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Abstract In this study, a new short‐term wind power prediction model based on a temporal convolutional network (TCN) and the Informer model is proposed to solve the problem of low prediction accuracy caused by large wind speed fluctuations in short‐term prediction. First, an input feature selection method based on the maximum information coefficient is proposed after considering the problem of information interference caused by excessively large input features. A dynamic time planning method is used to select the optimal input step of historical power. Then, the combined forecasting model composed of TCN and the Informer is constructed in accordance with the numerical weather forecast and historical power data. Lastly, the pinball loss function is used to expand the prediction model into a quantile regression model, measure the effect of volatility, quantify the volatility range of prediction, and finally, obtain a deterministic prediction result. The actual measured data of wind farms in the Bohai Sea area are selected for analysis and calculation. The results show that the prediction model proposed in this study achieves better accuracy in deterministic prediction and interval prediction than the traditional model.

Abstract Appropriate antibiotic dosing to ensure early and sufficient target attainment is crucial for improving clinical outcome in critically ill patients. Parametric survival analysis is a preferred modeling method to quantify time‐varying antibiotic exposure – response effects, whereas bias may be introduced in hazard functions and survival functions when competing events occur. This study investigated predictors of in‐hospital mortality in critically ill patients treated with meropenem by pharmacometric multistate modeling. A multistate model comprising five states (ongoing meropenem treatment, other antibiotic treatment, antibiotic treatment termination, discharge, and death) was developed to capture the transitions in a cohort of 577 critically ill patients treated with meropenem. Various factors were investigated as potential predictors of the transitions, including patient demographics, creatinine clearance calculated by Cockcroft–Gault equation (CLCRCG), time that unbound concentrations exceed the minimum inhibitory concentration (fT>MIC), and microbiology‐related measures. The probabilities to transit to other states from ongoing meropenem treatment increased over time. A 10 mL/min decrease in CLCRCG was found to elevate the hazard of transitioning from states of ongoing meropenem treatment and antibiotic treatment termination to the death state by 18%. The attainment of 100% fT>MIC significantly increased the transition rate from ongoing meropenem treatment to antibiotic treatment termination (by 9.7%), and was associated with improved survival outcome. The multistate model prospectively assessed predictors of death and can serve as a useful tool for survival analysis in different infection scenarios, particularly when competing risks are present.

Abstract The dose/exposure‐efficacy analyses are often conducted separately for oncology end points like best overall response, progression‐free survival (PFS) and overall survival (OS). Multistate models offer to bridge these dose‐end point relationships by describing transitions and transition times from enrollment to response, progression, and death, and evaluating transition‐specific dose effects. This study aims to apply the multistate pharmacometric modeling and simulation framework in a dose optimization setting of bintrafusp alfa, a fusion protein targeting TGF‐β and PD‐L1. A multistate model with six states (stable disease [SD], response, progression, unknown, dropout, and death) was developed to describe the totality of endpoints data (time to response, PFS, and OS) of 80 patients with non‐small cell lung cancer receiving 500 or 1200 mg of bintrafusp alfa. Besides dose, evaluated predictor of transitions include time, demographics, premedication, disease factors, individual clearance derived from a pharmacokinetic model, and tumor dynamic metrics observed or derived from tumor size model. We found that probabilities of progression and death upon progression decreased over time since enrollment. Patients with metastasis at baseline had a higher probability to progress than patients without metastasis had. Despite dose failed to be statistically significant for any individual transition, the combined effect quantified through a model with dose‐specific transition estimates was still informative. Simulations predicted a 69.2% probability of at least 1 month longer, and, 55.6% probability of at least 2‐months longer median OS from the 1200 mg compared to the 500 mg dose, supporting the selection of 1200 mg for future studies.

Abstract Osteoporosis (OP) is a systematic bone disease characterized by low bone mass and fragile bone microarchitecture. Conventional treatment for OP has limited efficacy and long‐term toxicity. Synthetic biology makes bacterial extracellular vesicle (BEVs)‐based therapeutic strategies a promising alternative for the treatment of OP. Here, we constructed a recombinant probiotics Escherichia coli Nissle 1917‐pET28a‐ClyA‐BMP‐2‐CXCR4 (ECN‐pClyA‐BMP‐2‐CXCR4), in which BMP‐2 and CXCR4 were overexpressed in fusion with BEVs surface protein ClyA. Subsequently, we isolated engineered BEVs‐BMP‐2‐CXCR4 (BEVs‐BC) for OP therapy. The engineered BEVs‐BC exhibited great bone targeting in vivo. In addition, BEVs‐BC had good biocompatibility and remarkable ability to promote osteogenic differentiation of BMSCs. Finally, the synthetic biology‐based BEVs‐BC significantly prevented the OP in an ovariectomized (OVX) mouse model. In conclusion, we constructed BEVs‐BC with both bone‐targeting and bone‐forming in one‐step using synthetic biology, which provides an effective strategy for OP and has great potential for industrialization.

