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AbstractContext Podophyllotoxin (PPT) derivatives, used in cancer therapy, require development toward enhanced efficacy and reduced toxicity.Objective This study synthesizes PPT derivatives to assess their anticancer activities.Materials and methods Compounds E1-E16 antiproliferative activity was tested against four human cancer cell lines (H446, MCF-7, HeLa, A549) and two normal cell lines (L02, BEAS-2B) using the CCK-8 assay. The effects of compound E5 on A549 cell growth were evaluated through molecular docking, in vitro assays (flow cytometry, wound healing, Transwell, colony formation, Western blot), and in vivo tests in female BALB/c nude mice treated with E5 (2 and 4 mg/kg). E5 (4 mg/kg) significantly reduced xenograft tumor growth compared to the DMSO control group.Results Among the 16 PPT derivatives tested for cytotoxicity, E5 exhibited potent effects against A549 cells (IC50: 0.35 ± 0.13 µM) and exceeded the reference drugs PPT and etoposide to inhibit the growth of xenograft tumours. E5-induced cell cycle arrest in the S and G2/M phases accelerated tubulin depolymerization and triggered apoptosis and mitochondrial depolarization while regulating the expression of apoptosis-related proteins and effectively inhibited cell migration and invasion, suggesting a potential to limit metastasis. Molecular docking showed binding of E5 to tubulin at the colchicine site and to Akt, with a consequent down-regulation of PI3K/Akt pathway proteins.Discussion and conclusions This research lays the groundwork for advancing cancer treatment through developing and using PPT derivatives. The encouraging results associated with E5 call for extended research and clinical validation, leading to novel and more effective cancer therapies.

Land subsidence, marked by a decline in surface elevation, poses a significant threat to urban infrastructure and safety. Accurate subsidence information and a reliable prediction model are crucial for prevention and control. In this study, we used persistent scatterer interferometric synthetic aperture radar (PS-InSAR) technology to obtain long-term land subsidence data and analyzed subsidence characteristics in Decheng District. By integrating hydrogeological and groundwater data, we developed a three-dimensional groundwater flow and one-dimensional compaction model through numerical simulation. Furthermore, the subsidence data monitored by PS-InSAR were used to further constrain and validate the model. The evolution trend of land subsidence under different groundwater exploitation scenarios was predicted and analyzed. The results showed that from May 2017 to December 2021, the cumulative maximum subsidence in Decheng District reached −173 mm. The subsidence area is mainly concentrated in the northern area, and its subsidence center is near Qiaoyuan Town. According to the Land Subsidence Prevention and Control Plan of Dezhou City, Shandong Province (2018–2025), we set up different groundwater mining scenarios with the goal that the rate of land subsidence in the key prevention and control area is less than 35 mm/yr in 2025.The Fluid-solid coupled model prediction analysis results indicated that a 30% reduction in groundwater exploitation is reasonable.

The fluctuations in groundwater levels (GWLs) in the Beijing Plain area are profoundly affected by precipitation (Pre) and groundwater (GW) overexploitation, altering regional water cycle processes and constraining regional economic and ecological development. The South-to-North Water Diversion Project (SWDP) has altered water supply structure in Beijing, leading to a new pattern in GWL fluctuations. This study quantitatively analyzes the evolution patterns of shallow GWLs and quantifies the response relationship between Pre-driven GWL-response on spatial and temporal scales before and after the SWDP. Using GWL and Pre data from 2000 to 2021, employs the coefficient of variation to analyze interannual variability, identifies variation points using the Pettitt and sliding T-test combined with correlation coefficient-based method for the classification of jump degree (R_Jump degree), subsequently divides the sub-sequences. The hydrological trend variation classification method based on correlation coefficient (R_Trend) is used to quantify the spatiotemporal evolution patterns of GWLs in each sub-sequence, and cross-correlation analysis is utilized to examine the time-lag characteristics of GWL responses to Pre in each sub-sequence. The results indicate: (1) GWLs exhibited jump variations in 2015 and 2017, with variation degrees mainly of moderate and strong, and correlation coefficients ranging from 0.18 to 0.67; (2) The overall trend of GWLs shifted from a significant decline to a substantial rebound before and after the SWDP. However, GWLs in the toe of the alluvial fan continued to show a decreasing trend until 2017; (3) The time lag between Pre and GWLs shortened by 6–10 months before and after the SWDP, with the toe of the alluvial fan showing a longer lag time due to over-exploitation. The Pre-GWL lag pattern mainly depends on GW extraction. Compared to existing methods, this paper proposes a research framework for systematically and comprehensively quantifying the evolution of GWLs and their response patterns to Pre, clearly revealing the natural-artificial water cycle processes in the Beijing Plain, providing scientific basis for ecological conservation and water resource management.

This case report describes a woman in her 70s who presented with a 3-month history of hip pain and inability to walk. Upon admission, she was diagnosed with the extremely rare condition of complete femoral head disappearance. A comprehensive examination was conducted to determine the cause and devise an effective treatment strategy, taking the patient’s medical history into account. Through interdisciplinary discussions, occult infection and other potential causes were ruled out. The femoral head disappearance was ultimately determined to be due to wear, ischemia, and absorption following a fracture. After informing the patient of the diagnosis and treatment plan, total hip arthroplasty was proposed. This case highlights the rarity and severity of femoral head disappearance in patients with femoral neck fractures, emphasizing the effectiveness of total hip arthroplasty and appropriate joint prostheses in managing such cases. This case has significant implications for clinical diagnosis, treatment, and complication prevention. The report also discusses the causes of acquired femoral head disappearance, relevant diagnostic assessments, and alternative treatment options.

Purpose As a global health concern, the diagnosis of obstructive sleep apnea hypopnea syndrome (OSAHS), characterized by partial reductions and complete pauses in ventilation, has garnered significant scientific and public attention. With the advancement of digital technology, the utilization of three-dimensional (3D) optical devices demonstrates unparalleled potential in diagnosing OSAHS. This study aimed to review the current literature to assess the accuracy of 3D optical devices in identifying the prevalence and severity of OSAHS. Methods A systematic literature search was conducted in the Web of Science, Scopus, PubMed/MEDLINE, and Cochrane Library databases for English studies published up to April 2024. Peer-reviewed researches assessing the diagnostic utility of 3D optical devices for OSAHS were included. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) guideline was employed to appraise the risk of bias. Results The search yielded 3216 results, with 10 articles meeting the inclusion criteria for this study. Selected studies utilized structured light scanners, stereophotogrammetry, and red, green, blue-depth (RGB-D) cameras. Stereophotogrammetry-based 3D optical devices exhibited promising potential in OSAHS prediction. Conclusions The utilization of 3D optical devices holds considerable promise for OSAHS diagnosis, offering potential improvements in accuracy, cost reduction, and time efficiency. However, further clinical data are essential to assist clinicians in the early detection of OSAHS using 3D optical devices.

Abstract Agriculture contributes to a decline in local species diversity and to above- and below-ground biotic homogenization. Here, we conduct a continental survey using 1185 soil samples and compare microbial communities from natural ecosystems (forest, grassland, and wetland) with converted agricultural land. We combine our continental survey results with a global meta-analysis of available sequencing data that cover more than 2400 samples across six continents. Our combined results demonstrate that land conversion to agricultural land results in taxonomic and functional homogenization of soil bacteria, mainly driven by the increase in the geographic ranges of taxa in croplands. We find that 20% of phylotypes are decreased and 23% are increased by land conversion, with croplands enriched in Chloroflexi, Gemmatimonadota, Planctomycetota, Myxcoccota and Latescibacterota. Although there is no significant difference in functional composition between natural ecosystems and agricultural land, functional genes involved in nitrogen fixation, phosphorus mineralization and transportation are depleted in cropland. Our results provide a global insight into the consequences of land-use change on soil microbial taxonomic and functional diversity.

