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Embedding mechanical logic into soft robotics, microelectromechanical systems (MEMS), and robotic materials can greatly improve their functional capacity. However, such logical functions are usually pre-programmed and can hardly be altered during in-life service, limiting their applications under varying working conditions. Here, we propose a reprogrammable mechanological metamaterial (ReMM). Logical computing is achieved by imposing sequential excitations. The system can be initialized and reprogrammed via selectively imposing and releasing the excitations. Realization of universal combinatorial logic and sequential logic (memory) is demonstrated experimentally and numerically. The fabrication scalability of the system is also discussed. We expect the ReMM can serve as a platform for constructing reusable and multifunctional mechanical systems with strong computation and information processing capability. Mechanical logic, while slower than its electronic counterpart, has the potential to be integrated into mechanical devices and a robustness in extreme environments. In this manuscript, Mei et al demonstrate reprogrammable mechanical logic which can perform combinatorial and sequential logic.

Metamaterials composed of different geometrical primitives have different properties. Corresponding to the fundamental geometrical forms of line, plane, and surface, beam-, plate-, and shell-based lattice metamaterials enjoy many advantages in many aspects, respectively. To fully exploit the advantages of each structural archetype, we propose a multilayer strategy and topology optimization technique to design lattice metamaterial in this study. Under the frame of the multilayer strategy, the design space is enlarged and diversified, and the design freedom is increased. Topology optimization is applied to explore better designs in the larger and diverse design space. Beam-plate-shell-combined metamaterials automatically emerge from the optimization to achieve ultrahigh stiffness. Benefiting from high stiffness, energy absorption performances of optimized results also demonstrate substantial improvements under large geometrical deformation. The multilayer strategy and topology optimization can also bring a series of tunable dimensions for lattice design, which helps achieve desired mechanical properties, such as isotropic elasticity and functionally grading material property, and superior performances in acoustic tuning, electrostatic shielding, and fluid field tuning. We envision that a broad array of synthetic and composite metamaterials with unprecedented performance can be designed with the multilayer strategy and topology optimization. High-performance mechanical metamaterials have been designed through a multilayer strategy and topology optimization, showing capability in approaching the theoretical stiffness limit, as well as prospects in treating multiphysics problems

Haptic displays are crucial for facilitating an immersive experience within virtual reality. However, when displaying continuous movements of contact, such as stroking and exploration, pixel-based haptic devices suffer from losing haptic information between pixels, leading to discontinuity. The trade-off between the travel distance of haptic elements and their pixel size in thin wearable devices hinders solutions that solely rely on increasing pixel density. Here we introduce a continuity reinforcement skeleton, which employs physically driven interpolation to enhance haptic information. This design enables the off-plane displacement to move conformally and display haptic information between pixel gaps. Efforts are made to quantify haptic display quality using geometric, mechanical, and psychological criteria. The development and integration of one-dimensional, two-dimensional, and curved haptic devices with virtual reality systems highlight the impact of the continuity reinforcement skeleton on haptic display, showcasing its potential for improving haptic experience. Discontinuity in haptic displays, caused by the loss of haptic information between pixels, compromises the user experience in thin wearable devices. Here, the authors employ beams to interpolate haptic information across pixel gaps, enhancing display continuity, especially for moving objects.

Objective Early detection and prognosis prediction are critical to improve patient survival in pancreatic cancer. This study aimed to investigate whether interleukins could serve as indicators of prognosis in pancreatic cancer. Methods Sixty-eight patients with pancreatic cancer were enrolled in the study during the period between 2012 and 2014. The serum levels of a broad spectrum of interleukins in these patients were determined, including IL-1β, IL-2, IL-6, IL-8, IL-10, IL-13, IL-15, and IL-23. Results IL-6, IL-8, and IL-10 showed significant positive correlations with each other. Moreover, high levels of serum IL-6, IL-8, and IL-10 were independently strongly associated with poor survival of patients with pancreatic cancer. Conclusions Our results suggest that serum levels of IL-6, IL-8, and IL-10 could be useful markers for prediction of prognosis in patients with pancreatic cancer.

