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Congenital pseudarthrosis of the tibia (CPT) is an uncommon congenital deformity and a special subtype of bone nonunion. The lower ability of osteogenic differentiation in CPT-derived mesenchymal stem cells (MSCs) could result in progression of CPT, and miR-30a could inhibit osteogenic differentiation. However, the role of miR-30a in CPT-derived MSCs remains unclear.The osteogenic differentiation of CPT-derived MSCs treated with the miR-30a inhibitor was tested by Alizarin Red S staining and alkaline phosphatase (ALP) activity. The expression levels of protein and mRNA were assessed by Western blot or quantitative reverse transcription-polymerase chain reaction (RT-qPCR), respectively. The interplay between miR-30a and HOXD8 was investigated by a dual-luciferase reporter assay. Chromatin immunoprecipitation (ChIP) was conducted to assess the binding relationship between HOXD8 and RUNX2 promoter.CPT-derived MSCs showed a lower ability of osteogenic differentiation than normal MSCs. miR-30a increased in CPT-derived MSCs, and miR-30a downregulation promoted the osteogenic differentiation of CPT-derived MSCs. Meanwhile, HOXD8 is a direct target for miR-30a, and HOXD8 could transcriptionally activate RUNX2. In addition, miR-30a could inhibit the osteogenic differentiation of CPT-derived MSCs by negatively regulating HOXD8.miR-30a inhibits the osteogenic differentiation of CPT-derived MSCs by targeting HOXD8. Thus, this study might supply a novel strategy against CPT.

We aimed to determine prognostic factors and develop an effective and practical nomogram for predicting cancer-specific survival in gastrointestinal stromal tumor (GIST) patients. Postoperative data were obtained from the SEER database (2000-2018). Patients were divided into training and validation cohorts at random (7 : 3). Prognostic factors were screened, and a prognostic nomogram was established using log-rank testing and Cox regression. We used DCA, ROC curves, C-index, and calibration curves to evaluate our model’s predictive performance. The clinical value of the nomogram and the modified National Institute of Health (M-NIH) classification were compared using the NRI and IDI. The Kaplan-Meier method was applied to examine survival by risk group, and log-rank tests were applied to compare variations in survival curves. Independent prognostic risk factors associated with cancer-specific survival on multivariate Cox proportional hazards regression analysis were age, race, and tumor location, size, grade, and stage. Clinically relevant variables need to be considered in addition to statistically significant variables when developing prognostic models to aid clinical decision-making. We included two additional variables (mitotic rate and chemotherapy) when constructing the prognostic model. The C-index was 0.766 (95% confidence interval (CI): 0.737-0.794) in the training cohort and 0.795 (95% CI: 0.754-0.836) in the internal validation group suggesting robustness. The areas under the ROC curve for three-year and five-year survival were >0.700, indicating satisfactory discrimination. The calibration curves showed good agreement between the predictions of the nomogram and the actual results. The NRI (0.346 for 3-year and 0.265 for 5-year cancer-specific survival for patients with GIST (GSS) prediction; validation cohort: 0.356 for 3-year and 0.246 for 5-year GSS prediction) and IDI values (0.047 for 3-year and 0.060 for 5-year GSS prediction; validation cohort: 0.071 for 3-year and 0.084 for 5-year GSS prediction) suggested that the established nomogram performed significantly better than the M-NIH classification. The DCA indicated that the nomogram was clinically useful and had a high discriminative ability in identifying patients who were at high risk of poor outcomes. According to nomogram findings, patients were divided into three groups (high, moderate, and low risk), with significantly different prognoses in both cohorts. Our nomogram satisfactorily predicted survival in postsurgical GIST patients, which may assist clinicians to evaluate the postoperative status and guide subsequent treatments.

This paper addresses the fault diagnosis problem of PLC-based systems that can be modeled as Petri nets under a certain level of abstraction. The existing Petri-net-based fault diagnosis approaches often associate transitions and/or places with sensors and require that any change in sensor readings needs to be treated by a PLC, leading to a situation that the PLC would be too busy processing the changes in sensor readings to perform other tasks. This paper assumes that a PLC does not monitor the changes of readings of sensors all the time, but periodically reads the values of sensors when needed. The system output is defined as a marking sequence interleaved with possible observed transitions. A fault diagnosis algorithm is developed by defining and solving integer linear programing (ILP) problems whose size is regardless of the length of the system output. The proposed approach enjoys high computational efficiency compared with other ILP-based approaches and is more suitable for fault diagnosis of PLC-based systems with low computing power.

To establish the optimal dose of indocyanine green (ICG) to administer intravenously 30 min before laparoscopic cholecystectomy (LC).In this randomized controlled trial (RCT), patients undergoing LC for cholecystitis, cholelithiasis, and/or cholecystic polyps were randomized into four groups given four different ICG doses (0.025, 0.1, 0.25, 2.5 mg). Using OptoMedic endoscopy combined with a near-infrared fluorescent imaging system, we evaluated the fluorescence intensity (FI) of the common bile duct and liver at three timepoints: before surgical dissection of the cystohepatic triangle, before clipping of the cystic duct, and before closure. The bile duct-to-liver ratio (BLR) of the FI was analyzed to assess the cholangiography effect.Sixty-four patients were allocated to one of four groups, with 40 patients included in the final analysis. Generally, with increasing ICG doses, the levels of FI in the bile duct and liver increased gradually at each of the three timepoints. Before surgical dissection of the cystohepatic triangle, 0.1-mg ICG showed the highest BLR (F = 3.47, p = 0.0259). Before clipping the cystic duct and before closure, the 0.025- and 0.1-mg groups showed a higher BLR than the 0.25- and 2.5-mg groups (p 0.05). When setting the ideal cholangiography at a BLR ≥ 1, ≥ 3, or ≥ 5, the 0.1-mg group showed the highest qualified case number at the three timepoints.The intravenous administration of 0.1-mg ICG, 30 min before LC, is significantly better for fluorescent cholangiography of the extrahepatic biliary structures before dissection and clipping of the cystohepatic triangle.This study was registered in the Chinese Clinical Trial Registry (ChiCTR) (ChiCTR2200057933).