Gynecological cancers are prevalent malignancies among females, and surgical intervention is the primary therapeutic approach offering the possibility of a definitive cure. Recent research has highlighted the susceptibility of gynecological cancer patients to experiencing anxiety symptoms during the perioperative and postoperative phases, with this psychological condition being linked to suboptimal recovery following surgery. Nevertheless, certain interventions have shown promise in mitigating perioperative and postoperative anxiety in gynecological cancer patients. In this study, we conducted a comprehensive review to collect the existing evidence on this subject. Through a systematic search across six common databases, we screened and included 28 pertinent studies. The current review emphasizes the elevated occurrence of perioperative and postoperative anxiety among patients with gynecological cancers (i.e., uterine, cervical, ovarian, endometrial, and vulval cancers). Specific nursing interventions (i.e., crisis intervention nursing, multidisciplinary collaborative continuous nursing, psychological nursing, comprehensive psychological nursing, reminiscence therapy involved care, cognitive behavioral stress management, hospital-family integrated continuation nursing, high-quality nursing care, relaxation-focused nursing program, and relaxation/counseling intervention) and psychotropic medications may serve as dependable approaches to mitigate perioperative and postoperative anxiety. This study represents a novel contribution to the literature by providing a characterization of perioperative and postoperative anxiety in the context of gynecological oncology. The findings underscore the significance of addressing perioperative and postoperative anxiety as a critical clinical concern for individuals with gynecological cancers, emphasizing the need for further research to develop effective interventions.

Recent years, the tremendous number of distributed energy resources, electric vehicles are integrated into the Low-Voltage Distribution Network (LVDN), large amount of data are generated by edge devices in LVDN. The cloud data centers are unable to process these data timely and accurately, making it impossible to meet the demand for fine-grained control of LVDN. To solve the above problems, this paper proposes a flexible orchestration of lightweight artificial intelligence (AI) for edge computing in LVDN. Firstly, the application requirements of LVDN are analysed through feature extraction of its historical data, and a lightweight AI library is constructed to meet its requirements. Secondly, based on the multi-factor priority, a flexible orchestration model is established, to allow the lightweight AI embedded in the edge devices of the LVDN. Finally, the particle swarm optimization algorithm is used to provide the best solution. The simulation results show that the method proposed in this paper can support the deployment of AI at the edge. It can significantly improve the utilization of edge computing resources, and reduce the pressure of cloud computing and the time of application processes.

BackgroundIn recent years, 3D printing technology has made significant strides in the medical field. With the advancement of orthopedics, there is an increasing pursuit of high surgical quality and optimal functional recovery. 3D printing enables the creation of precise physical models of fractures, and customized personalized steel plates can better realign and more comprehensively and securely fix fractures. These technologies improve preoperative diagnosis, simulation, and planning for complex limb fractures, providing patients with better treatment options.Patients and methodsFive typical cases were selected from a pool of numerous patients treated with 3D printing technology combined with personalized custom steel plates at our hospital. These cases were chosen to demonstrate the entire process of printing 3D models and customizing individualized steel plates, including details of the patients' surgeries and treatment procedures. Literature reviews were conducted, with a focus on highlighting the application of 3D printing technology combined with personalized custom steel plates in the treatment of complex limb fractures.Results3D printing technology can produce accurate physical models of fractures, and personalized custom plates can achieve better fracture realignment and more comprehensive and robust fixation. These technologies provide patients with better treatment options.ConclusionThe use of 3D printing models and personalized custom steel plates can improve preoperative diagnosis, simulation, and planning for complex limb fractures, realizing personalized medicine. This approach helps reduce surgical time, minimize trauma, enhance treatment outcomes, and improve patient functional recovery.

Land subsidence is an environmental geological phenomenon mainly caused by groundwater overexploitation. Long-term overexploitation of groundwater not only causes compaction of aquifer thickness and surface deformation but also leads to the loss of aquifer water storage capacity. The skeleton water storage coefficient (Sk) is an important parameter for evaluating the water storage capacity of aquifer groups. This article proposes a new research framework for obtaining the Sk of different aquifer groups: combining permanent scatter for SAR interferometry technology and a multiscale geographic weighted regression model to obtain subsidence information for different aquifer groups, inverting the Sk of different aquifer groups from the spatial scale, and discussing the deformation characteristics of soil layers under different water head change modes to evaluate the deformation and water storage characteristics of different aquifer groups. This framework is applied to the land subsidence region of the Beijing Plain. We calculated that the settlement proportions of different compression layer groups were 14.75%, 23.65%, 33.44%, and 28.16%. Due to the different lithological compositions and groundwater exploitation of different aquifers, the Sk values exhibit different spatial distribution characteristics. With the continuous development of subsidence, the water storage performance of the aquifer group is continuously declining. These findings contribute to managing the sustainable use of groundwater resources and controlling subsidence. It is demonstrated that the research framework proposed in this article can serve as an effective tool for obtaining settlement information and the Sk of different aquifer groups.

Abstract This study investigated the effectiveness of 3D printing technology in combination with personalized custom-made steel plates in the treatment of complex distal intra-articular trimalleolar fractures, with the aim of providing a new approach to improve ankle joint function in patients. The 48 patients with complex distal intra-articular trimalleolar fractures included in the study were randomly divided into two groups: the personalized custom-made steel plate group (n = 24) and the conventional steel plate group (n = 24). A comparison was made between the two groups in terms of preoperative preparation time, hospitalization duration, surgical time, fracture reduction and internal fixation time, intraoperative fluoroscopy instances, surgical incision length, fracture healing time, follow-up duration, degree of fracture reduction, ankle joint functional recovery, and the occurrence of complications. The personalized steel plate group exhibited longer preoperative preparation time and hospitalization duration compared to the conventional steel plate group (p 0.05). The personalized steel plate group showed a higher rate of successful fracture reduction (87.5% vs. 79.2%, p > 0.05) and a lower incidence of complications (8.3% vs. 20.8%, p = 0.22), although these differences did not reach statistical significance. Furthermore, the personalized steel plate group exhibited superior ankle joint function scores during follow-up compared to the conventional steel plate group (p

Abstract Background Novel ADC drugs provide a new therapeutic strategy for gastric cancer.The present study aimed to analyze the clinical efficacy and drug toxicities of disitamab vedotin (RC48) plus immune checkpoint inhibitors(ICIs) and RC48 as third-line therapies and beyond for advanced and metastatic gastric cancer patients. Methods This was an observational multicenter real-world study.From August 2021 to January 2022,patients with HER2-positive or HER2-low advanced and metastatic gastric cancer and failed from two or more lines of prior therapy were enrolled and treated with RC48 plus ICIs or RC48. In this study, progression free survival(PFS) was the primary end point. Other evaluation indicators were objective response rate(ORR),disease control rate(DCR),overall survival(OS) and drug toxicities. Results 45 patients were enrolled,of which 25 patients received RC48 plus ICIs,20 patients received RC48.Patients who received RC48 plus ICIs obtained better ORR (36.0% vs. 10.0%, P = 0.044) and DCR (80.0% vs. 50.0%, P = 0.034) compared with RC48,and simultaneously,the median PFS in RC48 plus ICIs group were superior to RC48 group(6.2 m vs. 3.9 m).The median OS was not reached.No statistically differences were found between HER2-positive and HER2-low group with respect to ORR (27.3% vs. 16.7%, P = 0.464),DCR (66.7% vs. 66.7%, P = 1.000),median PFS(5.7 m vs. 4.3 m, P = 0.299).The most common adverse events (AEs) were decreased white blood count,decreased neutrophil count,fatigue,hypoaesthesia and alopecia.Grade 3–4 AEs occurred in 7(35.0%) patients of RC48 group and 10(40.0%) patients of RC48 plus ICIs group,respectively. Conclusion Compared with RC48 monotherapy, ICIs plus RC48 demonstrated superior third-line and beyond therapeutic efficacy for HER2-positive or HER2-low advanced and metastatic gastric cancer patients with manageable safety.

