Reprogrammable and reconfigurable mechanical computing metastructures with stable and high-density memory.

Mechanical computing encodes information in deformed states of mechanical systems, such as multistable structures. However, achieving stable mechanical memory in most multistable systems remains challenging and often limited to binary information. Here, we report leveraging coupling kinematic bifurcation in rigid cube-based mechanisms with elasticity to create transformable, multistable mechanical computing metastructures with stable, high-density mechanical memory. Simply stretching the planar metastructure forms a multistable corrugated platform. It allows for independent mechanical or magnetic actuation of individual bistable element, serving as pop-up voxels for display or binary units for various tasks such as information writing, erasing, reading, encryption, and mechanologic computing. Releasing the pre-stretched strain stabilizes the prescribed information, resistant to external mechanical or magnetic perturbations, whereas re-stretching enables editable mechanical memory, akin to selective zones or disk formatting for information erasure and rewriting. Moreover, the platform can be reprogrammed and transformed into a multilayer configuration to achieve high-density memory.

Fully 3D-Printed Miniature Soft Hydraulic Actuators with Shape Memory Effect for Morphing and Manipulation.

Miniature shape-morphing soft actuators driven by external stimuli and fluidic pressure hold great promise in morphing matter and small-scale soft robotics. However, it remains challenging to achieve both rich shape morphing and shape locking in a fast and controlled way due to the limitations of actuation reversibility and fabrication. Here, fully 3D-printed, sub-millimeter thin-plate-like miniature soft hydraulic actuators with shape memory effect (SME) for programable fast shape morphing and shape locking, are reported. It combines commercial high-resolution multi-material 3D printing of stiff shape memory polymers (SMPs) and soft elastomers and direct printing of microfluidic channels and 2D/3D channel networks embedded in elastomers in a single print run. Leveraging spatial patterning of hybrid compositions and expansion heterogeneity of microfluidic channel networks for versatile hydraulically actuated shape morphing, including circular, wavy, helical, saddle, and warping shapes with various curvatures, are demonstrated. The morphed shapes can be temporarily locked and recover to their original planar forms repeatedly by activating SME of the SMPs. Utilizing the fast shape morphing and locking in the miniature actuators, their potential applications in non-invasive manipulation of small-scale objects and fragile living organisms, multimodal entanglement grasping, and energy-saving manipulators, are demonstrated.

Defected twisted ring topology for autonomous periodic flip-spin-orbit soft robot.

Periodic spin-orbit motion is ubiquitous in nature, observed from electrons orbiting nuclei to spinning planets orbiting the Sun. Achieving autonomous periodic orbiting motions, along circular and noncircular paths, in soft mobile robotics is crucial for adaptive and intelligent exploration of unknown environments-a grand challenge yet to be accomplished. Here, we report leveraging a closed-loop twisted ring topology with a defect for an autonomous soft robot capable of achieving periodic spin-orbiting motions with programmed circular and re-programmed irregular-shaped trajectories. Constructed by bonding a twisted liquid crystal elastomer ribbon into a closed-loop ring topology, the robot exhibits three coupled periodic self-motions in response to constant temperature or constant light sources: inside-out flipping, self-spinning around the ring center, and self-orbiting around a point outside the ring. The coupled spinning and orbiting motions share the same direction and period. The spinning or orbiting direction depends on the twisting chirality, while the orbital radius and period are determined by the twisted ring geometry and thermal actuation. The flip-spin and orbiting motions arise from the twisted ring topology and a bonding site defect that breaks the force symmetry, respectively. By utilizing the twisting-encoded autonomous flip-spin-orbit motions, we showcase the robot's potential for intelligently mapping the geometric boundaries of unknown confined spaces, including convex shapes like circles, squares, triangles, and pentagons and concaves shapes with multi-robots, as well as health monitoring of unknown confined spaces with boundary damages.

Physically intelligent autonomous soft robotic maze escaper.

Autonomous maze navigation is appealing yet challenging in soft robotics for exploring priori unknown unstructured environments, as it often requires human-like brain that integrates onboard power, sensors, and control for computational intelligence. Here, we report harnessing both geometric and materials intelligence in liquid crystal elastomer-based self-rolling robots for autonomous escaping from complex multichannel mazes without the need for human-like brain. The soft robot powered by environmental thermal energy has asymmetric geometry with hybrid twisted and helical shapes on two ends. Such geometric asymmetry enables built-in active and sustained self-turning capabilities, unlike its symmetric counterparts in either twisted or helical shapes that only demonstrate transient self-turning through untwisting. Combining self-snapping for motion reflection, it shows unique curved zigzag paths to avoid entrapment in its counterparts, which allows for successful self-escaping from various challenging mazes, including mazes on granular terrains, mazes with narrow gaps, and even mazes with in situ changing layouts.