Accurately simulating viscoelastic wave propagation in the subsurface is essential to image subsurface reservoirs. One established method to investigate constant- Q effects is based on the variable-order fractional viscoelastic wave equation. However, the mixed-domain operators introduced in this approach are cumbersome to calculate and impede a high-efficiency numerical solver. To solve this issue, we approximate the mixed-domain operator by using a polynomial approximation and derive the corresponding viscoelastic wave equation in anisotropic attenuative media. The constant-order fractional polynomial method is further developed to improve the approximation accuracy. Based on these polynomial approximations, only several constant-order Laplacians remain in the new form of the viscoelastic wave equations. Therefore, these equations can be easily solved using Fourier transform and finite-difference methods. In addition, we also perform an accuracy analysis among the conventional quadratic, cubic, and constant-order fractional polynomial approximations. It indicates that the relative error of the constant-order fractional polynomial method is much smaller than that generated by the conventional quadratic and cubic polynomial approximations. Compared to the variable-order fractional viscoelastic wave equation, our constant-order viscoelastic wave equation can simulate seismic wave propagations with comparable accuracy but with high efficiency. Numerical results based on our approach can well match reference solutions in homogeneous and heterogeneous models, demonstrating the accuracy and effectiveness of the new method.

The argillaceous surrounding rock of a horsehead roadway under high stress conditions is prone to deformation and failure, and the control of its long-term stability is difficult. Based on the engineering practices that control the argillaceous surrounding rock of a horsehead roadway in the return air shaft in the Libi Coal Mine in Shanxi Province, field measurements, laboratory experimentation, numerical simulation, and industrial tests are used to analyze the main influencing factors and mechanism of the deformation and failure of the surrounding rock of the horsehead roadway. We propose principles and countermeasures to control the stability of the horsehead roadway. The main factors of the surrounding rock failure of the horsehead roadway include the poor lithology of argillaceous surrounding rocks, horizontal tectonic stress, the superimposed influence of additional stress from the shaft and construction disturbance, the small thickness of the anchorage layer in the roof, and the insufficient depth of floor reinforcement. The results show that the shaft’s presence increases the horizontal stress peak and stress concentration range in the roof, and the plastic zone range. The stress concentration and plastic zones and deformations of the surrounding rock increase significantly with the increase in horizontal tectonic stress. The control principles for the argillaceous surrounding rock of the horsehead roadway include increasing the thickness of the anchorage ring, the floor reinforcement exceeding the minimum depth, and reinforced support in key positions. The key control countermeasures include an innovative prestressed full-length anchorage for the mudstone roof, active and passive reinforcement technology with cables, and a reverse arch for floor reinforcement. The field measurements show that the control of the surrounding rock using the prestressed full-length anchorage of the innovative anchor-grouting device is remarkable.

The etiology for a considerable proportion of patients with congenital radioulnar synostosis (RUS) remains unclear. This study aimed to investigate the genetic cause of RUS without a known cause.Patients with RUS were investigated. Exome sequencing and/or Sanger sequencing was performed. Bioinformatics analysis was also performed. Pathogenicity was evaluated for variants of interest.We identified unique missense variants in MECOM (encodes EVI1) associated with RUS in 8 families. Of them, 6 families had variants in residue R781, including 3 families with R781C (c.2341CT), 2 families with R781H (c.2342GA), and 1 family with R781L (c.2342GT). Another 2 variants included I783T (c.2348TC) in 1 family and Q777E (c.2329CG) in 1 family. All these variants were clustered within the ninth zinc finger motif of EVI1. Phenotype evaluation identified that most of these patients with RUS harboring mutant MECOM had finger malformations, but none of them had identifiable hematological abnormalities. Functional experiments showed that MECOM R781C led to alterations in TGF-β-mediated transcriptional responses.This study examined MECOM variants by focusing on RUS instead of hematological abnormalities. The R781 residue in EVI1 is a hotspot for human RUS variants. Mutant MECOM is the second most common cause for familial RUS.