Abstract Background Genetic generalized epilepsy (GGE) accounts for nearly one-third of all epilepsies. The feature of status epilepticus (SE) in patients with GGE has been rarely studied. We aimed to determine the electroclinical characteristics of SE in patients with GGE. Methods In this retrospective study, nine patients with GGE were enrolled at Xijing Hospital, Xi’an, China from May 2014 to May 2020. SE was confirmed by 24-h video-EEG recording. The demography, clinical manifestation, brain MRI and SE pattern were analyzed. Results Of the nine patients in the study, seven were female. The mean age of the patients at the time of inclusion was 16.8 years (range 7–31 years), and the mean age at the onset of epilepsy was 10.9 years (range 6–17 years). The follow-up time ranged from 3 months to 6 years. Myoclonic absence status was identified in four patients showing eyelid myoclonia with absence and one patient showing perioral myoclonia with absences. Myoclonic SE was identified in three patients showing juvenile myoclonic epilepsy. Autonomic SE was found in one patient with eyelid myoclonia with absence. SE was terminated by oral midazolam in four patients. In the other five patients, SE terminated spontaneously. Conclusions The seizure type of SE in patients with GGE is often consistent with their major symptoms. Oral midazolam may be an option to terminate SE in patients with GGE.

Background: For patients with human epidermal growth factor receptor-2 (HER2)-positive advanced or metastatic gastric cancer who have progressed on first-line trastuzumab therapy, the clinical value of the continuous use of trastuzumab beyond progression (TBP) is controversial. Objectives: The present study was conducted to evaluate the efficacy and explore new treatment strategies of TBP for patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer in the era of cancer immunotherapy. Design: Retrospective analysis. Methods: Patients with HER2-positive advanced or metastatic gastric cancer who have failed first-line treatment based on trastuzumab-targeted therapy from June 2019 to December 2020 were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Survival curves of patients were estimated by the Kaplan–Meier method and compared using the log-rank test. Results: In all, 30 patients received TBP with chemotherapy, immunotherapy, or anti-angiogenic therapy, and the other 26 patients received treatment of physician’s choice without trastuzumab. The median PFS in the TBP and non-TBP population was 6.0 [95% confidence interval (CI) = 3.8–8.2] and 3.5 (95% CI = 2.2–4.8) months, respectively ( p = 0.038), and the median OS was 12.3 (95% CI = 10.4–14.2) and 9.0 (95% CI = 6.6–11.4) months ( p = 0.008). The patients who received TBP treatment had more favorable PFS and OS than the non-TBP population. In the TBP group, patients who received trastuzumab plus chemotherapy and immunotherapy had higher ORR (40.0% versus 16.7%), DCR (90.0% versus 50.0%), and showed a significant improvement in PFS (7.0 versus 1.9 m) compared to TBP with chemotherapy alone. Subgroup analysis suggested that patients with male, HER2 positive with immunohistochemistry score 3+ and PFS of first-line treatment less than 6 months had a greater benefit from TBP. The incidence of Grade 3–4 adverse events in the TBP and non-TBP groups was 43.3% and 38.5%. Conclusion: The continuous use of TBP improves PFS and OS in patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer with well-tolerated toxicity. In the era of immunotherapy, TBP combined with chemotherapy and immunotherapy may further enhance the clinical benefit and provide a new treatment strategy. Trial registration: This study is a retrospective study, which does not require clinical registration.

Background: Severe delayed diarrhea and hematological toxicity limit the use of irinotecan. Uridine diphosphate glucuronosyltransferase 1A1 ( UGT1A1 ) is a critical enzyme in irinotecan metabolism. The study aims to investigate the safety and efficacy of irinotecan under the guidance of the pre-treatment UGT1A1 genotype in the second-line treatment of gastric cancer. Methods: This study involved 110 patients. Irinotecan was injected intravenously every 3 weeks, and the dose of irinotecan was determined by polymorphism of the UGT1A1 gene, which was divided into three groups (125 mg/m 2 : GG type; 100 mg/m 2 : GA type; 75 mg/m 2 : AA type). The primary end point was overall survival (OS), the secondary end points were progression-free survival (PFS) and safety. Results: One hundred and seven patients received irinotecan treatment and three patients with AA type received paclitaxel treatment. Among 107 patients, there were no significant differences in PFS (4.8 m vs 4.9 m vs 4.4 m; p = 0.5249) and OS (9.3 m vs 9.3 m vs NA; p = 0.6821) among patients with GG/GA/AA subtypes after dose adjustment. For the patient with homozygosity mutation, treatment was switched to paclitaxel. There were no significant differences in PFS and OS among patients with different alleles or after dose adjustment ( p > 0.05). There was a significant difference in the risk of delayed diarrhea ( p = 0.000), leukopenia ( p = 0.003) and neutropenia ( p = 0.000) in patients with different UGT1A1*6 genotypes, while no difference in patients with different UGT1A1* 28 genotypes. Additionally, grade 3/4 diarrhea, neutropenia, and leukopenia were significantly more common in AA genotype patients compared to GG (2%, 19%, 24%) or GA (23%, 31%, 31%) genotype patients. Conclusion: Individual irinotecan treatment shows encouraging survival and tolerability outcomes in patients with GG/GA subtype. Irinotecan may be not suitable for patients with AA subtype.

Abstract The interaction between cerebral endothelial cells (CEC) and brain parenchymal cells is critical to maintain neurovascular homeostasis, whereas extracellular vesicles (EVs) are essential to mediate the cell–cell communication. Previous researches demonstrated that CEC-derived EVs (CEC-EVs) confer neuroprotective actions. However, the molecular mechanisms remain unknown. In this study, we isolated EVs from CEC and assessed their immune-regulatory actions in microglial cells and mice following lipopolysaccharide (LPS) exposure. We found that CEC-EVs treatment significantly ameliorated LPS-induced inflammatory activation, shifting microglial polarization from pro-inflammatory phenotype to anti-inflammatory phenotype. Meanwhile, microglial cells can effectively internalize CEC-EVs and this process was further enhanced by immune activation. Next, the miRNA microarray analysis revealed that CEC-EVs increased expression of miR-672-5p, which was demonstrated to be the cargo of CEC-EVs. TGFβ-activated kinase 1 (TAK1)-binding proteins 2 (TAB2) was identified to be the target of miR-672-5p. Through inhibiting TAB2, miR-672-5p derived from CEC-EVs suppressed TAK1-TAB signaling and thereby mitigating the downstream NF-κB activation. Furthermore, we found that by delivering miR-672-5p, CEC-EVs promoted autophagy and hence stimulating autophagic degradation of NLRP3 inflammasome. Our work firstly revealed the neuroimmune-modulating actions of CEC-EVs and further demonstrated that miR-672-5p secreted from CEC-EVs inhibits microglial pro-inflammatory polarization and facilitates autophagic process via targeting TAB2.