Abstract Metastasis is the leading cause for the high mortality of lung cancer, however, effective anti‐metastatic drugs are still limited. Here it is reported that the RNA‐binding protein RBMS1 is positively associated with increased lymph node metastasis in non‐small cell lung cancer (NSCLC). Depletion of RBMS1 suppresses cancer cell migration and invasion in vitro and inhibits cancer cell metastasis in vivo. Mechanistically, RBMS1 interacts with YTHDF1 to promote the translation of S100P, thereby accelerating NSCLC cell metastasis. The RRM2 motif of RBMS1 and the YTH domain of YTHDF1 are required for the binding of RBMS1 and YTHDF1. RBMS1 ablation inhibits the translation of S100P and suppresses tumor metastasis. Targeting RBMS1 with NTP, a small molecular chemical inhibitor of RBMS1, attenuates tumor metastasis in a mouse lung metastasis model. Correlation studies in lung cancer patients further validate the clinical relevance of the findings. Collectively, the study provides insight into the molecular mechanism by which RBMS1 promotes NSCLC metastasis and offers a therapeutic strategy for metastatic NSCLC.

Abstract Architected materials design across orders of magnitude length scale intrigues exceptional mechanical responses nonexistent in their natural bulk state. However, the so‐termed mechanical metamaterials, when scaling bottom down to the atomistic or microparticle level, remain largely unexplored and conventionally fall out of their coarse‐resolution, ordered‐pattern design space. Here, combining high‐throughput molecular dynamics (MD) simulations and machine learning (ML) strategies, some intriguing atomistic families of disordered mechanical metamaterials are discovered, as fabricated by melt quenching and exemplified herein by lightweight‐yet‐stiff cellular materials featuring a theoretical limit of linear stiffness–density scaling, whose structural disorder—rather than order—is key to reduce the scaling exponent and is simply controlled by the bonding interactions and their directionality that enable flexible tunability experimentally. Importantly, a systematic navigation in the forcefield landscape reveals that, in‐between directional and non‐directional bonding such as covalent and ionic bonds, modest bond directionality is most likely to promotes disordered packing of polyhedral, stretching‐dominated structures responsible for the formation of metamaterials. This work pioneers a bottom‐down atomistic scheme to design mechanical metamaterials formatted disorderly, unlocking a largely untapped field in leveraging structural disorder in devising metamaterials atomistically and, potentially, generic to conventional upscaled designs.

Abstract Objectives Lung cancer is a major public health concern and represents the most common cause of cancer‐related death worldwide. Among eukaryotes, the G protein‐coupled receptor (GPCR) family stands as the largest group of membrane proteins. Alterations in GPCR gene expression and dysregulation of signal transduction have been recognized as the markers of malignancy. As a member of the GPCR family, G protein‐coupled receptor 37 (GPR37) exhibits unknown functions in tumors, particularly in non‐small‐cell lung cancer (NSCLC) Methods We explored the expression and prognosis of GPR37 in NSCLC through TCGA, GTEx, GEO, and GEPIA2. We detected the expression of GPR37 in NSCLC tissues and cell lines. The study explored the influence of GPR37 on tumor cell proliferation. Furthermore, we examined the effects of GPR37 on tumor cell apoptosis and invasion. Most importantly, we investigated whether GPR37 affects cisplatin‐induced drug resistance in NSCLC. Furthermore, by conducting animal experiments, we assessed the impact of GPR37 on NSCLC and delved into underlying mechanisms. Results (1) In NSCLC, the expression of GPR37 is markedly higher than that in corresponding normal tissues. We found that elevated GPR37 expression predicts an unfavorable prognosis. (2) It was demonstrated that GPR37 positively regulates NSCLC cell invasion, migration, and proliferation, suppresses cell apoptosis, heightens resistance to cisplatin, and promotes tumor formation and growth. Conversely, we observed that GPR37 knockdown suppresses NSCLC cell invasion, migration, and proliferation, promotes cell apoptosis, increases sensitivity to cisplatin, and affects tumor formation and growth. (3) GPR37 activates PI3K/Akt/mTOR signal transduction pathways to mediate epithelial‐mesenchymal transition (EMT), thereby promoting the progression of NSCLC. Conclusions It was suggested that GPR37 acts a crucial role in promoting the occurrence and development of NSCLC. Knockdown of GPR37 significantly inhibits the occurrence and development of NSCLC. Therefore, our findings demonstrated that GPR37 may represent a viable therapeutic target for NSCLC.

Abstract Background There is no consensus on the optimal regimen for unresectable recurrent hepatocellular carcinoma (HCC), so this retrospective study aimed to evaluate the efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib and PD‐1 inhibitors (T‐L‐P) versus TACE combined with lenvatinib (T‐L) or TACE alone. Method Data were collected from 204 patients with unresectable recurrent HCC who received T‐L‐P, T‐L, or TACE alone at three medical centers from January, 2019 to December, 2020 for analysis. The survival outcomes, tumor response, and adverse events were compared between three groups, and risk factors were further investigated. Results The median overall survival in the T‐L‐P, T‐L, and TACE alone groups were not reached, 25.6, and 15.7 months, respectively (p