Blue laser imaging combined with JNET (Japan NBI Expert Team) classification for pathological prediction of colorectal laterally spreading tumors.

BACKGROUND: Blue laser imaging (BLI) can provide useful information on colorectal laterally spreading tumors (LSTs) by visualizing the surface and vessel patterns in detail. The present research aimed to evaluate the diagnostic performance of BLI-combined JNET (Japan NBI Expert Team) classification for identifying LSTs. METHODS: This retrospective, multicenter study included 172 LSTs consisted of 6 hyperplastic polyps/sessile serrated polyps, 94 low-grade dysplasias (LGD), 60 high-grade dysplasias (HGD), 6 superficial submucosal invasive (m-SMs) carcinomas, and 4 deep submucosal invasive carcinomas. The relationship between the JNET classification and the histologic findings of these lesions were then analyzed. RESULTS: For all LSTs, non-experts and experts had a 79.7% and 90.7% accuracy for Type 2A (P = 0.004), a sensitivity of 94.7% and 96.8% (P = 0.718), and a specificity of 61.5% and 83.3% (P = 0.002) for prediction of LGD, respectively. The results also demonstrated 80.8% and 91.3% accuracy for Type 2B (P = 0.005), a sensitivity of 65.2% and 83.3% (P = 0.017), and a specificity of 90.6% and 96.2% (P = 0.097) for predicting HGD or m-SMs. For LST-granular (LST-G) lesions, Type 2A in experts had higher specificity (65.6% vs. 83.6%, P = 0.022) and accuracy (81.8% vs. 91.2%, P = 0.022). Type 2B in experts only had higher accuracy (82.5% vs. 92.0%, P = 0.019). However, no significant differences were noted for any comparisons between non-experts and experts for LST-non-granular (LST-NG) lesions. CONCLUSIONS: BLI combined with JNET classification was an effective method for the precise prediction of pathological diagnosis in patients with LSTs. Diagnostic performance of JNET classification by experts was better than that by non-experts for all examined LST or LST-G lesions when delineating between Type 2A and 2B, but there was no difference for the identification of LST-NG lesions by these two groups.

Snail/FOXK1/Cyr61 Signaling Axis Regulates the Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer.

BACKGROUND/AIMS: Metastasis is the primary cause of colorectal cancer (CRC)-related death. However, the molecular mechanisms underlying metastasis in CRC remain unclear. METHODS: We evaluated mRNA and protein expression levels by quantitative real-time reverse transcription PCR, western blotting, immunofluorescence, tissue microarrays, and immunohistochemistry assays. We also assessed the migration and invasion abilities of CRC cells in vitro by wound healing assays, invasion and migration assays, western blot analysis, and immunofluorescence. Tumor metastasis was evaluated in nude mice in vivo. RESULTS: A positive correlation was observed between the expression patterns of Forkhead box k1 (FOXK1) and Snail in CRC. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that Snail directly bound to and activated the human FOXK1 gene promoter. Moreover, the Snail-FOXK1 axis promote epithelial mesenchymal transition (EMT)-mediated CRC cell invasion and metastasis. FOXK1 and Snail expression levels were correlated with tumor progression and served as significant predictors of overall survival in patients with CRC. Furthermore, overexpression of FOXK1 induced the EMT by upregulating the expression of cysteine-rich angiogenic inducer 61 (Cyr61). Luciferase assays showed that Cyr61 was a direct transcriptional target of FOXK1. Down regulation of Cyr61 decreased FOXK1-enhanced "CRC cell" migration, invasion, and metastasis. Additionally, FOXK1 expression was positively correlated with Cyr61 expression and was associated with poor prognosis. CONCLUSIONS: The Snail/FOXK1/Cyr61 signaling axis regulates the EMT and metastasis of CRC.

Endoscopic mucosa-sparing lateral dissection for treatment of gastric submucosal tumors: a prospective cohort study.