Background: Evidence is limited regarding the relationship among physical activity, anxiety, and oral health in Chinese university students. This cross-sectional investigation aimed to assess the potential relationship between physical activity, anxiety, and oral health conditions among university students in China. Methods: An online questionnaire measuring physical activity, anxiety status, and oral health condition was completed by 1604 university students. The International Physical Activity Questionnaire Short Form (IPAQ-SF) and Generalized Anxiety Disorder-7 (GAD-7) were selected to evaluate physical activity and anxiety, respectively. Oral health condition was assessed through several self-reported variables, including self-reported toothache, gingival bleeding, frequency of tooth brushing, and use of dental floss. Multivariate logistic regression was performed to analyze the underlying relationship between outcome variables. The control variables included age, height, weight, gender, whether only one-child, education level, parental education level, smoking status, drinking habits, and length of sleep. Path analysis was conducted to disentangle the association between physical activity, anxiety, and oral health conditions. Results: Among 1604 university students, 666 (41.5 %) were males and 938 (58.5 %) were females, with an average of 21.9 ± 2.8 years. Only 833 (51.9 %) reported sufficient physical activity, while 684 (42.6 %) of the subjects displayed varying degrees of anxiety. Self-reported gingival bleeding was associated with insufficient physical activity (OR = 1.25; 95%CI: 1.02–1.55), anxiety (OR = 0.45; 95%CI: 0.27–0.74), frequency of tooth brushing (OR = 0.75; 95%CI: 0.60–0.95) and use of dental floss (OR = 0.75; 95%CI: 0.59–0.96), while toothache was not directly influenced by the physical activity and anxiety among university students. Anxiety markedly mediated the relationship between physical activity and oral health conditions. Conclusions: Anxiety was considered a factor associated with the level of physical activity, tooth brushing habits, and self-reported gingival bleeding among university students. Further investigations are required to elucidate whether oral health conditions could be enhanced through the improvement of anxiety and physical activity.

An increasing number of anthropogenic pressures can have negative effects on biodiversity and ecosystem functioning. However, our understanding of how soil microbial communities and functions in response to multiple global change factors (GCFs) is still incomplete, particularly in less frequently disturbed subsoils. In this study, we examined the impact of different levels of GCFs (0–9) on soil functions and bacterial communities in both topsoils (0–20 cm) and subsoils (20–40 cm) of an agricultural ecosystem, and characterized the intrinsic factors influencing community resistance based on microbial life history strategy. Our experimental results showed a decline in soil multifunctionality, bacterial diversity, and community resistance as the number of GCFs increased, with a more drastic reduction in community resistance of subsoils. Specifically, we observed a significantly positive relationship between the oligotroph/copiotroph ratio and community resistance in subsoils, which was also verified by the negative correlation between 16S rRNA operon (rrn) copy number and community resistance. Structural equation modeling further revealed the direct effects of community resistance in promoting the ecosystem functioning, regardless of top- and subsoils. Therefore, these results suggested that subsoils may recruit more oligotrophic microbes to enhance their originally weaker community resistance under multiple GCFs, which was essential for maintaining sustainable agroecological functions and services. Overall, our study represents a significant advance in linking microbial life history strategy to the resistance of belowground microbial community and functionality.

A direct way to reduce scan time for chemical exchange saturation transfer (CEST)-magnetic resonance imaging (MRI) is to reduce the number of CEST images acquired in experiments. In some scenarios, a sufficient number of CEST images acquired in experiments was needed to estimate parameters for quantitative analysis, and this prolonged the scan time. For that, we aim to develop a general deep-learning framework to reconstruct dense CEST Z-spectra from experimentally acquired images at sparse frequency offsets so as to reduce the number of experimentally acquired CEST images and achieve scan time reduction. The main innovation works are outlined as follows: (1) a general sequence-to-sequence (seq2seq) framework is proposed to reconstruct dense CEST Z-spectra from experimentally acquired images at sparse frequency offsets; (2) we create a training set from wide-ranging simulated Z-spectra instead of experimentally acquired CEST data, overcoming the limitation of the time and labor consumption in manual annotation; (3) a new seq2seq network that is capable of utilizing information from both short-range and long-range is developed to improve reconstruction ability. One of our intentions is to establish a simple and efficient framework, i.e., traditional seq2seq can solve the reconstruction task and obtain satisfactory results. In addition, we propose a new seq2seq network that includes the short- and long-range ability to boost dense CEST Z-spectra reconstruction. The experimental results demonstrate that the considered seq2seq models can accurately reconstruct dense CEST images from experimentally acquired images at 11 frequency offsets so as to reduce the scan time by at least 2/3, and our new seq2seq network contributes to competitive advantage.

Abstract Carbon monoxide (CO) gas therapy demonstrates great potential to induce cancer cell apoptosis and antitumor immune responses, which exhibits tremendous potential in cancer treatment. However, the therapeutic efficacy of CO therapy is inhibited by the immunosuppressive tumor microenvironment (TME). Herein, a facile strategy is proposed to construct hollow‐structured rough nanoplatforms to boost antitumor immunity and simultaneously reverse immunosuppression by exploring intrinsic immunomodulatory properties and morphological optimization of nanomaterials. The TME‐responsive delivery nanosystems (M‐RMH) are developed by encapsulating the CO prodrug within hollow rough MnO2 nanoparticles and the subsequent surface functionalization with hyaluronic acid (HA). Rough surfaces are designed to facilitate the intrinsic properties of HA‐functionalized MnO2 nanoparticles (RMH) to induce dendritic cell maturation and M1 macrophage polarization by STING pathway activation and hypoxia alleviation through enhanced cellular uptake. After TME‐responsive degradation of RMH, controlled release of CO is triggered at the tumor site for CO therapy to activate antitumor immunity. More importantly, RMH could modulate immunosuppressive TME by hypoxia alleviation. After the combination with aPD‐L1‐mediated checkpoint blockade therapy, robust antitumor immune responses are found to inhibit both primary and distant tumors. This work provides a facile strategy to construct superior delivery nanosystems for enhanced CO/immunotherapy through efficient activation of antitumor immune responses and reversal of immunosuppression.

Highly-deviated wells are the key technology to reduce the risk of drilling accidents and improve the utilization of reservoirs. However, for reservoirs with complex lithology, highly-deviated wells are faced with the problems of geomechanical transformation and fracturing parameter optimization. The research on fracturing parameter optimization technology of high-deviated wells in complex lithologic reservoirs is helpful to the research and application of geomechanics in deep unconventional reservoirs. This paper is based on geological mechanics laboratory experiments and logging interpretation, combined with regional geological background, to clarify the geological and mechanical characteristics of the Fengcheng Formation shale oil region in the Mabei Slope. On this basis, based on the current geostress field and natural fracture distribution pattern of the Mabei Slope, an integrated model of shale oil geological engineering in local well areas was established. Based on the finite element method, optimization design was carried out for the cluster spacing, construction fluid volume, displacement, and sand volume of highly deviated well fracturing, and three-dimensional simulation of fracturing fractures was completed. The research results indicate that: (1) The current dominant direction of the maximum principal stress in the Fengcheng Formation on the Mabei Slope is from northeast to southwest, with the maximum horizontal principal stress generally ranging from 90 to 120 MPa and the minimum horizontal principal stress generally ranging from 70 to 110 MPa. (2) The difference in stress between the two horizontal directions is relatively large, generally greater than 8 MPa. Two sets of natural fractures have developed in the research area, one with a northwest southeast trend and the other with a northeast southwest trend. The natural fracture density of the Fengcheng Formation shale reservoir in the Mabei Slope is 0.32–1.12/m, with an average of 0.58/m, indicating a moderate to high degree of fracture development. (3) The geological model and three-dimensional geo-mechanical model are established according to the actual drilling geological data, and different schemes are designed to carry out single parameter optimization. The optimization results show that the optimal cluster spacing of the subdividing cutting volume pressure of the highly deviated wells in the Fengcheng Formation of the Mabei Slope is 12 m, the optimal construction fluid volume is 1400–1600 m3/section, the optimal construction displacement is 8 m3/min, and the optimal sanding strength is 2.5 m3/m. At the same time, by comparing the fracturing implementation effect with the fracturing scheme design, it is proven that the artificial parameter optimization method for highly deviated wells based on the finite element method based on the regional stress background and the natural fracture development law proposed in this paper is feasible and can provide a scientific basis for the fracturing development of highly deviated wells in complex lithologic reservoirs. This research has been well applied in Mahu area of Xinjiang oilfield.

