle arrest at the G1 phase and promoted cell apoptosis by regulating the protein level of Caspase 3. And the combination of the application of 5-Fu and RPA1 silencing significantly enhanced the above effects. SIGNIFICANCE: RPA1 serves as an oncogene during gastrointestinal cancers progression. These studies reveal a new target for gastrointestinal cancers therapy, and the combination of 5-Fu and silencing of RPA1 provides a new attractive therapeutic measure for gastrointestinal cancers.

miR-135b-5p promotes gastric cancer progression by targeting CMTM3.

CKLF-like MARVEL transmembrane domain containing 3 (CMTM3) is considered to be a tumor suppressor gene in multiple types of malignancies. Previous studies have indicated that CMTM3 suppresses metastasis and epithelial-mesenchymal transition (EMT) in gastric cancer. However, its role in gastric cancer cell proliferation has rarely been discussed. Moreover, the regulatory mechanisms of CMTM3 in gastric cancer remain unclear. In this study, RT­qPCR and IHC were used to assess the expression of CMTM3 and miR­135b­5p in gastric cancer tissues and cell lines. We found that the expression of miR­135b­5p was negatively associated with CMTM3 in gastric cancer tissues, and we verified that miR­135b­5p directly targeted CMTM3 in gastric cancer cells by dual-luciferase reporter assay. CCK8 assay, Transwell assay and flow cytometric analysis were conducted to examine the functions of CMTM3 and miR­135b­5p in vitro. Our results demonstrated that the overexpression of CMTM3 or the suppression of miR­135b­5p using an inhibitor suppressed SGC­7901 gastric cancer cell proliferation, invasion and cell cycle progression, and promoted SGC­7901 cell apoptosis. Furthermore, a BALB/c nude mouse subcutaneous xenograft model was used to verify the function of miR­135b­5p and CMTM3. Our results revealed that miR­135b­5p inhibitor significantly suppressed SGC­7901 cell tumorigenesis in vivo. In addition, IHC revealed that CMTM3 expression was markedly increased in tumors infected with miR­135b­5p inhibitor lentivirus. On the whole, the findings of the present study suggest that the overexpression of miR­135b­5p inhibits CMTM3 expression, and promotes gastric cancer progression and metastasis. Our findings provide a novel therapeutic target for gastric cancer.

Gossypol induces cell death by activating apoptosis and autophagy in HT-29 cells.

Gossypol is a polyphenolic, yellowish compound derived from cottonseed extract. The present study examined the effects of gossypol on the apoptosis and autophagy of HT­29 cells. A Cell Counting Kit­8 assay, Annexin V­FITC, JC­1 staining and western blotting were used to identify the viability of cells, stages of apoptosis and the expression levels of the signaling proteins. Gossypol promoted apoptosis and induced the loss of mitochondrial membrane potential. Further investigation of the apoptotic mechanism revealed that gossypol increased the ratio of B­cell lymphoma 2 (Bcl-2)-associated X protein/Bcl­2 protein levels and upregulated the expression of caspase­3. Gossypol also enhanced the activity of microtubule­associated protein light chain 3 LC3­II and Beclin­1 and downregulated LC3­I, in a dose­dependent manner. Together, these finding suggested that gossypol may be a novel and potential antitumor agent.

Development of an in vivo visual robot system with a magnetic anchoring mechanism and a lens cleaning mechanism for laparoendoscopic single-site surgery (LESS).

BACKGROUND: Surgical robot systems which can significantly improve surgical procedures have been widely used in laparoendoscopic single-site surgery (LESS). For a relative complex surgical procedure, the development of an in vivo visual robot system for LESS can effectively improve the visualization for surgical robot systems. METHODS: In this work, an in vivo visual robot system with a new mechanism for LESS was investigated. A finite element method (FEM) analysis was carried out to ensure the safety of the in vivo visual robot during the movement, which was the most important concern for surgical purposes. A master-slave control strategy was adopted, in which the control model was established by off-line experiments. RESULTS: The in vivo visual robot system was verified by using a phantom box. The experiment results show that the robot system can successfully realize the expected functionalities and meet the demands of LESS. CONCLUSION: The experiment results indicate that the in vivo visual robot with high manipulability has great potential in clinical application.