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Purpose:Immunotherapies targeting immune checkpoint molecules have shown promising treatment for a subset of cancers; however, many “cold” tumors, such as prostate cancer, remain unresponsive. We aimed to identify a potential targetable marker relevant to prostate cancer and develop novel immunotherapy.Experimental Design:Analysis of transcriptomic profiles at single-cell resolution was performed in clinical patients' samples, along with integrated analysis of multiple RNA-sequencing datasets. The antitumor activity of YY001, a novel EP4 antagonist, combined with anti–programmed cell death protein 1 (PD-1) antibody was evaluated both in vitro and in vivo.Results:We identified EP4 (PTGER4) as expressed in epithelial cells and various immune cells and involved in modulating the prostate cancer immune microenvironment. YY001, a novel EP4 antagonist, inhibited the differentiation, maturation, and immunosuppressive function of myeloid-derived suppressor cells (MDSC) while enhancing the proliferation and anticancer functions of T cells. Furthermore, it reversed the infiltration levels of MDSCs and T cells in the tumor microenvironment by overturning the chemokine profile of tumor cells in vitro and in vivo. The combined immunotherapy demonstrated a robust antitumor immune response as indicated by the robust accumulation and activation of CD8+ cytotoxic T cells, with a significantly decreased MDSC ratio and reduced MDSC immunosuppression function.Conclusions:Our study identified EP4 as a specific target for prostate cancer immunotherapy and demonstrated that YY001 inhibited the growth of prostate tumors by regulating the immune microenvironment and strongly synergized with anti–PD-1 antibodies to convert completely unresponsive prostate cancers into responsive cancers, resulting in marked tumor regression, long-term survival, and lasting immunologic memory.

Purpose To evaluate the outcomes of distal femoral, proximal tibial, and distal tibial physeal bar resection combined with or without the Hemi-Epiphysiodesis procedure and provide a better understanding of the application of physeal bar resection combined with Hemi-Epiphysiodesis procedure in the treatment of physeal bar growth arrest. Methods We retrospectively reviewed the patients who suffered physeal bar and underwent physeal bar resection with or without the Hemi-Epiphysiodesis technique during 2010–2020. All were followed up for at least 2 years or to maturity. A modified mapping method was used to determine the area of a physeal bar by CT data. The aLDFA, aMPTA, aLDTA, MAD, and LLD were measured to assess the deformity of the lower limb. Results In total, 19 patients were included in this study. The average age was 8.9 years (range 4.4 to 13.3 years old). During the follow-up, 4 (21.1%) patients had an angular change 5° averaging 10.0° (range 5.3° to 23.2°), and 3 (15.8%) patients had improvement of the angular deformity averaging 16.8° (range 7.4° to 27.1°). Eleven patients (57.9%) had significant MAD improvement. After surgery, we found that 7 (36.8%) patients had an LLD change of 5 mm averaging 1.0 cm (range 0.7 to 1.3 cm), and 7 (36.8%) patients had increasing of LLD > 5 mm averaging 1.3 cm (range 0.5 to 2.5 cm). There were no postoperative fractures, infections, or intraoperative complications such as neurovascular injury. Conclusion Physeal bar resection combined with Hemi-epiphysiodesis is helpful for partial epiphysis growth arrest. Without statistically verifying, we still believe that patients with limited growth ability could benefit more from physeal bar resection combined with Hemi-epiphysiodesis.

Changes in cellular metabolism involving fuel sources are well-known mechanisms of cancer cell differentiation in the context of carcinogenesis. Metabolic reprogramming is regulated by oncogenic signaling and transcriptional networks and has been identified as an essential component of malignant transformation. Hypoxic and acidified tumor microenvironment contributes mainly to the production of glycolytic products known as lactate. Mounting evidence suggests that lactate in the tumor microenvironment of colorectal cancer(CRC) contributes to cancer therapeutic resistance and metastasis. The contents related to the regulatory effects of lactate on metabolism, immune response, and intercellular communication in the tumor microenvironment of CRC are also constantly updated. Here we summarize the latest studies about the pleiotropic effects of lactate in CRC and the clinical value of targeting lactate metabolism as treatment. Different effects of lactate on various immune cell types, microenvironment characteristics, and pathophysiological processes have also emerged. Potential specific therapeutic targeting of CRC lactate metabolism is also discussed. With increased knowledge, effective druggable targets might be identified, with the aim of improving treatment outcomes by reducing chemoresistance.

Decision trees have favorable properties, including interpretability, high computational efficiency, and the ability to learn from little training data. Learning a decision tree is known to be NP-complete. The researchers have proposed many greedy algorithms such as CART to learn approximate solutions. Inspired by the current popular neural networks, soft trees that support end-to-end training with back-propagation have attracted more and more attention. However, existing soft trees either lose the interpretability due to the continuous relaxation or employ the two-stage method of end-to-end building and then pruning. In this paper, we propose One-Stage Tree to build and prune the decision tree jointly through a bilevel optimization problem. Moreover, we leverage the reparameterization trick and proximal iterations to keep the tree discrete during end-to-end training. As a result, One-Stage Tree reduces the performance gap between training and testing and maintains the advantage of interpretability. Extensive experiments demonstrate that the proposed One-Stage Tree outperforms CART and the existing soft trees on classification and regression tasks.