Beijing has undergone severe settlement in recent years. Persistent Scatterers Interferometric Synthetic Aperture Radar (PS-InSAR) technique has been widely used to derive time-series land deformation. However, existing studies have faced two challenges: (1) the nonlinear characteristics of time-series subsidence has not been fully investigated; (2) since PS points are normally distributed in urban areas with high building density, measurement gaps usually exist in nonurban areas. To address the challenges, we presented a new method to reconstruct spatially continuous time-series deformation. First, PS-InSAR was used to retrieve the deformation based on 135 scenes of Envisat ASAR and Radarsat-2 images from 2003 to 2020. Polynomial Curve Fitting (PCF) was then used to model nonlinear time-series deformation for the PS points. In the PS measurement gaps, Iterative Self-Organizing Data Analysis Technique (ISODATA) and Multi-output Least Squares Support Vector Regression (MLS-SVR) were used to estimate the PCF coefficients and then time-series deformation considering 40 features including thickness of the compressible layers, annual groundwater level, etc. The major results showed that (1) compared to linear, quadratic, and quartic models, cubic polynomial model generated better fit for the time-series deformation (R2 ≈0.99), suggesting obvious nonlinear temporal pattern of deformation; (2) the time-series deformation over measurement gaps reconstructed by ISODATA and MLS-SVR had satisfactory accuracy (R2 = 0.92, MAPE

Study region: Beijing-Tianjin-Hebei (BTH) region, China Study focus: BTH has long been suffering from severe and uneven land subsidence. Finding out the spatial evolution of land subsidence is helpful to collaborative prevention and control. We innovatively revealed the spatial distribution of land subsidence from the mountains to the coastal area along four hydrogeological profiles, and inferred the land subsidence mechanism on the overall scale, local plain scale and typical regional scale. Small Baseline Subsets Interferometric Synthetic Aperture Radar was employed to collect displacement information in the BTH region from January 2012 to January 2020. We obtained groundwater storage data from the Gravity Recovery and Climate Experiment. New hydrological insights for the region: On the overall scale, from 2012 to 2019, the Changping-TongZhou district of Beijing suffered the most serious land subsidence, with an annual subsidence rate of 159 mm and a cumulative subsidence as high as 928 mm. On the local plain scale, areas experiencing severe subsidence were generally located in the central plain. Fractures in the area obviously influenced the spatial distribution of subsidence. On the typical regional scale, a positive correlation was found between land subsidence and groundwater depletion. The relationship between precipitation and land subsidence in Hebei was the most convincing (R2 = 0.64). This study provides a scientific basis for regional coordination in land subsidence control. Data availability: Data can be provided by the corresponding authors upon request.

Introduction: The unavailability of adequate human primary cells presents multiple challenges in terms of bone and cartilage regeneration and disease modeling experiments in vitro. Periosteal cells (PCs), which represent promising skeletal stem cell sources, could be a promising strategy in tissue engineering. The present study aimed to summarize the characteristics of PCs to investigate the efficacy of these cells in bone and cartilage regeneration in different models, paying special attention to the comparison of bone marrow stromal cells (BMSCs).Methods: A comprehensive literature search was conducted in Embase, PubMed/MEDLINE, Web of Science, and Scopus for articles published in English until April 2023. Only original researches in which PCs were employed for bone or cartilage regeneration experiments were included.Results: A total of 9140 references were retrieved. After screening the results, 36 publications were considered to be eligible for inclusion in the present literature review. Overall, PCs demonstrated beneficial bone and cartilage regenerative efficacy compared to the bare scaffold since almost all included studies reported positive results. The 9 studies assessing the differences in bone formation capacity between PCs and BMSCs indicated that PCs exhibited stronger in vivo osteogenic differentiation capabilities compared to BMSCs, while the other study demonstrated stronger chondrogenic potential of BMSCs.Discussion: PCs demonstrated beneficial to bone regenerative efficacy compared to the bare scaffold with a low risk of most studies included. However, the cartilage formation capacity of BMSCs still needs to be investigated due to the limited research available and the certain risk of bias. PCs exhibited higher osteogenic capabilities compared to BMSCs in combination with various scaffolds in vivo with good evidence. Further researches are needed to elucidate the comparative benefits of cartilage regeneration.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023411522, CRD42023411522.

BackgroundHyperuricemia is a known risk factor of lipid metabolism disorder. However, the mechanisms have not been fully understood.MethodsThe serum samples from hyperuricemia subjects were used to analyze the correlation between serum uric acid and clinical characteristics. Hyperuricemia mice induced by potassium oxonate (PO) and adenine were used to explore glucocorticoid metabolism.ResultsIn hyperuricemia patients, the levels of serum uric acid were positively correlated with the levels of γ-glutamyltransferase, associated with a cortisol metabolism disorder. In hyperuricemia state, the adrenal glands failed to respond to adrenocorticotropic hormone properly, leading to low cortisol, but not corticosterone production, and decreased mRNA levels of aldosterone synthase, 11β-hydroxylase, and 3β-hydroxysteroid dehydrogenase 1, three key enzymes for cortisol synthesis. The expression of both hepatic 5α-reductase and renal 11β-hydroxysteroid dehydrogenase 2 was significantly reduced, which led to low cortisol clearance. We denominated this cortisol metabolism disorder in hyperuricemia as pseudohypoadrenalism (PHAL).ConclusionPHAL increased exposure to the bioavailable cortisol in the liver, leading to local amplification of the biological action of corticosteroids. Unregulated biosynthesis pathway of bile acid expanded bile acid pool, and further aggravated cholestatic liver injury.

Diastasis recti abdominis (DRA) affects a significant number of postpartum women, while its treatments are still under debate. This study aimed to systematically evaluate the effectiveness of rehabilitation training programs for postpartum DRA treatment. Four databases were systematically searched to identify eligible studies published up to February 1, 2023. We followed the PRISMA for scoping reviews guideline in this study. The characteristics and the main findings of the included studies were extracted. Sixteen studies enrolling 1129 women during the ante- and/or postnatal period were included. The common rehabilitation training for DRA included physical exercise, non-exercise physical therapy, acupuncture, and electrotherapy. The presence of DRA could be diagnosed by ultrasound, caliper, or palpation, of which ultrasound had the best reliability. Besides, these assessments could also be used for evaluating the therapeutic efficacy after the rehabilitation training programs. Several studies concluded that patients with DRA could be effectively improved by specific interventions. But a few included studies revealed rehabilitation training might be not more effective than no interventions when treating DRA. For example, some investigators did not recommend physical exercise for DRA patients due to this intervention during pregnancy kept the linea alba less stressed by maintaining abdominal tone, strength, and control, and therefore might aggravate DRA. However, it should be noted that this evidence was derived from limited studies (16/60, 27 % papers) with small samples. To some extent, women with postpartum DRA can benefit from the specific rehabilitation regimen by alleviating postpartum inter-rectus distance. Further research is still warranted to propose strategies for improving postpartum DRA.