Abstract Background Early and late recurrence of hepatocellular carcinoma (HCC) have different clinical outcomes, especially for those accompanied by microvascular invasion (MVI), but the definition of early recurrence remains controversial. Therefore, a reasonable identification of the early recurrence time for HCC is urgently needed. Methods Resected recurrence patients were enrolled and divided into two cohorts, one for identification of the early recurrence time and another for verification of the accuracy of the point. Univariable and multivariable Cox regression analyses were adopted to identify the prognostic factors of recurrence HCC (rHCC) and Kaplan–Meier method was applied to analyze the overall survival (OS). The appropriate cutoff value was determined by the exhaustive method using different recurrence intervals from 1 to 24 months in turn. Results In total, 292 resected rHCC patients were analyzed to calculate the early recurrence interval, and another 421 resected rHCC patients with MVI were enrolled to verify the efficacy of adjuvant transarterial chemoembolization (TACE) in this recurrence interval. MVI was identified as an independent risk factor by multivariable analysis. The OS of rHCC patients without MVI is better than that of patients with MVI when the recurrence time was within 13 months, while not beyond 13 months. The verification cohort demonstrated that adjuvant TACE provided longer survival for rHCC with MVI when the recurrence time was within 13 months, while not beyond 13 months. Conclusion For HCC patients with MVI who underwent R0 resection, 13 months may be a reasonable early recurrence time point, and within this interval, postoperative adjuvant TACE may result in longer survival compared with surgery alone.

Conclusion: SMS used alone or combined with WM may have potential effectiveness on symptom alleviation, ECG recovery rate, myocardial injury markers, and cardiac function, but the effectiveness is uncertain due to the low quality and absence of placebo-controlled trials. The exact efficacy of SMS for VMC needs to be confirmed by high-quality double-blind RCTs in the future.

Abstract A20‐binding inhibitor of NF‐κB activation (ABIN1) is a polyubiquitin‐binding protein that regulates cell death and immune responses. Although Abin1 is located on chromosome 5q in the region commonly deleted in patients with 5q minus syndrome, the most distinct of the myelodysplastic syndromes (MDSs), the precise role of ABIN1 in MDSs remains unknown. In this study, mice with a mutation disrupting the polyubiquitin‐binding site (Abin1Q478H/Q478H) is generated. These mice develop MDS‐like diseases characterized by anemia, thrombocytopenia, and megakaryocyte dysplasia. Extramedullary hematopoiesis and bone marrow failure are also observed in Abin1Q478H/Q478H mice. Although Abin1Q478H/Q478H cells are sensitive to RIPK1 kinase–RIPK3–MLKL‐dependent necroptosis, only anemia and splenomegaly are alleviated by RIPK3 deficiency but not by MLKL deficiency or the RIPK1 kinase‐dead mutation. This indicates that the necroptosis‐independent function of RIPK3 is critical for anemia development in Abin1Q478H/Q478H mice. Notably, Abin1Q478H/Q478H mice exhibit higher levels of type I interferon (IFN‐I) expression in bone marrow cells compared towild‐type mice. Consistently, blocking type I IFN signaling through the co‐deletion of Ifnar1 greatly ameliorated anemia, thrombocytopenia, and splenomegaly in Abin1Q478H/Q478H mice. Together, these results demonstrates that ABIN1(Q478) prevents the development of hematopoietic deficiencies by regulating type I IFN expression.

Abstract The Hippo pathway is crucial to organ size control and its dysregulation contributes to tumorigenesis. The aberrant activation of YAP1 was identified in gallbladder cancer (GBC). However, the underlying mechanism and role in GBC remains unclear. The C terminal fragment of Mucin16, also known as carbohydrate antigen 125 (CA125) encoded product, MUC16c, plays extensive roles in tumor initiation and development. Our study showed that MUC16c binding with 14‐3‐3ε disrupted the interaction of 14‐3‐3ε and phosphorylated yes‐associated protein 1 (YAP1), which led to the activation of YAP1 in GBC. Furthermore, MUC16c decreased the phosphorylation of YAP1 at serine 397 (ser397) by inhibiting LATS1, which upregulated YAP1 protein stability. Interestingly, there was a potential Src kinase site in the MUC16c fragment. The MUC16c_del15Y polypeptides with the deletion of the Src kinase site promoted the interaction of YAP1 with 14‐3‐3ε and downregulated the YAP1 protein levels. Consistently, SU6656, a Src kinase inhibitor also blocked the activation of YAP1 by MUC16c. The MUC16c_del15Y polypeptides decreased GBC cell proliferation in vitro and the growth of xenograft tumors in vivo. Our study revealed the underlying mechanism of the activation of MUC16c on YAP1 mediated by Src signaling and the antitumor effect of MUC16c_del15Y, providing a potential target for GBC therapy.

Abstract Background Anwuligan (ANW) isolated from nutmeg, also known as myristyl lignan, has attracted attention due to its therapeutic potential in diseases. However, its effect on lung cancer is still unclear. Methods In this study, the cytotoxicity of ANW on non‐small cell lung cancer (NSCLC) cells was detected using a Cell Counting Kit‐8 (CCK‐8) assay. In vitro, clone formation, wound healing, and Transwell assays were used to investigate the migratory and invasive abilities of NSCLC cells after ANW treatment. The expression levels of the associated proteins were detected using Western blotting. A luciferase assay was used to validate the binding of let‐7c‐3p to the 3′‐untranslated region (UTR) of PIK3CA. In vivo, an A549 cell xenograft mouse model was used to verify the effect of ANW on tumor growth. Results The results showed that ANW treatment (20 or 50 μM) had obvious cytotoxicity against A549 and H460 cells, suppressing cell proliferation and migration in vitro. In vivo, the growth of the implanted tumor was inhibited by ANW in a nude mouse model. The growth of NSCLC cells was also inhibited by let‐7c‐3p overexpression in vitro and in vivo. The inhibitory effect of ANW on the proliferation and metastasis of NSCLC cells was weakened by the downregulation of let‐7c‐3p, whereas it was enhanced by the overexpression of let‐7c‐3p; PIK3CA was the main target of let‐7c‐3p. Conclusions In summary, ANW inhibits the growth and metastasis of NSCLC cells in vivo and in vitro by upregulating the expression of let‐7c‐3p, which can regulate the PI3K/AKT/mTOR signaling pathway. PIK3CA is the main target of let‐7c‐3p.

