PC4 promotes bladder cancer progression and stemness by directly interacting with Sp1 to transcriptionally activate the Wnt5a/ß-catenin pathway.

Bladder cancer is a common malignancy with a poor prognosis worldwide. Positive cofactor 4 (PC4) is widely reported to promote malignant phenotypes in various tumors. Nonetheless, the biological function and mechanism of PC4 in bladder cancer remain unclear. Here, for the first time, we report that PC4 is elevated in bladder cancer and is associated with patient survival. Moreover, PC4 deficiency obviously inhibited bladder cancer cell proliferation and metastasis by reducing the expression of genes related to cancer stemness (CD44, CD47, KLF4 and c-Myc). Through RNA-seq and experimental verification, we found that activation of the Wnt5a/ß-catenin pathway is involved in the malignant function of PC4. Mechanistically, PC4 directly interacts with Sp1 to promote Wnt5a transcription. Thus, our study furthers our understanding of the role of PC4 in cancer stemness regulation and provides a promising strategy for bladder cancer therapy.

MRTO4 Enhances Glycolysis to Facilitate HCC Progression by Inhibiting ALDOB.

BACKGROUND MRT4 Homolog, Ribosome Maturation Factor (MRTO4) is often upregulated in cancer cells. However, its impact in hepatocellular carcinoma (HCC) is less well understood. Herein, we explored the prognostic and energy metabolism reprogramming role of MRTO4 in HCC. MATERIAL AND METHODS Clinical data were obtained from The Cancer Genome Atlas (TCGA), and the expression of MRTO4 in clinical samples was analyzed. The association between different variables and overall survival (OS) was studied, as well as their potential as independent prognostic factors, using Cox regression analysis. We constructed a nomogram including clinical pathological variables and MRTO4 expression to provide a predictive model for prognosis. Heatmaps, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed the relationship between energy metabolism pathways and MRTO4. We used classic molecular biology research methods, including RT-qPCR, Western blotting, CCK8, TUNEL, Clone formation, Transwell assay, ELISA, and immunohistochemistry, to study the role of MRTO4 in promoting the progression of HCC through glycolysis regulation. RESULTS Our study showed that MRTO4 is an independent prognostic risk factor for HCC and that MRTO4 accelerates glycolysis of HCC cells, promotes proliferation and invasion, and suppresses apoptosis of HCC cells. The underlying mechanism involves MRTO4 promoting glycolysis and accelerating HCC by inhibiting ALDOB. CONCLUSIONS Our study revealed a novel mechanism by which MRTO4 promotes glycolysis and accelerates HCC progression, and suggests that inhibiting MRTO4 could be a potential therapeutic strategy for HCC.

Exosomal IGFBP2 derived from highly metastatic promotes hepatocellular carcinoma metastasis by inducing epithelial mesenchymal transition.

Liver cancer metastasis is the main cause of death in liver cancer patients. Exosomes, which are small vesicles released by cancer cells, play a crucial role in the metastasis of cancer. The aim of this study was to investigate the effect of exosomes derived from high metastatic potential liver cancer cells acting as cell to cell communication on liver cancer metastasis. Bioinformatics analysis was used to obtain the differential expression of exosomal mRNAs from the plasma of both liver cancer patients and healthy volunteers. Transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and protein blot were employed to characterize the exosomes. The molecular mechanisms and were explored by conducting CCK8, Transwell, Tunel, RTqPCR, western blot, and immunofluorescence staining. We examined IGFBP2 special expression in the plasma exosomes of both liver cancer patients and healthy volunteers, and its presence was associated with a poor prognosis in liver cancer patients. Furthermore, we observed that exosomes from highly metastatic liver cancer cells (MHCC97H) contained high levels of IGFBP2 and could enhance the metastatic potential of less aggressive liver cancer cells (Hep3B). Additionally, we discovered that IGFBP2 in MHCC97H-derived exosomes activated ERK signaling pathway, which triggered epithelial-mesenchymal transition (EMT) in Hep3B cells. Our study underscores the significance of exosomal IGFBP2 from highly metastatic liver cancer cells as a driver of metastasis in less invasive liver cancer cells. This suggests that targeting IGFBP2 in exosomes could be a promising strategy for the treatment and prognosis of liver cancer patients.