Abstract Objective This is the first clinical study that wants to investigate the treatment patterns, clinical outcomes, and prognostic factors of regorafenib plus PD-1 inhibitors therapy in Chinese elderly patients with advanced colorectal cancer. Methods A cohort of metastatic colorectal cancer patients 60 years or older who received treatment with regorafenib combined with PD-1 inhibitors was included in our analysis. The endpoints included overall survival (OS), progression-free survival (PFS), and prognostic factors. Results In total, 24 patients were enrolled with the median age of 68 years, and 62.5% were female. The median OS and PFS were 15.03 months (95% CI 7.0–23.0) and 4.0 months (95% CI 1.8–6.2), respectively. The objective response rate was 8.3%, and the disease control rate was 70.8%. Patients previously treated with regorafenib had a longer median PFS than those without (6.3 versus 2.8 months). In terms of final daily doses, it showed a trend toward better PFS (median PFS was 10.0 months) in high-dose group (daily dose above 80 mg of regorafenib) compared to low-dose group (daily dose no more than 80 mg of regorafenib) (median PFS was 3.5 months). Conclusions This real-world evidence confirms that Chinese elderly patients with advanced colorectal cancer may benefit from the treatment of regorafenib combined with PD-1 inhibitors, similarly with this combination therapy strategies in all age patients.

Acupuncture has gained growing attention in the management of osteoporosis (OP). However, a comprehensive review has not yet been conducted on the efficacy and challenges of acupuncture in preliminary research and clinical trials. Therefore, an extensive literature search was conducted using electronic databases, including PubMed (www.ncbi.nlm.nih.gov/pubmed), CNKI (www.cnki.net), and Web of Science, for studies published from the beginning of 2000 to the end of May 2022. Combinations of synonyms for OP, acupuncture, traditional Chinese medicine, clinical trial, preclinical study, and animal experiments were searched. A total of 290 papers were consulted, including 115 reviews, 109 clinical observations, and 66 preclinical studies. There is accumulating evidence to support the beneficial role of acupuncture in preserving bone quality and relieving clinical symptoms based on clinical and preclinical investigations. The top ten most commonly used acupoints are BL23, ST36, BL20, BL11, CV4, GV4, SP 6, KI3, BL18, and GB39. The underlying mechanisms behind the benefits of acupuncture may be linked with the regulation of the hypothalamic-pituitary-gonadal (adrenal) axis and activation of the Wnt/β-catenin and OPG/RANKL/RANK signaling pathways. In summary, strong evidence may still come from prospective and well-designed clinical trials to shed light on the potential role of acupuncture in preserving bone loss. Future investigations are needed to explore the potential underlying mechanisms, long-term clinical efficacy, and compliance of acupuncture in OP management.

Abstract Land subsidence induced by groundwater level decline has spatiotemporal variations. Taking the Interferometric Synthetic Aperture Radar (InSAR) results and the groundwater subsidence data acquired by the monitoring stations as the source material, this paper aims to reveal the spatiotemporal heterogeneity of groundwater-land subsidence in Beijing plain by using the Wind Rose Map (WRM) method and the Change Point Analysis (CPA) method. The WRM results show that the amount and variation in subsidence differs in different directions. This method detected the formation of new subsidence centers and the slowdown of land subsidence in 2008. The CPA results show that obvious changes are detected in subsidence development at the Wangsiying (WSY), Tianzhu (TZ) and Wangjing (WJ) stations. However, there is a relatively stable trend of groundwater decline and land subsidence at the Tianzhu (TZ) station. The stages of land subsidence development show a significant response to groundwater. Moreover, changes in land subsidence also show delayed response behind the changes in groundwater level. The time-lag could be affected by the variation in amplitude of the groundwater level.

As a thin fibrous layer covering the bone surface, the periosteum plays a significant role in bone physiology during growth, development and remodeling. Over the past several decades, the periosteum has received considerable scientific attention as a source of mesenchymal stem cells (MSCs). Periosteum-derived cells (PDCs) have emerged as a promising strategy for tissue engineering due to their chondrogenic, osteogenic and adipogenic differentiation capacities. Starting from the history of PDCs, the present review provides an overview of their characterization and the procedures used for their isolation. This study also summarizes the chondrogenic, osteogenic, and adipogenic abilities of PDCs, serving as a reference about their potential therapeutic applications in various clinical scenarios, with particular emphasis on the comparison with other common sources of MSCs. As techniques continue to develop, a comprehensive analysis of the characterization and regulation of PDCs can be conducted, further demonstrating their role in tissue engineering. PDCs present promising potentials in terms of their osteogenic, chondrogenic, and adipogenic capacities. Further studies should focus on exploring their utility under multiple clinical scenarios to confirm their comparative benefit over other commonly used sources of MSCs.

Cangzhou is located in the northeast part of the North China Plain; here, groundwater is the main water source for production and living. Due to the serious regional land subsidence caused by long-term overexploitation of groundwater, the monitoring of land subsidence in this area is significant. In this paper, we used the Small Baseline Subsets Interferometric Point Target Analysis (SBAS-IPTA) technique to process the Envisat-ASAR, Radarsat-2, and Sentinel-1A data and obtained the land subsidence of Cangzhou from 2004 to 2020. Additionally, we obtained winter wheat distribution information in Cangzhou using the Pixel Information Expert Engine (PIE-Engine) remote sensing cloud platform. On this basis, we analyzed the relationship between ground water level, winter wheat planting area, and the response of land subsidence according to the land use type and groundwater level monitoring data near the winter wheat growing area. The results show that during 2004–2020, the average annual subsidence rate of many places in Cangzhou was higher than 30 mm/year, and the maximum subsidence rate was 115 mm/year in 2012. From 2004 to 2020, the area of the subsidence funnel showed a trend of first increasing and then decreasing. In 2020, the subsidence funnel area reached 6.9 × 103 km2. The winter wheat planting area in the urban area showed a trend of first decreasing, then increasing and then decreasing, and it accounted for a large proportion in the funnel area. At the same time, we studied the relationship between the land subsidence rate and the water level at different burial depths and the response of winter wheat planting area. The results showed that the change of confined water level had a stronger response with the other two variables.

Sonneratia apetala is an essential mangrove wetland restoration tree species. Studying its molecular mechanism for salt tolerance could lay a foundation for further cultivating excellent resistant germplasm. This study used a combination of PacBio isoform sequencing (Iso-seq) and BGISEQ RNA sequencing (RNA-seq) to analyze the molecular mechanism to salt stress response of one-year-old S. apetala leaves. The growth and physiological analysis showed that physiological indexes such as growth rate, net photosynthetic rate and antioxidant enzyme activity all exhibit significant changes under salt stress. From Iso-seq, a total of 295,501 full-length transcripts, with an average length of 1418 bp, were obtained. RNA-seq produced 4712 differentially expressed genes (DEGs) as compared to a control group. Of these, 930 were identified to be co-expressed during the STEM time sequence analysis. Further, 715 and 444 co-expressed DEGs were annotated by GO and KEGG analyses, respectively. Moreover, 318 of the co-expressed DEGs were annotated as essential genes that were implicated in salt stress response of S. apetala, which were involved in transcription factors, signal transduction, hormone response, ROS homeostasis, osmotic balance, cell wall synthesis or modification. These results provide candidate targets for further characterization and offer insights into the salt-tolerant mechanism of S. apetala.