BACKGROUND: In our previous work, we developed a modified method for the removal of gastric submucosal tumors (SMTs), called endoscopic mucosa-sparing lateral dissection (EMSLD). This prospective study aimed to evaluate the efficacy and postoperative outcomes of EMSLD. METHODS: We prospectively enrolled 25 consecutive patients with gastric SMTs, who received EMSLD treatment. Clinicopathological characteristics and operation-related outcomes were analyzed. RESULTS: The mean age of patients was 49.3 ±â€Š9.7 years, and the mean tumor size was 14.6 ±â€Š6.1 mm. En bloc resection was achieved in all cases. The mean procedure time was 47.3 ± 25.9 minutes, and the estimated blood loss was 4.8 ±â€Š3.5 mL. Endoscopic full-thickness resection was performed in six patients (24 %) because the tumors originated from the deep muscularis propria layer. All perforations and resection defects were successfully closed by the retained mucosa and endoclips. No serious complications related to EMSLD were encountered during or after the procedure. CONCLUSIONS: EMSLD was reliable and effective for the removal of gastric SMTs. However, large-scale randomized controlled trials are needed.

Submucosal Tunnel Endoscopic Resection for Esophageal Submucosal Tumors: A Multicenter Study.

BACKGROUND: Submucosal tumors (SMTs) are primarily benign tumors, but some may have a malignant potential. Endoscopic submucosal dissection that has been used for removing esophageal SMTs could cause perforation. Submucosal tunnel endoscopic resection (STER) is an improved and an effective technique for treating esophageal SMTs. AIMS: This study was conducted to evaluate the efficacy and safety of STER for treating esophageal SMTs. METHODS: A retrospective study design was adopted to analyze the baseline characteristics, clinical outcomes, and follow-up data of patients with esophageal SMTs, which originated from the muscularis propria layer and were treated with STER from September 2011 to May 2018. RESULTS: A total of 119 lesions were included from 115 patients who were successfully treated with STER. The mean age of the patients was 49.7 ± 10.7 years. The lesions were primarily located in the middle and lower esophagus. The mean size of the lesions was 19.4 ± 10.0 mm. The mean operation duration was 46.7 ± 25.6 min, and the mean duration of hospitalization was 5.9 ± 2.8 days. The total en bloc resection rate and the complete resection rate were 97.5% and 100%, respectively. Regarding complications, there were 9 (7.8%) cases of perforation, 2 (1.7%) cases of pneumothorax, and 9 (7.8%) cases of subcutaneous emphysema. Histopathological results revealed 113 (95.0%) cases of leiomyoma, 5 (4.2%) cases of gastrointestinal stromal tumors, and 1 (0.8%) case of a granular cell tumor. During the mean 15-month follow-up, there were no cases of recurrence and distant metastasis. CONCLUSIONS: STER is a safe and feasible technique for treating esophageal SMTs originating from the muscularis propria layer.

Comparison of endoscopic submucosal tunneling dissection and thoracoscopic enucleation for the treatment of esophageal submucosal tumors.

BACKGROUND AND AIMS: Endoscopic submucosal tunneling dissection (ESTD) has been proved to be safe and effective for removal of esophageal submucosal tumors (SMTs) and can maintain the mucosal integrity compared with other endoscopic methods. The aim of the study was to estimate the safety and efficacy of ESTD as well as compare its efficacy with thoracoscopic enucleation for esophageal SMTs, which is used increasingly as a minimally invasive approach. METHODS: We retrospectively collected the clinical data of patients with esophageal SMTs <40 mm who underwent ESTD or thoracoscopic enucleation at Nanfang Hospital between January 2008 and August 2016. Epidemiologic data (sex, age), tumor location, tumor size, en bloc resection rate, adverse events, pathologic results, length of postoperative hospital stay, and cost were compared between ESTD and thoracoscopic enucleation. RESULTS: A total of 126 patients were included. A total of 74 patients underwent ESTD, and the other 52 underwent thoracoscopic enucleation. There was no significant difference between the 2 groups in sex, age, tumor size, hospitalization expense, infection, adverse events, and en bloc resection rate (P < .05). However, patients in the ESTD group had a shorter operating time, less estimated blood loss, shorter length of postoperative hospital stay, and lower chest pain level (P < .05). Kaplan-Meier curves for disease-free survival also showed no statistically significant difference between ESTD and thoracoscopic enucleation groups during the median follow-up of 19.5 and 42 months, respectively. CONCLUSIONS: The treatment efficacy was comparable between the ESTD and thoracoscopic enucleation for esophageal SMTs <40 mm. However, there was a significant advantage in the ESTD group for a shorter operating time, reduced postoperative chest pain, and shorter hospitalization.