Abstract Hyper‐spectral image (HSI) clustering has become a hot spot in remote sensing image research. However, due to the large amount and high dimension of HSI data, some traditional image clustering methods are no longer suitable, and even lead to poor clustering performance and long computing time. Therefore, this paper proposes a novel clustering method for HSI to make up for the shortcomings of traditional clustering methods. Firstly, a fuzzy similarity matrix is constructed by using the bipartite graph to obtain low‐dimensional hyper‐spectral data, which can reduce the complexity and the operation time of the algorithm. Secondly, fuzzy membership mapping is carried out through the constructed bipartite graph, and a non‐negative regularization term is added to limit ill‐conditioned problems. Thirdly, this paper uses the Geman‐McClure function to optimize Euclidean distance. Finally, in this paper, the spectral information of HSI is considered while the neighbourhood information of HSI is added to achieve the unity of space spectrum, which enhances the robustness of the algorithm and improves the clustering performance of the algorithm. Compared with existing HSI clustering algorithms, the proposed algorithm has higher clustering accuracy and efficiency.

Abstract Image prior plays a decisive role in the performance of widely studied model‐based restoration methods. To further improve restoration performance, this paper proposes an exponential scale mixture‐based simultaneous sparse prior (ESM‐SSP) to accurately characterize image prior information. Specifically, first, two structured dictionaries are adaptively learned to explore the local and non‐local sparsity of similar patch groups simultaneously. Then, the exponential scale mixture (ESM) is employed to model simultaneous sparse coefficients. The adoption of ESM enables us to accurately estimate simultaneous sparse coefficients by adaptively adjusting the regularization parameters. With the aid of ESM‐SSP, an effective image restoration algorithm is developed to preserve more image details. Extensive experimental results on image denoising and deblocking demonstrate that compared with many state‐of‐the‐art model‐based methods, the proposed ESM‐SSP‐based restoration algorithm not only has competitive peak signal‐to‐noise ratio, but also produces higher structural similarity index and better visuals. More importantly, the proposed method can also compete favourably with the superior deep learning‐based restoration methods.

Abstract The highly conserved matrix protein 2 ectodomain (M2e) of influenza viruses presents a compelling vaccine antigen candidate for stemming the pandemic threat of the mutation‐prone pathogen, yet the low immunogenicity of the diminutive M2e peptide renders vaccine development challenging. A highly potent M2e nanoshell vaccine that confers broad and durable influenza protectivity under a single vaccination is shown. Prepared via asymmetric ionic stabilization for nanoscopic curvature formation, polymeric nanoshells co‐encapsulating high densities of M2e peptides and stimulator of interferon genes (STING) agonists are prepared. Robust and long‐lasting protectivity against heterotypic influenza viruses is achieved with a single administration of the M2e nanoshells in mice. Mechanistically, molecular adjuvancy by the STING agonist and nanoshell‐mediated prolongation of M2e antigen exposure in the lymph node follicles synergistically contribute to the heightened anti‐M2e humoral responses. STING agonist‐triggered T cell helper functions and extended residence of M2e peptides in the follicular dendritic cell network provide a favorable microenvironment that induces Th1‐biased antibody production against the diminutive antigen. These findings highlight a versatile nanoparticulate design that leverages innate immune pathways for enhancing the immunogenicity of weak immunogens. The single‐shot nanovaccine further provides a translationally viable platform for pandemic preparedness.

Abstract Natural and artificial cells are two common chassis in synthetic biology. Natural cells can perform complex tasks through synthetic genetic constructs, but their autonomous replication often causes safety concerns for biomedical applications. In contrast, artificial cells based on nonreplicating materials, albeit possessing reduced biochemical complexity, provide more defined and controllable functions. Here, for the first time, the authors create hybrid material‐cell entities termed Cyborg Cells. To create Cyborg Cells, a synthetic polymer network is assembled inside each bacterium, rendering them incapable of dividing. Cyborg Cells preserve essential functions, including cellular metabolism, motility, protein synthesis, and compatibility with genetic circuits. Cyborg Cells also acquire new abilities to resist stressors that otherwise kill natural cells. Finally, the authors demonstrate the therapeutic potential by showing invasion into cancer cells. This work establishes a new paradigm in cellular bioengineering by exploiting a combination of intracellular man‐made polymers and their interaction with the protein networks of living cells.