Cancerous inhibitor of protein phosphatase 2A (CIP2A), initially reported as a tumor-associated antigen (known as p90), is highly expressed in most solid and hematological tumors. The interaction of CIP2A/p90, protein phosphatase 2A (PP2A), and c-Myc can hinder the function of PP2A toward c-Myc S62 induction, thus stabilizing c-Myc protein, which represents a potential role of CIP2A/p90 in tumorigeneses such as cell proliferation, invasion, and migration, as well as cancer drug resistance. The signaling pathways and regulation networks of CIP2A/p90 are complex and not yet fully understood. Many previous studies have also demonstrated that CIP2A/p90 can be used as a potential therapeutic cancer target. In addition, the autoantibody against CIP2A/p90 in sera may be used as a promising biomarker in the diagnosis of certain types of cancer. In this Review, we focus on recent advances relating to CIP2A/p90 and their implications for future research.

High-speed railways in the Beijing–Tianjin–Hebei (BTH) Plain are gradually becoming more widespread, covering a greater area. The operational safety of high-speed railways is influenced by the continuous development of land subsidence. It is necessary to predict the subsidence along the high-speed railways; thus, this work is of critical importance to the safety of high-speed railway operation. In this study, we processed Sentinel-1A data using the Persistent Scatterer Interferometric Synthetic Aperture Radar (PS-InSAR) technique to acquire the land subsidence in the typical BTH area. Then, we combined the Empirical Mode Decomposition (EMD) and Gradient Boosting Decision Tree (GBDT) methods (EMD-GBDT) to forecast land subsidence along high-speed railways. The results revealed that some parts of the high-speed railways in the BTH plain had passed through or approached the land subsidence area; the maximum cumulative subsidence of the Beijing–Shanghai, Tianjin–Baoding and Shijiazhuang–Jinan high-speed railways reached 326 mm, 384 mm and 350 mm, respectively. The forecasting accuracy for land subsidence along high-speed railways was enhanced by the EMD-GBDT model. The Root Mean Square Error (RMSE) and Mean Absolute Error (MAE) were 0.38 mm to 0.56 mm and 0.23 mm to 0.38 mm, respectively.

Objective. It is well known that paclitaxel (PTX)-induced neurotoxicity seriously affects the quality of life of patients and is the main reason for reducing the dose of chemotherapy or even stopping chemotherapy. The current data are limited, and further information is required for practice and verification. The aims of this study were to clarify the molecular mechanism underlying PTX-induced neurotoxicity by combining in vivo and in vitro metabolomics studies and provide new targets for the prevention and treatment of PTX-induced neurotoxicity. Methods. In the in vivo study, a PTX-induced neurotoxicity mouse model was established by intraperitoneal injection of PTX (6 mg/kg every three days) for two consecutive weeks. After verification by water maze tests and HE staining of pathological sections, hippocampal metabolites were measured and the differential metabolites and related metabolic pathways were identified by multivariate statistical analysis. In the in vitro study, we investigated the effects of PTX on mouse hippocampal neuron cells, assessing the concentration and time of administration by MTT assays. After modeling, the relevant metabolites in the TCA cycle were quantified by targeted metabolomics using stable isotope labeling. Finally, the key enzymes of the TCA cycle in tissues and cells were verified by RT-PCR. Results. Administration of PTX to model mice resulted in neurological damage, shown by both water-maze tests and hippocampal tissue sections. Twenty-four metabolites and five associated metabolic pathways were found to differ significantly between the hippocampal tissues of the model and control groups. These included metabolites and pathways related to the TCA cycle and pyruvate metabolism. Metabolomics analysis using stable isotope labeling showed significant changes in metabolites associated with the TCA cycle compared with the control group (P

Background: The monitoring and removal of heavy metal ions in wastewater will effectively improve the quality of water and promote the green and sustainable development of ecological environment. Using more efficient adsorption materials and more accurate detection means to treat heavy metal ions in water has always been a research focus and target of researchers.Method: A novel titania nanomaterial was modified with sulfhydryl group (nano TiO2-SH) for detection and adsorption of heavy metal ions in water, and accurately characterize the adsorption process using Surface-Enhanced Raman Spectroscopy (SERS) and other effective testing methods.Results: The maximum adsorption efficiency of nano TiO2-SH for the Hg2+, Cd2+, Pb2+ three heavy metal ions reached 98.3%, 98.4% and 98.4% respectively. And more importantly, after five cycles of adsorption and desorption, the adsorption efficiency of nano TiO2-SH for these three metal ions is still above 96%.Conclusion: These results proved the nano TiO2-SH adsorbent has great potential in practical water pollution purification.

Objectives: This study was carried out to assess the efficacy and drug toxicity of anti-angiogenic tyrosine kinase inhibitor (TKI) plus chemotherapy as second-line or above therapeutic regime in advanced or metastatic gastric cancer patients. Methods: From November 2017 to April 2020, advanced or metastatic gastric cancer patients who have failed from prior treatment and received apatinib combined with irinotecan or irinotecan treatment were analyzed. The primary observed indicator was progression-free survival (PFS). Objective: response rate (ORR), disease control rate (DCR), overall survival (OS), and drug toxicity were also evaluated. Results: 26 patients received apatinib combined with irinotecan and 29 patients received irinotecan. The ORR in the combination therapy and monotherapy population was 26.9% and 17.2%, respectively. The DCR in the apatinib combined with irinotecan group was higher than in irinotecan monotherapy population (80.8% vs 55.2%, P = .043). Median PFS was 4.2 months in the combination group and 3.3 months in the monotherapy group ( P = .020). Median OS was 8.0 months in the combination group and 5.9 months in the monotherapy group ( P = .048). Except for ECOG PS 2, PFS and OS were generally consistent across subgroups by sex, age, number of metastatic sites and primary tumor site. The incidence of Grade 3–4 adverse events in combination and monotherapy group was 23.1% and 20.7%, respectively. In apatinib combined with irinotecan group, adverse events that were attributed to apatinib were secondary hypertension (in seven patients, 26.9%), hand-foot syndrome (5,19.2%), and proteinuria (5, 19.2%). Univariate analysis demonstrated that secondary hypertension was considered to be a favorable factor ( P = .040) for longer OS in combination therapy group. Conclusions: Compared with chemotherapy alone, anti-angiogenic TKI plus chemotherapy showed better PFS, OS and DCR in advanced or metastatic gastric cancer as second-line or above therapy, with a tolerable and manageable safety profile.

Beijing’s Sub-Administrative Center (BSAC) is located in the South-eastern Beijing Plain, which exhibits severe subsidence. The rapid urban expansion in recent years has aggravated land subsidence and threatens the safe operation of Beijing. First, this study applied the persistent scatterer-interferometric synthetic aperture radar (PS-InSAR) to extract BSAC subsidence time series data. Second, combined with the index-based built-up index (IBI), expansion intensity index (EII), and expansion gradient index (EGI), the spatiotemporal characteristics of urban expansion were retrieved from optical data. Finally, we examined the urban expansion effects on land subsidence at the regional and single-building scales. The results showed that the maximum subsidence velocity in the BSAC reached 121 mm/year from 2015 to 2018, and the urban construction land area increased by 22%. At the regional scale, there existed a positive correlation between land subsidence and EGI or EII. This indicated that urban expansion had a certain impact on land subsidence. Therefore, we further explored the relationship between construction and land subsidence at the single-building scale. The engineering construction effects on land subsidence were divided into three periods, namely, rapid settlement, rebound, and stable periods. Although construction had a significant influence on land subsidence, it did not cause subsidence mutation.