Background Long non-coding RNA X-inactive specific transcript (XIST) regulates the progression of a variety of tumors, including osteosarcoma. Bone marrow mesenchymal stem cells (BMSCs) can be recruited into osteosarcoma tissue and affect the progression by secreting exosomes. However, whether BMSCs derived exosomes transmit XIST to regulate the growth and metastasis of osteosarcoma and the related mechanism are still unclear. Method In this study, BMSCs derived exosomes were used to treat human osteosarcoma cells MG63 and 143B, and the level of XIST in BMSCs was intervened by siRNA. CCK-8, EdU, transwell assays were used to analyze the changes of cell proliferation, migration and invasion. Bioinformatics analysis, RNA pulldown and dual-luciferase reporter gene assays validated the targeted relationship of XIST with miR-655 and the interaction between miR-655 and ACLY 3’-UTR. 143B/LUC cell line was used to establish an animal model of in situ osteosarcoma to verify the found effects of XIST on osteosarcoma. Oil Red O staining, Western blot and so on were used to detect the changes of lipid deposition and protein expression. Results It was found that BMSCs derived exosomes promoted the proliferation, migration and invasion of osteosarcoma cells, and the down-regulation of XIST inhibited this effect. miR-655 mediated the role of BMSCs derived exosomal XIST in promoting the progression of osteosarcoma and down-regulation of miR-655 could reverse the effects of inhibiting XIST on the proliferation, migration and invasion of osteosarcoma cells. Meanwhile, animal level results confirmed that BMSCs derived exosomal XIST could promote osteosarcoma growth and lung metastasis by combining with miR-655. In-depth mechanism study showed that BMSCs derived exosomal XIST combined with miR-655 to increase the protein level of ACLY, which led to lipid deposition and activate β-catenin signal to promote the proliferation, migration and invasion of osteosarcoma cells. Conclusion This study showed that BMSCs derived exosomal XIST could enter osteosarcoma cells, bind and down-regulates the level of miR-655, resulting in an increase in the level of ACLY, thus increasing the lipid deposition and the activity of β-catenin signal to promote the growth and metastasis of osteosarcoma.

The separation of xylene isomers still remains an industrially challenging task. Here, porous purine-based metal-organic frameworks (MOFs) have been synthesized and studied for their potential in xylene separations. In particular, Zn(purine)I showed excellent

The Yanzhou coalfield is an important coal production base in north China, wherein a huge amount of mine drainage has occurred; however, there has been relatively little research on the multi-layer groundwater system. In this study, the Dongtan Coal Mine was considered as the research object and a total of 95 samples were collected. Furthermore, hydrogeochemical and statistical methods were employed to better understand the hydrogeochemical characteristics of the groundwater system in the Yanzhou coalfield. The results show that the groundwater in the area is alkaline. The Ordovician limestone aquifer is quite different from the other aquifers, and the karst herein shows regional distribution characteristics. During the hydrogeochemical evolution of the groundwater, more carbonate and sulfate dissoluted, more cation exchanged, and a lesser extent of silicate weathering and halite dissolution occurred. A conceptual hydrogeological model was created. It shows that the changes in the drainage conditions further resulted in the water chemistry being complex, and induced the hydrogeochemical evolution. The changes in the groundwater dynamic field and the hydrochemical field should be studied to better understand the evolution of the hydrogeochemical properties and accordingly make preparations for preventing mine water disasters and environmental pollution.

Background The current surgical treatment of choice is the combination surgical technique, involving tibial intramedullary fixation to maintain the mechanical axis and mechanical stability of tibial pseudarthrosis. In traditional combined surgery, the Williams rod is often used. Long-term intramedullary fixation of the foot and ankle will affect the ankle joint function of children. The intramedullary rod is relatively shorter due to the growth of the distal tibia. In addition, there are some complications such as epiphyseal bone bridge and high-arched foot. The use of a telescopic intramedullary rod may avoid these complications. Purposes To investigate the initial effect of the “telescopic rod” in a combined surgical technique for the treatment of congenital pseudarthrosis of the tibia in children. Methods A retrospective study including 15 patients with Crawford type IV CPT who were treated using a combined surgical technique and the telescopic rod from January 2017 to May 2018. The average age at the time of surgery was 43.3 months (16–126 months). Of the 15 patients, 7 had proximal tibia dysplasia and 12 exhibited neurofibromatosis type 1. The combined surgical technique using the telescopic rod included the excision of pseudarthrosis, intramedullary rod insertion, installation of Ilizarov’s fixator, tibia-fibular cross union, and wrapping autogenic iliac bone graft. The incidence of refracture, ankle valgus, tibial valgus, and limb length discrepancy (LLD) in patients were investigated. Results All patients achieved primary union with an average follow-up time of 37.3 months (26–42 months). The mean primary union time was 4.5 months (4.0–5.6 months). Nine cases showed LLD (60%), with an average limb length of 1.1 cm (0.5–2.0 cm). Ankle valgus, proximal tibial valgus, telescopic rod displacement, and epiphyseal plate tethering occurred in 1 case (6.6%) (18°), 3 cases (20%) (10°, 5°, and 6°, respectively), 6 cases (40%), and 2 cases (13%), respectively. There were no refractures during the follow-up periods. Conclusion Although there are complications such as intramedullary rod displacement while using the telescopic rod in a combined surgery, the primary healing rate of congenital pseudarthrosis of the tibia in children is high.

A highly stereoselective synthesis of a cyclic dinucleotide (CDN) STING agonist containing two chiral thiophosphoramidate linkages is described. These rare, yet key functional groups were, for the first time, installed efficiently and with high diastereoselectivity using a specially designed P(V) reagent. By utilizing this strategy, the CDN was prepared in greater than sixteen-fold higher yield than the prior P(III) approach, with fewer hazardous reagents and chromatographic purifications.