Abstract Objective The aim of this study was to investigate whether there was a difference in survival after initial percutaneous coronary intervention (PCI) among ST‐segment elevation myocardial infarction (STEMI) patients with different body mass index (BMI). Methods Literature retrieval was conducted on PubMed, Web of Science, Embase, CNKI, and Wanfang databases to obtain the published studies on the survival of STEMI patients with different BMI after initial PCI from the establishment of the database to 2022. All statistical analyses were performed using STATA16.0. Results Two hundred thirty‐nine studies were retrieved, and 12 studies were eventually included. Meta‐analysis showed that overweight patients [OR = 0.66, 95% CI (0.58, 0.76), p .05], short‐term mortality [OR = 1.04, 95% CI (0.89, 1.22), p > .05], and long‐term mortality [OR = 1.07, 95% CI (0.95, 1.20), p > .05] between overweight and obese patients. Conclusion This meta‐analysis confirmed an obesity paradox in STEMI patients following PCI. The obesity paradox exists in in‐hospital, short‐term, and long‐term conditions.

Objective To compare and analyze the clinical outcomes between unstemmed and stemmed constrained condylar knees (CCK) in complex primary total knee arthroplasty (TKA) in terms of implant survivorship, change in outcome evaluations, and complications. Methods We reviewed 156 consecutive patients who received primary TKA using PFC®SIGMA®TC3 (TC3) of constrained condylar design between January 2009 and January 2017 at our institution. After removing patients who met exclusion criteria, 25 patients were identified as unstemmed TC3 cases and 81 as stemmed TC3 cases. Propensity score matching was used to select 25 stemmed cases as a control group for the unstemmed group with comparable preoperative conditions including preoperative demographics, preoperative diagnosis, preoperative range of motion, main reason to use TC3, ASA score (American Society of Anesthesiologists), and follow‐up duration. Preoperative and postoperative clinical evaluations including Knee Society Score (KSS), Hospital for Special Surgery (HSS) score, the 12‐Item Short‐Form Health Survey (SF‐12), and the range of motion (ROM) were obtained and compared. The instability, periprosthetic fracture, radiolucent lines, polyethylene wear, and heterotrophic ossification were assessed according to the anteroposterior and lateral radiographs of the knee. The complications and implant survivorship between the two groups were also recorded and compared. Results 3After the index surgery, both groups showed substantial improvement in KSS (knee and function), HSS score, SF‐12, and ROM compared with baseline. There was no significant difference in the mean KSS scores (knee and function), HSS score, SF‐12, and ROM between the unstemmed and stemmed group postoperatively. No statistically significant difference was found in the overall complication rate between the two groups. The overall Kaplan–Meier survivorship was 98.0% (95% confidence interval 94.1%–100.0%) at 7 years. No significant difference was found in the survival rate between the unstemmed group (100.0%) and the stemmed group (96.0%) at 7 years (log rank, P = 0.317). The mean duration of follow‐up was 7.0 years for unstemmed group and 7.7 years for stemmed group. Conclusions In patients with adequate bone stock receiving complex primary TKA, unstemmed CCK could achieve similar clinical outcomes at mid‐term follow‐up as stemmed CCK.

A two-way parabolic equation (2W-PE) method based on complex-valued neural networks (CVNNs) and a physics-informed neural network (PINN) is proposed to predict the spatial field in the environment of dielectric obstacles with high efficiency and accuracy. In the framework of the 2W-PE method, CVNNs are used to calculate the lumped transmission field and the lumped reflection field considering the influence of the obstacle, thus avoiding the long calculation time caused by the internal multilayered reflection processes. The incident directions and field strength of the waves on the regional boundaries vary greatly with the propagation environment, so coefficients of the boundary conditions are obtained by using the PINN. Next, the training results are applied to the examples using the continuation method and compared with the numerical results of the method of moments (MoM). The proposed 2W-PE method has high computational accuracy and efficiency, which reflects the applicability of machine learning in solving the computational efficiency problem of radio wave propagation. Therefore, this study provides a very effective and reliable method for solving the spatial field in the obstacle environment.

Objective. Patients with anti-Jo-1 antibodies (Abs) and anti–melanoma differentiation-associated protein 5 (MDA5) Abs are at a higher risk of interstitial lung disease (ILD) and have a mortality rate higher than that of patients with anti-Jo-1 Abs. This study investigated differences in the clinical characteristics and prognosis of patients with anti-Jo-1 Abs and anti-MDA5 Abs with dermatomyositis (DM). Methods. We retrospectively reviewed the medical records of 38 patients with DM from January 2000 to December 2021. The patients were divided into anti-Jo-1 Abs and anti-MDA5 Abs groups. The basic demographic data, clinical manifestations, and 1-year mortality rates of the groups were compared. Results. Among the 38 patients, 30 were anti-Jo-1-Abs positive and 8 patients were anti-MDA5 Aba positive. The patients with anti-MDA5 Abs presented with more apparent cutaneous symptoms and aggressive pulmonary manifestations than did those with anti-Jo-1 Abs. The mortality rate in the anti-MDA5 Abs group (1.95/person-year (PY)) was much higher than that in anti-Jo-1 Abs group (0.094/PY), and most of the mortalities occurred within the first 1–3 months of follow-up. Conclusion. Distinct cutaneous and pulmonary manifestations were observed in the anti-Jo-1 Abs and anti-MDA5 Abs groups. The mortality rate in the anti-MDA5 Abs group was significantly higher than that in the anti-Jo-1 Abs group. Early recognition is crucial to ensuring higher chances of survival for patients with anti-MDA5 Abs.