Towards Semi-Autonomous Colon Screening Using an Electromagnetically Actuated Soft-Tethered Colonoscope Based on Visual Servo Control.

OBJECTIVE: Conventional colonoscopy using a flexible colonoscope remains two major limitations, including patient discomfort and difficult manipulations for surgeons. Robotic colonoscopes have been developed to conduct colonoscopy in a patient-friendly manner. However, most robotic colonoscopes still maintain nonintuitive and difficult manipulations, which limits their clinical applications. In this paper, we demonstrated visual servo-based semi-autonomous manipulations of an electromagnetic actuated soft-tethered (EAST) colonoscope, which aims to lower difficulties of robotic colonoscope manipulations. METHODS: Kinematic modeling of EAST colonoscope is conducted, with an adaptive visual servo controller established. Template matching method and a lumen and polyp detection model are developed to enable semi-autonomous manipulations, including region-of-interest automatic tracking and autonomous navigation with automatic polyp detection. RESULTS: The EAST colonoscope demonstrates visual servoing with an average convergence time of around 2.5 s and performs disturbance rejection within 3.0 s. Semi-autonomous manipulations were conducted in both a commercialized colonoscopy simulator and an ex-vivo porcine colon to show the efficacy of reducing the user workload compared to manual control. CONCLUSION: The EAST colonoscope can perform visual servoing and semi-autonomous manipulations with the developed methods in both laboratory and ex-vivo environments. SIGNIFICANCE: The proposed solutions and techniques improve the autonomy level of robotic colonoscopes and reduce user workloads, which promotes the development and clinical translation of robotic colonoscopy.

Overexpression of Lias Gene Alleviates Cadmium-Induced Kidney Injury in Mice Involving Multiple Effects: Metabolism, Oxidative Stress, and Inflammation.

Oxidative stress is an important mechanism underlying toxicity induced by cadmium (Cd) exposure. However, there are significant differences of the antioxidant baseline in different populations. This means that different human has different intensity of oxidative stress in vivo after exposure to toxicants. LiasH/H mouse is a specific model which is created by genetically modifying the Lias 3'-untranslated region (3'-UTR). LiasH/H mice express high levels of LA and have high endogenous antioxidant capacity which is approximately 150% higher than wild-type C57BL/6 J mice (WT, Lias+/+). But more importantly, they have dual roles of metal chelator and antioxidant. Here, we applied this mouse model to evaluate the effect of endogenous antioxidant levels in the body on alleviating Cd-induced renal injury including Cd metabolism, oxidative stress, and inflammation. In the experiment, mice drank water containing Cd (50 mg/L), for 12 weeks. Many biomarkers of Cd metabolism, oxidative stress, inflammation, and major pathological changes in the kidney were examined. The results showed overexpression of the Lias gene decreased Cd burden in the body of mice, mitigated oxidative stress, attenuated the inflammatory response, and subsequent alleviated cadmium-induced kidney injury in mice.

Hyaluronic Acid-Conjugated Fluorescent Probe-Shielded Polydopamine Nanomedicines for Targeted Imaging and Chemotherapy of Bladder Cancer.