Gastric cancer is a highly prevalent type of cancer among digestive system tumors. Early screening and intervention of gastric cancer can significantly improve the prognosis of patients. This paper aims to explore the driver genes associated with gastritis-gastric cancer progression and the therapeutic role of Chinese medicine based on bioinformatics analysis of microarray data. First, the microarray dataset GSE55696 of gastritis and gastric cancer was downloaded from the GEO database. The weighted gene co-expression network analysis was used to identify the gene modules associated with gastritis and gastric cancer. And the microarray dataset GSE130823 of gastritis and gastric cancer was downloaded for validation by differential gene analysis, and a total of 15 crossover genes were obtained. Second, the Kaplan-Meier plotter was used for survival analysis to determine the relationship between crossover genes and gastric cancer survival, resulting in CA1, CARNS1, CHAD, CLIC5, CXCL5, KRT6B, OSM, PEBP4, and RGL3 as biomarkers for the progression of chronic gastritis to early gastric cancer. Finally, the HERB database was used to search for compounds and herbs related to gastritis and gastric cancer progression, and to build a “target-compound-herb” network. And operating AutoDockTools 1.5.7 software for molecular docking of core components and core targets. Scopolamine alcohol, fraxetin, 6-aminopurine, citrulline and coumarin showed good docking activity with CA1, CARNS1, CXCL5, CHAD, and KRT6B. In conclusion, CA1, CARNS1, CHAD, CLIC5, CXCL5, KRT6B, OSM, PEBP4, and RGL3 may be used as biomarkers for the progression of chronic gastritis to early gastric cancer. Scopolamine, fraxetin, 6-aminopurine, citicoline, and coumarin may be novel agents against gastritis-gastric cancer progression.

Cancer has become one of the major causes of human death. Several anticancer drugs are available; howeve their use and efficacy are limited by the toxic side effects and drug resistance caused by their continuous application. Many natural products have antitumor effects with low toxicity and fewer adverse effects. Moreover, they play an important role in enhancing the cytotoxicity of chemotherapeutic agents, reducing toxic side effects, and reversing chemoresistance. Consequently, natural drugs are being applied as potential therapeutic options in the field of antitumor treatment. As natural medicinal plants, some components of ginseng have been shown to have excellent efficacy and a good safety profile for cancer treatment. The pharmacological activities and possible mechanisms of action of ginseng have been identified. Its broad range of pharmacological activities includes antitumor, antibacterial, anti-inflammatory, antioxidant, anti-stress, anti-fibrotic, central nervous system modulating, cardioprotective, and immune-enhancing effects. Numerous studies have also shown that throuth multiple pathways, ginseng and its active ingredients exert antitumor effects on gastrointestinal (GI) tract tumors, such as esophageal, gastric, colorectal, liver, and pancreatic cancers. Herein, we introduced the main components of ginseng, including ginsenosides, polysaccharides, and sterols, etc., and reviewed the mechanism of action and research progress of ginseng in the treatment of various GI tumors. Futhermore, the pathways of action of the main components of ginseng are discussed in depth to promote the clinical development and application of ginseng in the field of anti-GI tumors.

Introduction: The incidence and mortality of gastric cancer ranks among the highest, and the 5-year survival rate of advanced gastric cancer (AGC) is less than 10%. Currently, chemotherapy is the main treatment for AGC, and oxaliplatin is an important part of the commonly used chemotherapy regimen for AGC. A large number of RCTs have shown that Chinese herbal medicine (CHM) combined with oxaliplatin-based chemotherapy can improve objective response rate (ORR) and disease control rate (DCR), reduce the toxic and side effects of chemotherapy. There is currently a lack of systematic evaluation of the evidence to account for the efficacy and safety of CHM combined with oxaliplatin-based chemotherapy in AGC. Therefore, we carried out this study and conducted the sensitivity analysis on the herbal composition to explore the potential anti-tumor efficacy.Methods: Databases of PubMed, EMBASE, CENTRAL, Web of Science, the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, the Wanfang database, and the Chinese Scientific Journals Database were searched from their inception to April 2022. RCTs evaluating the efficacy of CHM combined with oxaliplatin-based chemotherapy on AGC were included. Stata 16 was used for data synthesis, RoB 2 for quality evaluation of included RCTs, and GRADE for quality of synthesized evidence. Additional sensitivity analysis was performed to explore the potential anti-tumor effects of single herbs and combination of herbs.Results: Forty trials involving 3,029 participants were included. Most included RCTs were assessed as “Some concerns” of risk of bias. Meta-analyses showed that compare to oxaliplatin-based chemotherapy alone, that CHM combined with oxaliplatin-based chemotherapy could increase the objective response rate (ORR) by 35% [risk ratio (RR) = 1.35, 95% confidence intervals (CI) (1.25, 1.45)], and disease control rate (DCR) by 12% [RR = 1.12, 95% CI (1.08, 1.16)]. Subgroup analysis showed that compare to SOX, FOLFOX, and XELOX regimens alone, CHM plus SOX, CHM plus FOLFOX, and CHM plus XELOX could significantly increase the ORR and DCR. Sensitivity analysis identified seven herbs of Astragalus, Liquorice, Poria, Largehead Atractylodes, Chinese Angelica, Codonopsis, and Tangerine Peel with potentials to improve tumor response of oxaliplatin-based chemotherapy in AGC.Conclusion: Synthesized evidence showed moderate certainty that CHM plus oxaliplatin-based chemotherapy may promote improvement in tumor response in AGC. CHM treatment is safe for AGC. Due to the poor quality of included RCTs and small samplesizes, the quality of synthesized evidence was not high. Specific combinations of herbs appeared to produce higher contributions to ORR than the herb individually. Each of this seven above mentioned herbs has been shown in experimental studies to potentially contribute to the improvement of tumor response. To support this conclusion, these seven herbs are worthy of further clinical research.Systematic Review Registration: [http://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=262595], identifier [CRD42022262595].