CD24 promoted cancer cell angiogenesis via Hsp90-mediated STAT3/VEGF signaling pathway in colorectal cancer.

CD24 is involved in tumor progression of various cancers, but the effects of CD24 on tumor angiogenesis in colorectal cancer are still unknown. We aimed to investigate the underlying mechanism and role of CD24 on colorectal cancer (CRC) angiogenesis. Our data showed that the microvessal density (MVD) was related to the expression of CD24 in primary and metastasis CRC. Silencing of CD24 could dramatically decrease human umbilical vein endothelial cell (HUVEC) migration, invasion and tubule formation, but trivially affected cell proliferation. We also mechanically showed that silencing CD24 could downregulate the expression of VEGF via inhibiting the phosphorylation and translocation of STAT3. Moreover, Hsp90 was identified as the down-interaction protein of CD24 with co-immunoprecipitation assay and systematic mass spectrometry. Immunofluorescence results showed Hsp90 partly co-localized with CD24 in CRC cell membrane and there was a positive correlation between CD24 and Hsp90 expression in CRC tissues. We gradually evidenced that Hsp90 modulated the stability and degradation of CD24 in a proteasome-depended manner, and transferred the signal transmission from CD24 to STAT3. 17-AAG, a specific Hsp90, could abrogate the CD24 induce- HUVEC migration, invasion and tubule formation in vitro and in vivo. Collectively, our results suggested that CD24 induced CRC angiogenesis in Hsp90-dependent manner and activated STAT3-mediated transcription of VEGF. We provided a new insight into the regulation mechanism of tumor angiogenesis by exploring the role of CD24 in angiogenesis.

Co-expression of XIAP and cyclin D1 complex correlates with a poor prognosis in patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Despite improved diagnosis and treatment, the prognosis for HCC patients remains poor. The goal of this study was to identify key regulatory proteins and signaling pathways important for cell apoptosis and proliferation as biomarkers for prognostication and targeted therapy. Protein Pathway Array was applied to screen 38 signaling proteins and phosphoproteins in 12 paired HCC tumors and surrounding benign tissues and found that 20 of them, including XIAP, CDK4, CDK6, and Cyclin D1, were overexpressed in HCC tissues. Immunostaining results of XIAP, CDK4, and Cyclin D1 in an additional 59 HCC tissues showed that the expression of XIAP correlated with the expression of CDK4/Cyclin D1, and that the increased expression of these proteins correlated with poor overall survival in these patients. Further studies using the HCC Huh7 cell line transfected with XIAP siRNA or expression vector demonstrated that XIAP regulated the expression of CDK4, CDK6, and Cyclin D1 via NF-êB and PTEN pathways. Finally, inhibition of XIAP using embelin, a XIAP-specific small molecule, leads to an increased apoptosis and decreased cell proliferation via arrest at G1 phase. Taken together, XIAP is a central modulator regulating cell apoptosis and cell cycle progression. Therefore, XIAP together with cell cycle regulatory proteins can be used as prognostic markers and therapeutic targets.

PAK1-dependent MAPK pathway activation is required for colorectal cancer cell proliferation.

P21-activated protein kinase1 (PAK1), a main downstream effector of small Rho GTPases, Rac1, and Cdc42, plays an important role in the regulation of cell morphogenesis, motility, mitosis, and angiogenesis. Despite its importance, the molecular mechanisms of PAK1 that contributed to colorectal carcinogenesis remain unclear. Our immunohistochemistry showed that PAK1 expression was increased with colorectal cancer (CRC) progression through the adenoma to carcinoma sequence. Furthermore, our results suggested a relationship between PAK1 nuclear localization and the Dukes staging. In the present study, we showed that PAK1 knockdown decreased proliferation and delayed the G1/S cell-cycle transition, and increased apoptosis in vivo and in vitro. In addition, PAK1 knock-down downregulated c-Jun amino terminal kinases (JNK) activity and the levels of cyclinD1, CDK4/6. Inhibition of the JNK activity by chemical inhibitor (SP600125) significantly reduced the effects of PAK1 on CRC proliferation via accumulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). In conclusion, our results demonstrate that knockdown of PAK1 could enhance the chemosensitivity of CRCs to 5-fluorouracil through G1 arrest. The mechanism by which PAK1 induced cancer growth might involve activation of JNK as well as downregulation of PTEN. Targeting PAK1 may represent a novel treatment strategy for developing novel chemotherapeutic agents.

[Changes in the biological behaviors of colon cancer cells under simulated hypoxia in vitro].