Bladder cancer is one of the most common malignancies in the urinary system, with high risk of recurrence and progression. However, the difficulty in detecting small tumor lesions and the lack of selectivity of intravesical treatment seriously affect the prognosis of patients with bladder cancer. In the present work, a nanoparticle-based delivery system with tumor targeting, high biocompatibility, simple preparation, and the ability to synergize imaging and therapy was fabricated. Specifically, this nanosystem consisted of the core of doxorubicin (DOX)-loaded polydopamine nanoparticles (PDD NPs) and the shell of hyaluronic acid (HA)-conjugated IR780 (HA-IR780). The HA-IR780-covered PDD NPs (HR-PDD NPs) demonstrated tumor targeting and visualization both in vitro and in vivo with properties of promoted cancer cell endocytosis and lysosomal escape, efficiently delivering drugs to the target site and exerting a killing effect on tumor cells. Encouragingly, intravesical instillation of HR-PDD NPs improved drug retention in the bladder and promoted its accumulation in tumor tissue, resulting in better tumor proliferation inhibition and apoptosis in an orthotopic bladder cancer model in rats. This study provides a promising strategy for the diagnosis and therapy of bladder cancer.

Intravesical IR-780 instillation prevents radiation cystitis by protecting urothelial integrity.

PURPOSE: To explore an efficient preventive strategy for radiation cystitis. METHODS: We instilled IR-780 into the bladders of rats 1 h before bladder irradiation, and its bio-distribution was observed at different times. Bladders were then examined for pathogenic alterations and inflammation levels by day 3 and week 12 postirradiation, and the functional characteristics of the bladder were tested via cystometry by week 12. Human uroepithelial sv-huc-1 cells were used to determine the effect of IR-780 on cell viability, regardless of irradiation. We measured the intracellular levels of oxidative stress, DNA damage, apoptosis proportion, and the expression of antioxidant proteases and apoptotic caspases in IR-780 pretreated cells after radiation. RESULTS: IR-780 is localized in the urothelium after intravesical instillation in vivo. Ionizing radiation could induce acute impairment of the bladder urothelium and inflammation in the bladder on day 3. Fibrosis of the irradiated bladder progressed and eventually affected voiding function at 12 weeks. Treatment with IR-780 before irradiation ameliorated these changes. In vitro, IR-780 protected against cell viability and apoptosis of sv-huc-1 cells after irradiation. Additionally, IR-780 may assist in eliminating reactive oxygen species and repairing irradiation-induced DNA damage. CONCLUSION: Our data indicate that IR-780 can be used before irradiation to prevent acute urinary mucosal injury and late bladder dysfunction. Moreover, early urothelial impairment plays a significant role in radiation cystitis development.

Hyperbaric oxygen enhanced the chemotherapy of mitochondrial targeting molecule IR-780 in bladder cancer.

BACKGROUND: Bladder cancer has a high rate of recurrence and drug resistance due to the lack of effective therapies. IR-780 iodide, a near-infrared (NIR) mitochondria-targeting fluorescent agent, has been demonstrated to achieve higher selectivity than other drugs in different tumor types and exhibited tumor-killing effects in some cancers. However, this therapeutic strategy is rarely studied in bladder cancer. MATERIAL AND METHODS: The accumulation of IR-780 in bladder cancer was measured by NIR imaging. Human bladder cell lines (T24, 5637, and TCCSUP) were treated with IR-780 or combined IR-780 and hyperbaric oxygen (HBO). Cell viability, cell apoptosis, cellular ATP production, mitochondrial reactive oxygen species (ROS), and plasma membrane potential were detected. Mitochondrial complex I protein NDUFS1 was measured by western blot. To confirm the anti-tumor efficacy of IR-780 + HBO, mouse bladder cell line (MB49) tumor-bearing mice were established and tumor size and weight were recorded. Besides, cell apoptosis and tumor size were assessed in drug-resistant bladder cancer cells (T24/DDP) and xenografts to evaluate the effect of IR-780 + HBO on drug-resistant bladder cancer. RESULTS: IR-780 selectively accumulated in bladder cancer (bladder cancer cells, transplanted tumors, and bladder cancer tissue from patients) and could induce cancer cell apoptosis by targeting the mitochondrial complex I protein NDUFS1. The combination with HBO could significantly enhance the anti-tumor effect of IR-780 in vitro by promoting cancer cell uptake and inducing excessive mitochondrial ROS production, while suppressing tumor growth and recurrence in animal models without causing apparent toxicity. Moreover, this combination antitumor strategy was also demonstrated in drug-resistant bladder cancer cells (T24/DDP) and xenografts. CONCLUSION: We identified for the first time a combination of IR-780 and HBO (IR-780 + HBO), which exhibits mitochondria-targeting and therapeutic capabilities, as a novel treatment paradigm for bladder cancer.