China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2–3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. This randomised, open-label, phase 2–3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab–bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab–bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8–46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5–11·7) in the sintilimab–bevacizumab biosimilar group and 10·0 months (8·4–11·7) in the sorafenib group. Patients in the sintilimab–bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1–5·7]) than did patients in the sorafenib group (2·8 months [2·7–3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46–0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab–bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached–not reached] vs 10·4 months [8·5–not reached]; HR 0·57, 95% CI 0·43–0·75; p<0·0001). The most common grade 3–4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab–bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab–bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab–bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. Innovent Biologics. For the Chinese translation of the abstract see Supplementary Materials section.

Blocking the interaction between PD-1 and its ligands is a promising treatment strategy for advanced hepatocellular carcinoma. This study aimed to assess the antitumour activity and safety of the anti-PD-1 inhibitor camrelizumab in pretreated patients with advanced hepatocellular carcinoma. This is a multicentre, open-label, parallel-group, randomised, phase 2 trial done at 13 study sites in China. Eligible patients were aged 18 years and older with a histological or cytological diagnosis of advanced hepatocellular carcinoma, had progressed on or were intolerant to previous systemic treatment, and had an Eastern Cooperative Oncology Group performance score of 0–1. Patients were randomly assigned (1:1) to receive camrelizumab 3 mg/kg intravenously every 2 or 3 weeks, via a centralised interactive web-response system using block randomisation (block size of four). The primary endpoints were objective response (per blinded independent central review) and 6-month overall survival, in all randomly assigned patients who had at least one dose of study treatment. Safety was analysed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02989922, and follow-up is ongoing, but enrolment is closed. Between Nov 15, 2016, and Nov 16, 2017, 303 patients were screened for eligibility, of whom 220 eligible patients were randomly assigned and among whom 217 received camrelizumab (109 patients were given treatment every 2 weeks and 108 every 3 weeks). Median follow-up was 12·5 months (IQR 5·7–15·5). Objective response was reported in 32 (14·7%; 95% CI 10·3–20·2) of 217 patients. The overall survival probability at 6 months was 74·4% (95% CI 68·0–79·7)]. Grade 3 or 4 treatment-related adverse events occurred in 47 (22%) of 217 patients; the most common were increased aspartate aminotransferase (ten [5%]) and decreased neutrophil count (seven [3%]). Two deaths were judged by the investigators to be potentially treatment-related (one due to liver dysfunction and one due to multiple organ failure). Camrelizumab showed antitumour activity in pretreated Chinese patients with advanced hepatocellular carcinoma, with manageable toxicities, and might represent a new treatment option for these patients. Jiangsu Hengrui Medicine.

The skeleton-based action recognition networks often focus on extracting features such as joints from samples, while neglecting the semantic relationships inherent in actions, which also contain valuable information. To address the lack of utilization of semantic information, this paper proposes a semantics-assisted training graph convolution network (SAT-GCN). By dividing the features outputted by the skeleton encoder into four parts and contrasting them with the text features generated by the text encoder, the obtained contrastive loss is used to guide the overall network training. This approach effectively improves recognition accuracy while reducing the number of model parameters. In addition, angle features are incorporated into the skeleton model input to aid in classifying similar actions. Finally, a multi-feature skeleton encoder is designed to separately extract features such as joints, bones, and angles. These extracted features are then integrated through feature fusion. The fused features are then passed through three graph convolution blocks before being fed into fully connected layers for classification. Extensive experiments were conducted on three large-scale datasets, NTU RGB + D 60, NTU RGB + D 120, and NW-UCLA to validate the performance of the proposed model. The results show that the SAT-GCN outperforms others in terms of both accuracy and number of parameters.