Abstract Membrane‐lytic peptides offer broad synthetic flexibilities and design potential to the arsenal of anticancer therapeutics, which can be limited by cytotoxicity to noncancerous cells and induction of drug resistance via stress‐induced mutagenesis. Despite continued research efforts on membrane‐perforating peptides for antimicrobial applications, success in anticancer peptide therapeutics remains elusive given the muted distinction between cancerous and normal cell membranes and the challenge of peptide degradation and neutralization upon intravenous delivery. Using triple‐negative breast cancer as a model, the authors report the development of a new class of anticancer peptides. Through function‐conserving mutations, the authors achieved cancer cell selective membrane perforation, with leads exhibiting a 200‐fold selectivity over non‐cancerogenic cells and superior cytotoxicity over doxorubicin against breast cancer tumorspheres. Upon continuous exposure to the anticancer peptides at growth‐arresting concentrations, cancer cells do not exhibit resistance phenotype, frequently observed under chemotherapeutic treatment. The authors further demonstrate efficient encapsulation of the anticancer peptides in 20 nm polymeric nanocarriers, which possess high tolerability and lead to effective tumor growth inhibition in a mouse model of MDA‐MB‐231 triple‐negative breast cancer. This work demonstrates a multidisciplinary approach for enabling translationally relevant membrane‐lytic peptides in oncology, opening up a vast chemical repertoire to the arms race against cancer.

Abstract Background The distant metastasis (DM) mode and treatment efficacies in the advanced biliary tract cancer (BTC) were obscure, and a credible evaluation is urgently needed. Method A total of 6348 advanced BTC patients (ICC, intrahepatic cholangiocarcinoma, n = 1762; PHCC, perihilar cholangiocarcinoma, n = 1103; GBC, gallbladder cancer, n = 2580; DCC, distal cholangiocarcinoma, n = 538; AVC, carcinoma of Vater ampulla, n = 365) were enrolled from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) process was carried out for less bias. Result The proportion of M1 patients in each subtype at first diagnosis was 26.4% (ICC), 37.2% (PHCC), 41. 0% (GBC), 24.5% (DCC), and 12.7% (AVC), and the constitution of DM sites in different subtypes varied apparently. Moreover, the survival of metastasis sites was different (P

Abstract Background To ascertain if concurrent chemotherapy (CCT) benefits people with stage II nasopharyngeal carcinoma (NPC) treated with two‐dimensional radiotherapy (2DRT) or intensity‐modulated radiotherapy (IMRT). Methods A total of 4157 patients diagnosed with stage II NPC were evaluated. Patients received radiotherapy (RT) with/without CCT. Patients were divided into 2DRT and IMRT subgroups. After propensity score matching, the role of CCT was explored in these two subgroups. Overall survival (OS) was the primary endpoint and progression‐free survival (PFS), locoregional relapse‐free survival (LRFS) and distant metastasis‐free survival (DMFS) were secondary endpoints. Results In the 2DRT subgroup, CCT addition to RT benefited cases with T1N1/T2N1 in OS, PFS and LRFS (P

Abstract We described an 87‐year‐old man who presented with fever and hemoptysis. Nosocomial pneumonia was initially suspected. However, the patient had worsening hemoptysis despite defervescence. Chest computed tomography disclosed ruptured thoracic aortic aneurysm. Emergent surgery was then commenced for adequate treatment.

The social force model has been widely used in simulating and analyzing pedestrian behavior. Like any agent-based models, the fidelity of the social force model largely relies on its numerical parameters that characterizes pedestrians’ behaviors. While parameters describing normal walking behaviors have been observed and calibrated in field experiments, those describing behaviors under abnormal and urgent circumstances have rarely been studied but are of practical significance in evaluating safety functionality of facilities, particularly those serving children or elders. Specifically aiming at providing a set of social force model parameters characterizing children’s behavior during evacuation, this study conducted evacuation experiments with preschool children under multiple emergency scenarios involving impaired-vision and flame scenarios and benchmarked against a normal scenario. A simulation-calibration framework is developed based on the social force model to calibrate evacuation behavior parameters by minimizing trajectory distance. The numerical approximation results indicate evident parameter disparities of preschool children from adults. This study can improve evacuation strategies and the designing/evaluation process of dedicated facilities layouts such as kindergarten corridors, activity rooms, and playgrounds.