Sulfhydryl functionalized hyaluronic acid hydrogels attenuate cyclophosphamide-induced bladder injury.

Clinical management of cyclophosphamide (CYP) results in numerous side effects including hemorrhagic cystitis (HC), which is characterized by inflammation and oxidative stress damage. Intravesical hyaluronic acid (HA) supplementation, a therapeutic method to restore barrier function of bladder, avoid the stimulation of metabolic toxicants on bladder and reduce inflammatory response, has shown good results in acute or chronic bladder diseases. However, there are unmet medical needs for the treatment of HC to temporarily restore bladder barrier and reduce inflammation. Herein, sulfhydryl functionalized HA (HA-SH) and dimethyl sulfoxide (DMSO) were used to prepared a hydrogel system for optimizing the treatment of HC. We systematically evaluated the physicochemical of hydrogels and their roles in a rat model of CYP-induced HC. The prepared hydrogels exhibited outstanding gel forming properties, injectability, and biosafety. Swelling and retention studies showed that hydrogels were stable and could prolong the residence time of HA in the bladder. Histopathology and vascular permeability studies indicated that the hydrogels significantly attenuated bladder injury caused by CYP administration. Moreover, the hydrogels also showed excellent anti-inflammation and anti-oxidation properties. In conclusion, these data suggest that intravesical instillation of HA-SH/DMSO hydrogels reduces CYP-induced bladder toxicity and this work provides a new strategy for the prevention and early treatment of HC.

Matrine Inhibits Proliferation, Invasion, and Migration and Induces Apoptosis of Colorectal Cancer Cells Via miR-10b/PTEN Pathway.

Background: Colorectal cancer (CRC) is the third most common malignancy worldwide. Matrine can act as a potential antitumor drug, and its antitumor activities have been tested in various cancers, including CRC. However, the effect of matrine and the related mechanisms on CRC cells remains poorly defined. Materials and Methods: CRC cells were treated with different concentrations of matrine, and then MTT, flow cytometric, and transwell assays were used to assess cell proliferation, apoptosis, invasion, and migration. MiR-10b-5p and Phosphatase and tensin homolog (PTEN) expression levels were measured by quantitative real-time polymerase chain reaction and Western blot assay. The binding interaction of miR-10b-5p and PTEN were predicted by TargetScan and verified by a dual-luciferase reporter and RIP assay. The effect of matrine, miR-10b-5p, and PTEN on CRC cell proliferation, apoptosis, migration, and invasion was detected by MTT, flow cytometric, and transwell assays severally. Results: Matrine notably restrained proliferation, invasion, and migration and boosted apoptosis of CRC cells, as well as downregulated miR-10b-5p expression and upregulated PTEN protein level. PTEN was a direct target of miR-10b-5p in CRC cells. MiR-10b-5p knockdown and matrine treatment inhibited cell proliferation, migration, and invasion and induced apoptosis, and reintroduction of si-PTEN partly regained the inhibiting effect. Besides, MiR-10b-5p knockdown and matrine treatment repressed CRC growth in vivo. Conclusion: Matrine could suppress proliferation, migration, and invasion and induce apoptosis of CRC cells via the miR-10b/PTEN pathway, providing the potential molecular mechanism of matrine in blocking CRC progression.

MiR-200a-3p promotes gastric cancer progression by targeting DLC-1.