BackgroundCongenital pseudarthrosis of the tibia (CPT) is a refractory and rare disease. Because of its extremely low incidence, little is known about its clinical features. In this retrospective study, we aim to analyze the clinical characteristics of patients with CPT.Materials and methodsThis is a retrospective study of children with CPT identified by the radiological review. Investigations of CPT included general conditions, the characteristics of CPT, treatment methods, and surgical complications.ResultsWe collected 514 CPT cases from March 1999 to March 2020 in our hospital, such as 317 (61.67%) boys, 197 (38.33%) girls; 330 (62.86%) in Crawford IV; 510 (97.14%) in mid and distal 1/3 tibia; 481 (93.58%) in less than 3 years at onset age; 297 (57.78%) in less than 3 years at the first outpatient visit. The most common post-operative complication was ankle valgus (101, 39.60%), followed by limb length discrepancy (91, 35.69%), refracture (38, 14.90%), osteomyelitis (15, 5.88%), and removal of internal fixation (10, 3.93%).ConclusionsCPT with a higher incidence of Crawford IV frequently occurs in boys and the middle or distal part of the tibia; most patients have the onset age and first outpatient visit before 3 years; the major surgical complications are ankle valgus and limb length discrepancy.

Recent studies have shown that deep neural networks-based recommender systems are vulnerable to adversarial attacks, where attackers can inject carefully crafted fake user profiles (i.e., a set of items that fake users have interacted with) into a target recommender system to achieve malicious purposes, such as promote or demote a set of target items. Due to the security and privacy concerns, it is more practical to perform adversarial attacks under the black-box setting, where the architecture/parameters and training data of target systems cannot be easily accessed by attackers. However, generating high-quality fake user profiles under black-box setting is rather challenging with limited resources to target systems. To address this challenge, in this work, we introduce a novel strategy by leveraging items' attribute information (i.e., items' knowledge graph), which can be publicly accessible and provide rich auxiliary knowledge to enhance the generation of fake user profiles. More specifically, we propose a knowledge graph-enhanced black-box attacking framework (KGAttack) to effectively learn attacking policies through deep reinforcement learning techniques, in which knowledge graph is seamlessly integrated into hierarchical policy networks to generate fake user profiles for performing adversarial black-box attacks. Comprehensive experiments on various real-world datasets demonstrate the effectiveness of the proposed attacking framework under the black-box setting., Comment: Accepted in the KDD'22

The exact etiology and pathogenesis of congenital pseudarthrosis of tibia (CPT) are not clear. Quantitative proteomics analysis plays a vital role in disease pathology research. Tandem mass tag (TMT)-based proteomics techniques were employed to identify and analyze the differentially expressed proteins (DEP) in the tibia periosteum tissues of CPT patients.The samples were divided into three groups: CPT with NF1 group, CPT without NF1 group (non-NF1-CPT), and control group (patients with open tibial fracture). A fold change ≥1.5 or ≤0.66 and P-value0.05 were used as the thresholds to screen DEPs. Subsequently, bioinformatics resources such as online tools DAVID and String were used to generate gene ontology (GO) annotation, KEGG pathways enrichment, and protein-protein interaction (PPI) network for these DEPs.The results show that a total of 347 proteins were differentially expressed in NF1-CPT groups, 212 of which were upregulated and 135 were downregulated. There were more DEPs in non-NF1-CPT groups; we identified 467 DEPs, including 281 upregulated and 186 downregulated. Among them, NF1-CPT groups and non-NF1-CPT groups shared 231 DEPs, and the remaining 230 DEPs showed the same expression trend in the two disease groups, with 117 upregulated and 113 downregulated. In particular, 116 proteins were altered only in NF1-CPT groups (94 were upregulated and 22 were downregulated), whereas 236 proteins were altered only in non-NF1-CPT groups (164 were upregulated and 72 were downregulated). Finally, compared with non-NF1-CPT groups, 47 proteins changed 1.5-fold and P-value0.05 in NF1-CPT groups.To sum up, we found that common DEPS in periosteum of NF1-CPT and non-NF1-CPT groups are mainly involved in cell matrix assembly, cell adhesion, AKT-PI3K signal pathway activation, and vascular agglutination, which indicate that these are the pathological characteristics of CPT. The osteogenic ability is weak, the osteoclastic ability is strong, the vascular lumen is narrow, the invasive growth and the proliferation of fibroblasts are enhanced in CPT patients.