Background According to the current clinical guidelines, chemoradiotherapy is considered the standard treatment for locally advanced non‐small cell lung cancer (NSCLC). We analyzed the prognostic effect of adjuvant chemotherapy (ACT) in resected patients using the new eighth tumor node metastasis (TNM) staging systems based on the Surveillance, Epidemiology and End Results database. Methods We identified 3008 patients with stage IIIA NSCLC (T4N0M0) who underwent sublobar resection, lobectomy, or pneumonectomy. Covariates affecting treatment selection or survival were included as part of propensity score models for matching and weighting. The effect of ACT on survival was assessed, stratified by postoperative radiation therapy (PORT) use, tumor size, and age. Results Analyses of 2016 patients were conducted with standardized differences in covariates < 10% after matching. ACT was associated with significantly improved five‐year overall survival (51.1% vs. 39.7%; P = 0.0260) in patients aged 21–65 with > 7 cm tumors, even after adjusting for the presence or absence of the superior sulcus (P = 0.0003). No significant outcomes were observed using other stratifications in the matched analysis. Moreover, ACT with PORT conferred a potential survival benefit in 21–65‐year‐old patients with 0–7 cm tumors (for all causes of death: hazard ratio 0.414, 95% confidence interval 0.251–0.684). Conclusion In this population‐based cohort, ACT prolonged the survival of patients aged 21–65 with a tumor > 7 cm, with or without PORT. Inverse probability of treatment weighting can estimate the treatment effect and is suitable for use with survival data.

As a useful descriptive tool for emergency service effectiveness, the hypercube queuing model has been applied in systems of many countries, such as the SAMU system in Brazil. However, the traditional hypercube queuing model and its extended forms assume that the service provider performs independent services, lacking a compelling description of the situation where emergency vehicles perform cooperative services (e.g., NEPPHE in China). To this end, we assume that vehicles in the same fleet simultaneously start and end services and propose a cooperative hypercube queuing (CHQ) model that can describe the state of emergency systems which apply multivehicle dispatches. In order to verify the accuracy of the model, we apply Arena simulation software in Wuhan case. The results show that the CHQ model can illustrate cooperative performance effectively. Sensitivity analyses under more general parameters are conducted to reveal insights into the model application.

Due to the poor stability of the loose sandy soil layer, if the support force is not properly controlled during the construction process of the shield tunnel using the earth pressure balance method, it is easy to cause the ground to collapse or uplift. Therefore, understanding the support force of the excavation surface of shield tunneling in sandy soil layer is very vital to ensure the stability of the excavation surface. Firstly, it is assumed that the damaged soil is a three-dimensional wedge and a modified three-dimensional wedge in the active and passive failure modes, respectively. The shallow soil pressure theory and the soil plastic limit equilibrium theory are derived by analyzing the stress distribution on the damaged soil. The equation for revealing the inner essence between the support force of the shield excavation surface and excavation surface displacement under the condition of sand-covered soil is used. Secondly, the numerical simulation method analyzes the displacement of the excavation surface when the support force changes under different working conditions, and the relationship curve between the excavation surface support force and the shield tunneling displacement is obtained. The comparison and analysis between the numerical simulation calculation and the theoretical analysis indicate that the deduced calculation equation for the excavation surface support force based on the displacement earth pressure is reasonable.

Teriparatide, also known as 1-34 parathyroid hormone (PTH (1-34)), is commonly used for the treatment of osteoporosis in postmenopausal women. But its therapeutic application is restricted by poor metabolic stability, low bioavailability, and rapid clearance. Herein, PTHG2, a glycosylated teriparatide derivative, is designed and synthesized to improve PTH stability and exert more potent antiosteoporosis effect. Surface plasmon resonance (SPR) analysis shows that PTHG2 combines to PTH 1 receptor. Additional acetylglucosamine covalent bonding in the first serine at the N terminal of PTH (1-34) improves stability and increases protein hydrolysis resistance. Intermittent administration of PTHG2 preserves bone quality in ovariectomy- (OVX-) induced osteoporosis mice model, along with increased osteoblastic differentiation and bone formation, and reduced marrow adipogenesis. In vitro, PTHG2 inhibits adipogenic differentiation and promotes osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs). For molecular mechanism, PTHG2 directs BMSCs fate through stimulating the cAMP-PKA signaling pathway. Blocking PKA abrogates the pro-osteogenic effect of PTHG2. In conclusion, our study reveals that PTHG2 can accelerate osteogenic differentiation of BMSCs and inhibit adipogenic differentiation of BMSCs and show a better protective effect than PTH (1-34) in the treatment of osteoporosis.

Based on large-scale triaxial tests of sandy gravel materials, the strength and deformation characteristics under loading/unloading conditions are analyzed. At the same time, the applicability of the hyperbolic constitutive model to sandy gravel is studied using experimental data. The results indicate that sandy gravel under low confining pressures (0.2 and 0.4 MPa) shows a weak softening trend; the higher the confining pressure, the more obvious the hardening tendency (0.6 and 0.8 MPa) and the greater the peak strength. During unloading tests, strain softening occurs, and the peak strength increases with increasing confining pressure. During loading tests, dilatancy appears when the confining pressure is low (0.2 MPa). With increasing confining pressure (0.4, 0.6, and 0.8 MPa), the dilatancy trend gradually weakens, and the cumulative volume tric strain increases, which reflects the relevance of the stress paths. Through research, it is found that the hyperbolic constitutive model has good applicability to sandy gravel soils, and the corresponding model parameters are obtained.