Gastric cancer (GC) is one of the most common malignancies, ranking the third highest mortality rate worldwide. Due to the insidious symptoms and difficulty in early detection, patients with GS were mostly in the middle and late stages when they were diagnosed. Although ontogenetic or tumor-suppressive effects of miRNA-200a-3p have been demonstrated, the exact mechanism underlying GC is not clear. Therefore, the expression, effect, and mechanism of miRNA-200a-3p in GC progression were systematically investigated in this study. qRT-PCR, Western blotting, and immunohistochemical staining were applied to investigate the miRNA-200a-3p and deleted in liver cancer 1 (DLC-1) expression. Cell viability, proliferation, apoptosis, migration, and invasion capabilities of GC cells were assessed using cell counting kit-8 (CCK-8) colorimetry, EdU integration, flow cytometry, wound healing, and the transwell assay. The relationship between miRNA-200a-3p and tumor growth was investigated by tumor xenograft assay in vivo. A dual-luciferase reporter assay was estimated to verify the connection between miR-200-3p and DLC-1. The results showed that miRNA-200a-3p expression was significantly increased in both GC tissues and cells. Furthermore, via DLC-1, miRNA-200a-3p promotes tumor growth and development. miRNA-200a-3p, by targeting DLC-1, can function as an oncogene in GC cells. Collectively, our findings indicated that the miRNA-200a-3p/DLC axis might provide a theological basis for potential improvements in GC treatment strategies.

MiR-200c-3p aggravates gastric cell carcinoma via KLF6.

BACKGROUND: Gastric cell carcinoma (GCC) is a common and high-incidence malignant gastrointestinal cancer that seriously threatens human life and safety. Evidences suggest that microRNAs (miRNAs) exhibit an essential role in regulating the occurrence and development of GCC, while the effects and possible mechanisms remain to be further explored. OBJECTIVE: This study was designed to explore whether miR-200c-3p exerted its functional role in the growth and metastasis of GCC, and investigate the possible mechanisms. METHODS: The expression levels of miR-200c-3p in GCC tissues and cell lines were detected by qRT-PCR analysis. The functional role of miR-200c-3p in the viability, proliferation, migration and invasion of GCC cells were evaluated by CCK-8, EdU, wound healing and Transwell assays. In addition, the candidate targets of miR-200c-3p was predicted and confirmed by dual-luciferase reporter assay. Moreover, the relationship between miR-200c-3p and target (Krüppel like factor 6, KLF6) was assessed by qRT-PCR and western blot assays. Besides, the expression levels of KLF6 in GCC cells were determined by qRT-PCR and western blot assays. Furthermore, the role of KLF6 in the viability, proliferation, migration and invasion of GCC cells mediated with miR-200c-3p mimics was evaluated by CCK-8, EdU, wound healing and Transwell assays. RESULTS: In the present study, a new tumor promoting function of miR-200c-3p was disclosed in GCC. We found that the expression of miR-200c-3p was obviously increased in clinic GCC tissues and cell lines. In addition, down-regulation of miR-200c-3p suppressed cell viability, proliferation, migration, and invasion in GCC cells. Moreover, KLF6 was verified as a direct target of miR-200c-3p by binding its 3'-UTR. Additionally, KLF6 was remarkably decreased and was negatively associated with the miR-200c-3p expression in GCC cell lines. Furthermore, over-expression of KLF6 retarded the effects of miR-200c-3p on the growth and metastasis of GCC cell lines. CONCLUSIONS: MiR-200c-3p potentially played a tumor-promoting role in the occurrence and development of GCC, which may be achieved by targeting KLF6.

hsa­miR­15a­5p inhibits colon cell carcinoma via targeting CCND1.