Background: Distraction osteogenesis (DO) is an approach for bone lengthening and reconstruction. The pixel value ratio (PVR), an indicator calculated from X-ray images, is reported to assess the final timing for the external fixator removal. However, the early PVR and its potential influencing factors and the relationship between the early PVR and clinical outcomes are rarely discussed. Therefore, this study was employed to address these issues.Methods: A total of 125 patients with bone lengthening were investigated retrospectively. The early PVR of regenerated bone was monitored in the first 3 months after osteotomy. The potential effect of sex, chronological age, BMI, lengthening site, and involvement of internal fixation during the consolidation period was analyzed. Moreover, the associations of the healing index (HI) and lengthening index (LI) with early PVR were also investigated.Results: The early PVRs were 0.78 ± 0.10, 0.87 ± 0.06, and 0.93 ± 0.06 in the first 3 months after osteotomy, respectively. Moreover, the PVR in juvenile was significantly higher than that in adults in the first 3 months after osteotomy (0.80 ± 0.09 vs. 0.74 ± 0.10; p = 0.008), (0.89 ± 0.06 vs. 0.83 ± 0.06; p = 0.018), and (0.94 ± 0.05 vs. 0.87 ± 0.05; p = 0.003). In addition, the PVR in males was significantly higher than that in females in the first month after osteotomy (0.80 ± 0.09 vs. 0.76 ± 0.10; p = 0.015), and the PVR in femur site was significantly higher than that in the tibia site in the second and third months after osteotomy (0.88 ± 0.07 vs. 0.87 ± 0.06; p = 0.015) and (0.93 ± 0.06 vs. 0.92 ± 0.06, p = 0.037). However, the BMI and involvement of the internal fixator during the consolidation period seem to not influence the early PVR of regenerated callus during DO. Interestingly, the early PVR seems to be moderately inversely associated with HI (mean = 44.98 ± 49.44, r = -0.211, and p = 0.029) and LI (mean = 0.78 ± 0.77, r = -0.210, and p = 0.029), respectively.Conclusion: The early PVR is gradually increasing in the first 3 months after osteotomy, which may be significantly influenced by chronological age, sex, and the lengthening site. Moreover, the early PVR of callus may reflect the potential clinical outcome for DO. Our results may be beneficial to the clinical management of the subjects with bone lengthening.

Background. Tumor microenvironment (TME) takes a vital effect on the occurrence and development of cancer. Radix Rhei Et Rhizome (RRER, Da-Huang in pinyin), a classical Chinese herb, has been widely used in gastric cancer (GC) for many years in China. However, inadequate systematic studies have focused on the anti-GC effect of RRER in TME. This study intended to uncover the mechanism of it by network pharmacology. Methods. We collected compounds and targets of RRER from traditional Chinese medicine system pharmacology database and analysis platform (TCMSP) and SwissTargetPrediction. GC targets were obtained from GeneCards. Protein-protein interaction (PPI) network and RRER-GC-target network were built by STRING and Cytoscape 3.2.1. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed using Database for Annotation, Visualization, and Integrated Discovery (DAVID). Results. We obtained 92 compounds of RRER. A total of 10 key compounds and 20 key targets were selected by “RRER-GC-target network” topological analysis. GO analysis showed that the biological process mainly involved in response to the tumor necrosis factor, positive regulation of fibroblast proliferation, and DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest. Molecular functions included cyclin-dependent protein serine/threonine kinase activity, RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding, and transmembrane receptor protein tyrosine kinase activity. Cellular components mainly were centrosome, cell surface, and membrane. KEGG pathway enrichment results mainly involved in the p53 signaling pathway, estrogen signaling pathway, and regulation of lipolysis in adipocytes. Conclusion. This study explored the anti-GC mechanism of RRER from the perspective of TME based on network pharmacology, which contributed to the development and application of RRER.

Purpose This study aims to explore the characteristics and related factors of insomnia of patients after operation for gastric cancer. Methods A cross-sectional survey was carried out and finally 115 patients with insomnia after operation for gastric cancer were included. The general information, gastric cancer-related information, sleep quality, and other symptoms were investigated. Results ① The Pittsburgh sleep quality index score of most insomnia patients after gastric cancer surgery was 11-15 points, and the sleep quality rating was “poor”. ② The sleep quality of patients with insomnia after surgery for gastric cancer is related to the number of chemotherapy cycles, fatigue, and depression. ③ The probability of reduced sleep quality with the number of chemotherapy cycles >6 is 3.640 times that of ≤6. The probability of reduced sleep quality during moderate to severe fatigue was 4.390 times that of patients with no or mild fatigue. Conclusion Attention to related factors may be associated with improvement of sleep quality in patients with gastric cancer after surgery.

Background: Idiopathic congenital talipes equinovarus (ICTEV) is one of the most common congenital deformities of children, and dysplasia of the striated muscle may be one of the causes of ICTEV. P...

In this article, we present a fault diagnosis approach for discrete event systems using labeled Petri nets. In contrast to the existing works, a new fault class containing all the fault transitions is additionally introduced in the diagnosis function, leading to a more informative and precise diagnosis result. An integer linear programming (ILP) problem is built according to an observed word. By specifying different objective functions to the ILP problem, the diagnosis result is obtained without enumerating all observable transition sequences consistent with the observed word, which is more efficient in comparison with the existing ILP-based approaches.