Background and Aims. Left-sided portal hypertension (LSPH) is a rare type of portal hypertension, which occurs due to obstruction, stenosis, or thrombosis within the splenic vein. Pancreatic diseases are the most common etiology of LSPH. This study is aimed at reporting our experiences and discussing the presentation, management, and prognosis of LSPH secondary to pancreatic diseases. Patients and Methods. We retrospectively reviewed five patients who were diagnosed with LSPH secondary to pancreatic diseases at our department. We collected the demographic information, history, comorbidities, clinical presentations, laboratory tests, esophagogastroduodenoscopy (EGD), images, and outcome data. Results. Three elderly patients (>60 years old) were diagnosed with pancreatic cancer, of whom one underwent laparoscopic radical distal pancreatectomy and splenectomy, one received chemotherapy, and another one chose conservative management due to multiple systemic metastases. Two younger patients (

To evaluate the physical and rheological properties of rejuvenated styrene-butadiene-styrene-modified asphalt (SBSMA) binders designed for rapid in-place pavement recycling, an aged SBSMA binder was rejuvenated with three rejuvenators (i.e., Types I, II, and III) in different dosages. The physical properties of rejuvenated SBSMA were obtained to determine the optimal type and dosage of rejuvenators for the first and second rejuvenation. Performance grade (PG) tests, multiple stress creep recovery (MSCR) tests, and linear amplitude sweep (LAS) tests were conducted to measure the rheological properties using the dynamic shear rheometer (DSR) and bending beam rheometer (BBR). The results exhibited that the rejuvenators could soften the multiple aged binder and enhance its high- and low-temperature performance. The rejuvenation effect of rejuvenator Type I with the optimal dosage of 6∼8% was the most appropriate for the first rejuvenation. The optimal dosage of the second rejuvenation was 10∼12%. The addition of rejuvenators decreased the rutting factor G∗/sin δ, creep stiffness (S), delta Tc (ΔTc) parameter, recovery response (R), and yield stress of rejuvenated SBSMA. On the other hand, an increase in the rate of relaxation (m-value), nonrecoverable creep compliance (Jnr), and yield strain of rejuvenated SBSMA was recorded. Overall, the study findings indicated an improvement in the elastic properties of rejuvenated SBSMA, which contributes to improving the rutting, thermal, and fatigue cracking resistance of asphalt binder and ultimately the response of asphalt pavements.

Toxicity induced by crizotinib, a small-molecule tyrosine kinase inhibitor, is a significant clinical issue during treatment. A tissue distribution study is required to explore the organs affected by this molecule. In this study, a simple liquid chromatography tandem mass spectrometry method was developed and validated for the determination of crizotinib in various mouse tissues. Mouse tissue homogenates were processed by protein precipitation with methanol, and apatinib was chosen as the internal standard. The analytes were separated on a Phenomenex Kinetex C18 (50 mm × 2.1 mm, 2.6 μm) column with gradient elution using methanol and 0.3% formic acid water solution. Tandem mass spectrometric detection was conducted using multiple reaction monitoring via an electrospray ionization source in the positive mode. The monitored ion transitions were m/z 450.1 ⟶ 260.2 for crizotinib and m/z 398.2 ⟶ 212.0 for apatinib. The problem of the severe carryover effect was successfully resolved. The method was validated and applied to a tissue distribution study of crizotinib in mice, which was reported for the first time. The results of the study showed that the main target organs of crizotinib were the lung, liver, and spleen, and a high concentration of crizotinib was found in the gastrointestinal tract. This study offers a reliable method for quantifying crizotinib and provides a basis for further research on crizotinib toxicity.

B cell activating factor (BAFF), a member of the tumor necrosis factor (TNF) family, plays a critical role in the pathogenesis and progression of rheumatoid arthritis (RA). Chlorogenic acid (CGA) is a phenolic compound and exerts antiarthritic activities in arthritis. However, it is not clear whether the anti-inflammatory property of CGA is associated with the regulation of BAFF expression. In this study, we found that treatment of the collagen-induced arthritis (CIA) mice with CGA significantly attenuated arthritis progression and markedly inhibited BAFF production in serum as well as the production of serum TNF-α. Furthermore, CGA inhibits TNF-α-induced BAFF expression in a dose-dependent manner and apoptosis in MH7A cells. Mechanistically, we found the DNA-binding site for the transcription factor NF-κB in the BAFF promoter region is required for this regulation. Moreover, CGA reduces the DNA-binding activity of NF-κB to the BAFF promoter region and suppresses BAFF expression through the NF-κB pathway in TNF-α-stimulated MH7A cells. These results suggest that CGA may serve as a novel therapeutic agent for the treatment of RA by targeting BAFF.

A novel cost-effective isolator reinforced by engineering plastics has been designed and manufactured for seismic protection for low-rise buildings in less developed areas. The reinforcement is flexible in tension, which is similar to fiber-reinforced isolators. However, available solutions for fiber-reinforced isolators are not applicable, because the Poisson effect of engineering plastics cannot be neglected, which is done for fiber reinforcement. In this paper, analytical solutions for compression and bending stiffness for rectangular isolators reinforced by engineering plastics are proposed, with both the Poisson effect of the reinforcement and the effect of rubber compressibility taken into consideration. Then, the simplified solutions are also derived, which can greatly improve calculation efficiency. To validate the solutions, finite element analysis is conducted on a set of isolators with different reinforcement stiffnesses. The results show the superiority of the proposed solutions to the previous solutions for fiber-reinforced isolators. A series of experimental tests of the isolators are also carried out to verify the solutions. Both the analytical and the simplified solutions match well with the experimental results.