Colon carcinoma is one of the most common cancers worldwide. Epidemiological studies have revealed that colon cancer is the third leading cause of cancer­related deaths, which is due to the increased incidence and mortality rates. However, the treatment strategies for colon cancer remain unsatisfactory for patients, especially for those with advanced or recurrent colon cancer. Dysregulated microRNAs (miRNAs) are considered to influence tumor development and metastasis. However, the molecular mechanism through which miRNAs affect cancer progression is not yet completely understood. The aim of the present study was to investigate the expression levels of has­miR­15a­5p and its molecular mechanism in colon cell carcinoma. In the present study, the expression levels of hsa­miR­15a­5p were found to be decreased in colon tumor tissues and cancer cell lines. Hsa­miR­15a­5p overexpression inhibited colon cell proliferation and migration. Mechanistically, the G1/S­specific cyclin­D1 (CCND1) gene was predicted as a target of hsa­miR­15a­5p, as evidenced by bioinformatics and dual­luciferase reporter assay analyses. CCND1 overexpression significantly increased the progression of colon cancer. Furthermore, CCND1 was demonstrated to mediate the effects of hsa­miR­15a­5p on colon cancer cells. The present study demonstrated that hsa­miR­15a­5p alleviated the proliferation, migration and invasion of colon cancer by targeting the CCND1 gene, which represents a potential molecular target for the diagnosis and treatment of colon cancer.

IR-61 Improves Voiding Function via Mitochondrial Protection in Diabetic Rats.

Diabetic bladder dysfunction (DBD) afflicts nearly half of diabetic patients, but effective treatment is lacking. In this study, IR-61, a novel heptamethine cyanine dye with potential antioxidant effects, was investigated to determine whether it can alleviate DBD. Rats were intraperitoneally injected with IR-61 or vehicle after diabetes was induced with streptozotocin. Before evaluating the effects of IR-61 in improving DBD by filling cystometry, we detected its distribution in tissues and subcellular organelles by confocal fluorescence imaging. Near infrared (NIR) imaging showed that IR-61 could accumulate at high levels in the bladders of diabetic rats, and confocal images demonstrated that it was mainly taken up by bladder smooth muscle cells (BSMCs) and localized in mitochondria. Then, filling cystometry illustrated that IR-61 significantly improved the bladder function of diabetic rats. The histomorphometry results showed that IR-61 effectively mitigated the pathological changes in bladder smooth muscle (BSM) in diabetic rats. Furthermore, IR-61 remarkably reduced the number of apoptotic BSMCs and the unfavorable expression of proteins related to the mitochondrial apoptotic pathway (Bcl-2, BAX, Cytochrome C, and cleaved Caspase-9) in diabetic rats. Moreover, the frozen section staining and transmission electron microscopy results proved that IR-61 significantly reduced the reactive oxygen species (ROS) levels and prevented the mitochondrial mass and morphology damage in the BSM of diabetic rats. In addition, IR-61 upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its associated antioxidant proteins in the BSM of diabetic rats. Together, these results indicate that IR-61 can improve the voiding function of rats with DBD by protecting the mitochondria of BSMCs from oxidative stress, which is possibly mediated through the activation of the Nrf2 pathway.

The lncRNA PTTG3P promotes the progression of CRPC via upregulating PTTG1.

BACKGROUND: Overexpression of certain long non-coding RNAs (lncRNAs) promotes the progression of castration-resistant prostate cancer (CRPC). The significance and potential role of the lncRNA designated pituitary tumour-transforming 3, pseudogene (PTTG3P) in CRPC is unknown. METHODS: We detected PTTG3P expression by qPCR. Upregulated PTTG3P expression was performed to explore the role of PTTG3P in PCa cells resistant to ADT (androgen deprivation therapy). The relationship among PTTG3P, mir-146a-3p and PTTG1 were validated by qPCR, western blot and luciferase assay. RESULTS: PTTG3P levels were significantly increased in the androgen-independent PC cell lines, as well as in CRPC tissues compared with those of the androgen-dependent prostate cancer cell line LNCaP and tumour tissues of patients with hormone-naive prostate cancers. Enforced expression of PTTG3P in androgen-deprived LNCaP cells significantly enhanced survival, clonogenicity, and tumorigenicity. Further, PTTG3P acted as a competing endogenous RNA (ceRNA, natural miRNA sponge) to upregulate PTTG1 expression by competing for mir-146a-3p in the progression to CRPC. CONCLUSION: Our findings suggest that PTTG3P promotes the resistance of prostate cancer cells to androgen-deprivation therapy via upregulating PTTG1. PTTG3P may therefore represent a potential target for therapy of CRPC.