Background Non-small-cell lung cancer (NSCLC) is usually diagnosed at an advanced stage, and chemotherapy is the main treatment for this disease. Kanglaite injections (KLTi) have been widely used for the treatment of cancer in China. KLTi combined with chemotherapy could improve the short-term efficacy, quality of life, and performance status for NSCLC compared with chemotherapy alone. This trial aims to assess the long-term efficacy and safety of KLTi in combination with chemotherapy for the treatment of advanced NSCLC. Methods This will be an investigator-initiated multicenter open-label randomized controlled trial. We will randomly assign 334 eligible participants with stage IIIA-IV NSCLC to the treatment or control groups in a 1:1 ratio. Patients in both groups will be administered 4–6 cycles of first-line platinum-based double chemotherapy regimens. Patients with complete response, partial response, or stable disease after 4–6 cycles will receive non-platinum single-agent chemotherapy. Patients in the treatment group are to receive intravenous KLTi 200 ml per day continuously for 14 days, commencing on the first day of chemotherapy. The treatment will be discontinued at the time of disease progression or until unacceptable toxicity is noted. The follow-up will be conducted every 2 months until death, loss of follow-up, or 12 months from randomized enrollment. The primary outcome will be progression-free survival (PFS). The secondary outcomes will be the objective response rate, 1-year survival rate, quality of life, living ability, and blood lipids. The safety outcome will be the rate of adverse events. Discussion This study will be the first randomized controlled trial in which PFS is used as the primary outcome to test whether KLTi combined with first-line chemotherapy has superior efficacy and reduced toxicity compared to chemotherapy alone in advanced NSCLC. This will also be the first clinical study to observe the effects of KLTi on blood lipids. Trial registration ClinicalTrials.gov NCT03986528. Prospectively registered on 30 May 2019.

In this article, we propose a two-layer-structure called hierarchical basis reachability graph that is useful for marking estimation in Petri nets that contain unobservable transitions. On the basis of a hierarchical partition of the set of observable transitions, a hierarchical basis reachability graph consists of a primary and a secondary structures. Simulation shows that the time-consumption to compute a hierarchical basis reachability graph is in general much less than that of computing the corresponding basis reachability graph. A marking estimation algorithm is proposed by the structural analysis of the corresponding hierarchical basis reachability graph.

There are lacking standard treatment guidelines for aggressive fibromatosis (AF) because of its rarity.This study aimed to investigate the risk factors for recurrence and survival of abdominal AF after radical surgical resection.From August 2012 to December 2020, a retrospective analysis was conducted on the clinical data of 69 AF in Shanghai Public Health Clinical Center Affiliated to Fudan University, with the tumor locating either in the abdominal wall or in the abdominal cavity. The main observation end point was progression-free survival time (PFS) and overall survival time (OS).All 69 patients achieved microscopic R0 resection, 10 (14.5%) had local recurrence, and 3 (4.3%) died. The PFS rate after 1, 3, 5, and 10 years was 96.8%, 87.7%, 78.8%, and 78.8%, respectively. The OS rate after 1, 3, 5, and 10 years was 100%, 100%, 92.9%, and 81.3%, respectively. In 10 patients with recurrence, the median recurrence time was 17.6 months. Concomitant familial adenomatous polyposis (FAP) and history of previous recurrence were independent risk factors of post-operative recurrence.After radical surgery of abdominal AF, the local recurrence rate was 15%. Concomitant FAP and a previous history of recurrence were independent risk factors of post-operative recurrence. R0 and a combined organ resection should be performed especially in FAP patients to minimize the recurrence and improve the prognosis.The present study identifies the risk factors of recurrence in AF and suggests R0 resection especially in concomitant FAP patients. A wait-and-see strategy should not be generally implemented and radical surgery will bring clinical benefits to patients with such kind of rare disease.

Background:Congenital pseudarthrosis of the tibia (CPT) is a rare and difficult-to-treat congenital disease in neonates. Our previous study found that exosomes derived from serum of children with CPT inhibit bone formation. In this study, we used ultrasound bone densitometry to detect the bone strength differences between hospitalized children with CPT and with non-metabolic diseases to determine the bone strength of children with CPT.MethodsA total of 37 children with CPT with a mean age of 3.14 ± 1.81 years and 40 hospitalized children with a mean age of 3.32 ± 2.66 years with supracondylar fracture of the humerus and without a bone metabolic disease (control group) were recruited in our hospital. The ultrasonic bone densitometer was used to examine the bilateral calcaneus of the subjects. We collected the broadband ultrasonic attenuation (BUA), speed of sound (SOS), quantitative ultrasound index (QUI), bone strength index (STI) and bone mineral density estimation (BMDe) values. Multivariable regression was used to examine the associations between quantitative ultrasound measurement differences and age, body mass index (BMI), neurofibromatosis type 1 (NF1) and CPT Crawford type. Intra-class correlation coefficient (ICC) was calculated to estimate intra- and inter-rater agreements.Results74 calcaneus scans were taken from CPT patients (23 boys and 14 girls) and 80 calcaneus scans were taken from the control (24 boys and 16 girls). The CPT patients exhibited significantly lower SOS (1,368.75 ± 136.78 m/s), STI (7.2319 ± 38.6525), QUI (8.2532 ± 56.1720), and BMDe (−0.0241 ± 0.3552 g/cm3) than the control (SOS: 1,416.02 ± 66.15 m/s, STI: 7.96 ± 16.884, QUI: 28.8299 ± 25.461, BMDe: 0.0180 ± 0.1610 g/cm3). Multiple regression revealed that SOS, STI and QUI were statistically significant and negatively correlated with CPT Crawford classification.ConclusionsWe found the incidence of decreased bone strength in CPT group was higher than that in the non-bone metabolic disease group. This phenomenon was not related to NF1 but related to CPT Crawford classification, which suggested that the higher the grade of the CPT Crawford classification, the lower the bone strength and the higher the risk of fracture.