Fracture resistance presents a pivotal challenge in mechanical metamaterials, as traditional designs often fail to mitigate crack propagation and enhance energy dissipation. Despite efforts to enlarge the fracture process zone, energy dissipation remains highly localized near the crack tip, restricting improvements in fracture toughness. This study introduces dual-bond fracture metamaterials that integrate weak and strong bonds to achieve full-field energy dissipation before crack propagation. Through the sequential breaking of weak bonds and the formation of plastic hinges, these materials redistribute stress across the entire structure, significantly expanding the fracture process zone and enhancing toughness. The specific fracture energy, a metric we propose to characterize structural fracture resistance, is governed by extrinsic energy dissipation and scales linearly with specimen size. Additionally, the concept of an equivalent force concentration factor is introduced to characterize fracture behavior in dual-bond fracture metamaterials. Gradient designs further enable asymmetric fracture sensitivity and surface crack shielding, thereby improving resilience in defect-prone environments. These metamaterials offer versatility, with potential applications in protective nets, shock absorbers, and blast containment vessels. Finally, the dual-bond design can be realized with a variety of materials, highlighting its generality and broad applicability for diverse engineering applications. Fracture resistance presents a challenge in mechanical metamaterials. Here, authors introduce dual-bond fracture metamaterials that enable full-field energy dissipation, making it tougher, more versatile, and better suited for advanced structural applications.

Background Kaempferol, a natural flavonoid, exhibits anticancer properties by scavenging reactive oxygen species (ROS). However, increasing evidence has demonstrated that, under certain conditions, kaempferol can inhibit tumor growth by upregulating ROS levels. In this study, we aimed to investigate whether kaempferol effectively suppresses pancreatic cancer through upregulation of ROS, and to explore the underlying molecular mechanism. Methods PANC-1 and Mia PaCa-2 cells were exposed to different concentrations of kaempferol. Cell proliferation and colony formation were evaluated by CCK-8 and colony formation assays. Flow cytometry was performed to assess the ROS levels and cell apoptosis. The mRNA sequencing and KEGG enrichment analysis were performed to identify differentially expressed genes and to reveal significantly enriched signaling pathways in response to kaempferol treatment. Based on biological analysis, we hypothesized that tissue transglutaminase (TGM2) gene was an essential target for kaempferol to induce ROS-related apoptosis in pancreatic cancer. TGM2 was overexpressed by lentivirus vector to verify the effect of TGM2 on the ROS-associated apoptotic signaling pathway. Western blot and qRT-PCR were used to determine the protein and mRNA levels, respectively. The prognostic value of TGM2 was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) tools based on public data from the TCGA database. Results Kaempferol effectively suppressed pancreatic cancer in vitro and in vivo. Kaempferol promoted apoptosis in vitro by increasing ROS generation, which was involved in Akt/mTOR signaling. TGM2 levels were significantly increased in PDAC tissues compared with normal tissues, and high TGM2 expression was positively correlated with poor prognosis in pancreatic cancer patients. Decreased TGM2 mRNA and protein levels were observed in the cells after treatment with kaempferol. Additionally, TGM2 overexpression downregulated ROS production and inhibited the abovementioned apoptotic signaling pathway. Conclusions Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling, and TGM2 may represent a promising prognostic biomarker for pancreatic cancer.

ObjectivePancreatic ductal adenocarcinoma (PDAC) is difficult to diagnose at resectable stage. Recent studies have suggested that extracellular vesicles (EVs) contain long RNAs. The aim of this study was to develop a diagnostic (d-)signature for the detection of PDAC based on EV long RNA (exLR) profiling.DesignWe conducted a case-control study with 501 participants, including 284 patients with PDAC, 100 patients with chronic pancreatitis (CP) and 117 healthy subjects. The exLR profile of plasma samples was analysed by exLR sequencing. The d-signature was identified using a support vector machine algorithm and a training cohort (n=188) and was validated using an internal validation cohort (n=135) and an external validation cohort (n=178).ResultsWe developed a d-signature that comprised eight exLRs, including FGA, KRT19, HIST1H2BK, ITIH2, MARCH2, CLDN1, MAL2 and TIMP1, for PDAC detection. The d-signature showed high accuracy, with an area under the receiver operating characteristic curve (AUC) of 0.960, 0.950 and 0.936 in the training, internal validation and external validation cohort, respectively. The d-signature was able to identify resectable stage I/II cancer with an AUC of 0.949 in the combined three cohorts. In addition, the d-signature showed superior performance to carbohydrate antigen 19-9 in distinguishing PDAC from CP (AUC 0.931 vs 0.873, p=0.028).ConclusionThis study is the first to characterise the plasma exLR profile in PDAC and to report an exLR signature for the detection of pancreatic cancer. This signature may improve the prognosis of patients who would have otherwise missed the curative treatment window.