Membranous nephropathy and thymoma in a patient with ankylosing spondylitis: A case report.

RATIONALE: We report a rare case with ankylosing spondylitis (AS), thymoma, and membranous glomerulonephritis. The pathogenic mechanisms of these 3 diseases may be associated with each other. Here, we discuss the course of diagnosis and treatment. PATIENT CONCERNS: A 64-year-old woman with bilateral pain of the sacroiliac joints for 10 years and anasarca for 10 days. DIAGNOSES: A diagnosis of AS by HLA-B27 and pelvic X-ray tests, thymoma based on computed tomography and pathological diagnosis, and membranous glomerulonephritis based on renal biopsy. INTERVENTIONS: We administered methylprednisolone 500 mg/d for 3 consecutive days, followed by methylprednisolone 40 mg oral QD, for a month. OUTCOMES: The patient was followed up once a month. In the sixth month, the patient's serum creatinine had decreased to 0.96 mg/dL, urine microalbumin/creatinine decreased to 173.3 mg/g, and albumin had risen to 33.1 g/L. Pain and morning stiffness were relieved, and the Bath Ankylosing Spondylitis Disease Activity Index score dropped to 4.0. LESSONS: Although the causal relationship between AS, thymoma, and membranous nephropathy in this patient still needs to be established, the pathogenesis between the 3 diseases may have some association. In clinical practice, patients with AS need to be screened for tumors and renal complications.

An Accelerated Finite-Time Convergent Neural Network for Visual Servoing of a Flexible Surgical Endoscope With Physical and RCM Constraints.

This article designs and analyzes a recurrent neural network (RNN) for the visual servoing of a flexible surgical endoscope. The flexible surgical endoscope is based on a commercially available UR5 robot with a flexible endoscope attached as an end-effector. Most of the existing visual servo control frameworks of the robotic endoscopes or robot arms have not considered either the physical limits of the robot or the remote center of motion (RCM) constraints (i.e., the fulcrum effect). To tackle this issue, this article first conducts the kinematic modeling of the flexible robotic endoscope to achieve automation by visual servo control. The kinematic modeling results in a quadratic programming (QP) framework with physical limits and RCM constraints involved, making the UR5 robot applicable to surgical field. To solve the QP problem and accomplish the visual task, an RNN activated by a sign-bi-power activation function (AF) is proposed. The motivation of using the sign-bi-power AF is to enable the RNN to exhibit an accelerated finite-time convergence, which is more preferred in time-critical applications. Theoretically, the finite-time convergence of the RNN is rigorously proved using the Lyapunov theory. Compared with the previous AFs applied to the RNN, theoretical analysis shows that the RNN activated by the sign-bi-power AF delivers an accelerated convergence speed. Comparative validations are performed, showing that the proposed finite-time convergent neural network is effective to achieve visual servoing of the flexible endoscope with physical limits and RCM constraints handled simultaneously.

Elevated Expression of NOTCH1 Associates with Lymph Node Metastasis of Gastric Cancer and Knock-Down of NOTCH1 Attenuates Tumor Cell Progression.