OBJECTIVE: To investigate the reactivity of colon cancer cell line SW480 and CD133(+) SW480 subsets to hypoxia in vitro and the changes in the expressions of anti-apoptosis and angiogenesis genes. METHODS: SW480 cells was subjected to CoCl(2) exposure at varying concentrations and for different time lengths to induce hypoxia, and the protein expression of hypoxia induced factor 1α (HIF-1α) was detected by Western blotting. The CD133(+) SW480 cells were sorted by magnetic activated cell sorting (MACS) and their proportion was assayed by flow cytometry (FCM). The CD133(+) SW480 subsets were exposed to CoCl(2) at the optimal concentration with exposure time selected in terms of HIF-1α level, and their tumor stem cell sphere formation ability was evaluated. Real-time PCR was used to compare the mRNA expression levels of the surface markers of colon cancer stem cells (CD133 and PROM1), survivin, and vascular endothelial growth factor (VEGF). RESULTS: Exposure to 200 µmol/L CoCl(2) for 8 h resulted in the highest HIF-1α expression in SW480 cells, but the same exposure failed to induce HIF-1α expression in CD133(+) SW480 subsets. The CD133(+) SW480 subsets, after CoCl(2)-induced hypoxia, showed significantly enhanced ability of cell sphere formation. Hypoxia of SW480 cells caused significant increases in CD133, survivin and VEGF mRNA levels by 1.607∓0.103, 2.745∓0.370 and 3.798∓0.091 folds, respectively (P<0.05). CONCLUSION: CoCl(2) can simulate hypoxia in colon cancer cells in vitro to induce stable HIF-1α expression, which is concentration- and time-dependent. The hypoxia-stimulated tumor stem sells show an enhanced sphere formation and anti-apoptotic and anti-angiogenic abilities.

p21-activated kinase 5 inhibits camptothecin-induced apoptosis in colorectal carcinoma cells.

p21-activated kinase 5 (PAK5) is a recently identified member of the group B PAK family. The PAK proteins are effectors of the small GTPase Cdc42 and Rac1 and are known to regulate cell motility and activate cell-survival signaling pathways. Especially, the mitochondrial localization of PAK5 is vital to its effects on apoptosis and cell survival. Previously, we demonstrated that PAK5 expression increased significantly during the malignant progression of colorectal carcinoma (CRC) and that PAK5 promoted CRC metastasis by regulating CRC cell adhesion and migration. In the present study, we aim to investigate the role of PAK5 in camptothecin-induced apoptosis and its potential mechanism of action. Our results showed that overexpression of PAK5 inhibited camptothecin-induced apoptosis by inhibiting the activity of caspase-8 in CRC cells. Accordingly, knockdown of PAK5 in LoVo cells resulted in increased apoptosis. Mechanistically, we found that PAK5 directly phosphorylated Bad on serine 112 and indirectly led to phosphorylation of serine 136 via the Akt pathway. In conclusion, our study revealed previously unappreciated inhibitory role of PAK5 in camptothecin-induced apoptosis, thus suggesting PAK5 as a novel therapeutic target in CRC.

CD24-dependent MAPK pathway activation is required for colorectal cancer cell proliferation.

CD24 is a glycosylphosphatidylinositol-anchored membrane protein reported to be overexpressed in human tumorigenesis and progression. Our purpose was to determine the role of CD24 in the proliferation of colorectal cancer cells and the potential mechanisms in this process. Our data showed that CD24 promoted cell growth and induced activation of extracellular signal-regulated kinases, Raf-1, and p38 mitogen-activated protein kinase. Furthermore, suppression of extracellular signal-regulated kinases and p38 mitogen-activated protein kinase activity by their specific inhibitors, U0126 and SB203580, abrogated CD24-induced proliferation in vitro. By tumorigenicity assay in female BALB/c nude mice, we further demonstrated that CD24 promoted tumor growth in vivo. Immunohistochemical analysis revealed that CD24 expression occurred in 92.5% of human colorectal cancer tissue, and increased with tumor progression. More importantly, the stainings of phospho-extracellular signal-regulated kinases and phospho-p38 mitogen-activated protein kinase were strongly correlated with CD24 expression. Taken together, our data suggest that CD24-dependent extracellular signal-regulated kinases and p38 mitogen-activated protein kinase activations are required for colorectal cancer cell proliferation in vitro and in vivo. The linkage of CD24 and the mitogen-activated protein kinase pathway may unravel a novel mechanism in the regulation of colorectal cancer proliferation.