BACKGROUND Gastric cancer is the third leading cause of cancer-related death, while its molecular mechanism has not been fully clarified. This study aims to explore the role of Notch signaling in the pathogenesis of gastric cancer. MATERIAL AND METHODS A total of 64 patients with gastric cancer were enrolled. The expressions of NOTCH1 in tumor tissues and adjacent non-tumor tissues were detected by immunohistochemistry staining. The correlation between NOTCH1 expression and clinicopathological features of patients was analyzed. NOTCH1 was knocked down in gastric cancer cells. The effects of NOTCH1 blockade on cell proliferation, migration and cell cycle distribution were analyzed. The expressions of ERK1/2 and phospho-ERK1/2 (p-ERK1/2) were detected using western blotting. RESULTS Gastric cancer tissues expressed higher level of NOTCH1 than adjacent non-tumor tissues (P<0.05). The high level of NOTCH1 was found to be correlated with gender (male) and lymph node metastasis. However, the expression level of NOTCH1 did not affect the overall survival of patients with gastric cancer. NOTCH1 knock-down repressed the migration and proliferation of gastric cancer cells. Moreover, the cell cycle was arrested at G0/G1 phase by NOTCH1 blockade. The expressions of ERK1/2 and p-ERK1/2 decreased with NOTCH1 knock-down. Further inhibition of ERK1/2 signaling by a MEK1/2 inhibitor U0126 reduced the proliferation of AGS cells, which aggravated the inhibition effect of NOTCH1 knock-down on cell proliferation. CONCLUSIONS NOTCH1 may play an oncogenic role in gastric cancer. Inhibition of NOTCH1 can efficiently attenuate gastric cancer cell progression, probably in part through cross-talking with ERK1/2 signaling pathway.

Simultaneous Measurement of Neuronal Activity in the Pontine Micturition Center and Cystometry in Freely Moving Mice.

Understanding the complex neural mechanisms controlling urinary bladder activity is an extremely important topic in both neuroscience and urology. Simultaneously recording of the bladder activity and neural activity in related brain regions will largely advance this field. However, such recording approach has long been restricted to anesthetized animals, whose bladder function and urodynamic properties are largely affected by anesthetics. In our recent report, we found that it is feasible to record bladder pressure (cystometry) and the related cortical neuron activity simultaneously in freely moving mice. Here, we aimed to demonstrate the use of this combined method in freely moving mice for recording the activity of the pontine micturition center (PMC), a more difficultly approachable small region deeply located in the brainstem and a more popularly studied hub for controlling bladder function. Interestingly, we found that the duration of urination events linearly correlated to the time course of neuronal activity in the PMC. We observed that the activities of PMC neurons highly correlated with spike-like increases in bladder pressure, reflecting bladder contractions. We also found that anesthesia evoked prominent changes in the dynamics of the Ca2+ signals in the PMC during the bladder contraction and even induced the dripping overflow incontinence due to suppression of the neural activity in the PMC. In addition, we described in details both the system for cystometry in freely moving mice and the protocols for how to perform this combined method. Therefore, this work provides a powerful approach that enables the simultaneous measurement of neuronal activity of the PMC or any other brain sites and bladder function in freely behaving mice. This approach offers a promising possibility to examine the neural mechanisms underlying neurogenic bladder dysfunction.

The human positive cofactor 4 promotes androgen-independent prostate cancer development and progression through HIF-1α/ß-catenin pathway.

Androgen-dependent prostate cancer (ADPC) eventually progresses to androgen-independent prostate cancer (AIPC), that has a poor prognosis owing to its unclear mechanism and lack of effective therapeutic targets. The human positive cofactor 4 (PC4) is a transcriptional cofactor, and plays a potential role in cancer development. However, the significance and mechanism of PC4 in AIPC progression are unclear. By analyzing the clinical data, we find that PC4 is overexpressed in prostate cancer and closely correlated with the progression, metastasis and prognosis of patients. Additionally, PC4 is significantly upregulated in AIPC cells compared with ADPC cells, implying its importance in the development and progression of AIPC. Then, in vivo and in vitro studies reveal that loss of PC4 inhibits cell growth by suppressing c-Myc/P21 pathway and inducing cell cycle arrest at G1/S phase transition in AIPC. PC4 knockdown also attenuates EMT-mediated metastasis in AIPC. Moreover, for the first time, we find that PC4 exerts its oncogenic functions by promoting the expression of HIF-1α and activating ß-catenin signaling. Therefore, our findings determine the signatures and molecular mechanisms of PC4 in AIPC, and indicate that PC4 might be a promising therapeutic target for AIPC.