Background: There is currently still a lack of effective therapeutic manner after the failure of first-line therapy for patients with advanced or metastatic gastric cancer. The present study aimed to evaluate the clinical efficacy and safety of different treatment strategies as second-line or above therapy for patients with advanced or metastatic gastric cancer.Methods: This was an observational multicenter real-world study. From January 2018 to December 2020, advanced or metastatic gastric cancer patients who have failed prior therapy were enrolled and treated with chemotherapy, anti-angiogenic TKIs (tyrosine kinase inhibitors) + chemotherapy or TKIs + ICIs (immune checkpoint inhibitors). In this study, progression free survival (PFS) was the primary end-point. Other evaluation indicators were objective response rate (ORR), disease control rate (DCR), overall survival (OS) and drug toxicities.Results: 162 patients were enrolled, of which 61 patients received chemotherapy, 47 patients received TKIs plus chemotherapy, and 54 patients received TKIs + ICIs. No statistically significant difference existed in ORR among groups (16.4% vs. 19.1% vs. 18.5%, p = 0.924). Patients who received TKIs plus chemotherapy obtained better DCR compared with the chemotherapy group (78.7% vs. 54.1%, p = 0.008), and simultaneously, the median PFS (3.3 m vs. 2.8 m, p = 0.001) and OS (8.0 m vs. 5.8 m, p = 0.005) in TKIs plus chemotherapy group were superior to chemotherapy group. Consistent results were observed in subgroup analysis, including sex, age, ECOG, number of metastatic sites and treatment line. No statistically differences were found between TKIs + ICIs and the chemotherapy group concerning DCR (63.0% vs. 54.1%, p = 0.336), median PFS (3.0 m vs. 2.8 m, p = 0.051) and OS (5.2 m vs. 5.8 m, p = 0.260). Different treatment manner present a special spectrum of adverse events (AEs), and the incidence of Grade 3–4 AEs were 31.1%, 38.3% and 18.5%, respectively.Conclusion: Compared with chemotherapy, anti-angiogenic TKIs plus chemotherapy demonstrated superior second-line or above therapeutic efficacy for advanced or metastatic gastric cancer with well tolerated toxicity. However, TKIs + ICIs failed to demonstrate a clinical advantage over chemotherapy.

With the outbreak of COVID-19 in late 2019, people’s awareness of actively searching for health information has been growing. Coupled with the promotion of “Internet + medical and health,” social media, as an important platform for health information dissemination, has become one of the important information sources for users to obtain health information. However, health information seeking behavior in public health emergencies are quite different from those in daily life. Therefore, the research question of this paper is to explore the influencing factors of health information seeking behavior of social media users in the context of COVID-19. To this end, based on the research framework of social cognition theory, this paper selects six variables to construct a structural equation modeling, including information and platform quality, experience, social support, emotional arousal, self-efficacy, and social media users’ health information seeking behavior. The empirical study is carried out by collecting 219 valid questionnaires. The research results show that: (1) Information and platform quality, and use experience have a significant positive effect on emotional arousal; (2) Experience, social support, and emotional arousal have a significant positive effect on self-efficacy; (3) Emotional arousal and self-efficacy have a significant positive effect on social media users’ health information seeking behavior. The research provides an important theoretical reference for social media users and operators to cope with the huge demand for health information in the post-COVID-19 era.

Based on increasing research evidence, hepatocellular carcinoma (HCC) is heterogeneous, and genetic profiling has led to the identification of multiple subtypes of this disease. To advance our knowledge and the ability to use individualized medicine in the treatment of HCC, it is essential to perform a complete and methodical characterization of various molecular subtypes. The canonical Wnt/β-catenin pathway is an evolutionarily conserved complicated signaling mechanism that plays a role in carcinogenesis and progression of HCC. In this study, we acquired RNA sequencing, somatic mutation, and clinical data from 701 patients from The Cancer Genome Atlas and Gene Expression Omnibus databases and stratified patients into two subgroups: WNT-high and WNT-low. In general, the WNT-high subtype is associated with an immunosuppressive microenvironment, poor prognosis, cancer-related pathways, and a low response to immune checkpoint therapy. We also found that WNT3 is negatively linked to CD8+ T-cell infiltration using multiple immunofluorescence assays. Finally, we developed a WNT-related prognostic model to predict the survival time of patients with HCC. In summary, we developed a new classification scheme for HCC based on Wnt signaling signatures. This classification produced substantial clinical effects, both in terms of assessing patient prognosis and immunotherapy administered to patients with HCC.

ObjectivesThe antitumor activity of nivolumab plus regorafenib in colorectal cancer from a phase Ib REGONIVO study is encouraging. The present study was conducted to evaluate the efficacy and safety of regorafenib or fruquintinib plus sintilimab as third-line or above therapy in patients with microsatellite stable (MSS) metastatic colorectal cancer.MethodsPatients with MSS metastatic colorectal cancer who have failed from prior treatment and received regorafenib or fruquintinib plus sintilimab as third-line or above therapy from January 2019 to December 2020 were prospectively analyzed based on real-world clinical practice. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.Results42 patients received regorafenib plus sintilimab(RS), and the other 30 patients received fruquintinib plus sintilimab(FS). In the general population, the ORR and DCR were 13.9% and 70.8%, and the median PFS and OS was 4.2(95% CI=2.9-5.5) and 10.5 (95% CI=8.6-12.4) months, respectively. There were no statistically significant differences between RS and FS group in PFS (3.5(2.2-4.8) vs. 5.5(3.5-7.5) months, P=0.434) and OS (11.0(7.0-15.0) vs. 10.5(3.8-17.2) months, P=0.486). Subgroup analysis suggested that patients without liver metastasis responded well to this combination regimen (ORR: 21.4% vs. 9.1%) and obtained better OS (26(8.8-43.2) vs. 10.0(7.4-12.6) months, P=0.016). The incidence of Grade 3-4 adverse events (AEs) was 15.3% and the toxicities were generally tolerable and manageable.ConclusionsRegorafenib or fruquintinib plus sintilimab as third-line or above therapy provide a feasible treatment regimen for MSS metastatic colorectal cancer with tolerated toxicity. Patients without liver metastasis may be the preferred population for this combination regimen.

Rehmanniae Radix Preparata (RRP) has been used to management of osteoporotic pain in traditional Chinese medicine trials. However, how RRP exhibits the anti-nociceptive effect remains largely unknown. To this end, estrogen-deficient rats were orally gavaged with aqueous RRP extracts for 12 weeks. The tail flick latency, Von-Frey and formalin assays were employed to evaluate pain sensitization. The administration of RRP alleviates allodynia and hyperalgesia in estrogen-deficient rats. These alterations were associated with a decrease in the expression of substance P (SP), neurokinin-1 receptor (NK-1R), phospho (p)-PI3K, p-protein kinase B (Akt), and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the spinal cord. In addition, RRP improves bone quality in the rats. These results suggest RRP could attenuate pain sensitization and improve bone quality through regulation of PI3K/Akt/TRPV1 signaling pathway during menopause stages. And RRP is considered a novel source of anti-osteoporotic pain drug candidates.

Background and Objective: Triptolide (TP), one of the fat-soluble components extracted from the Chinese medicinal herb Tripterygium wilfordii Hook F. (TWHF), possesses strong antitumor bioactivities, but its dose-dependent side effects restrict its wide application. This study was designed to investigate whether inflammatory factors increased the antitumor effects of the nontoxic dose of TP on gastric cancer cells and tried to explore the possible molecular mechanisms.Method: AGS and MKN45 cells were treated with different doses of TP and TNF-α. Cell viability and apoptosis were detected in vitro. In addition, NF-κB mediated prosurvival signals and cytoprotective proteins, especially FLICE-inhibitory protein (FLIP), were detected to determine their effects on TP/TNF-α–induced apoptosis. Moreover, the function of lncRNA H19/miR-204-5p/NF-κB/FLIP axis was investigated in vitro, and the antigastric cancer effect of TP plus TNF-α was proved in the mice xenograft model.Result:In vitro experimental results showed that TP pretreatment promoted apoptosis in AGS and MKN45 cells upon TNF-α exposure. TP/TNF-α–mediated apoptosis was partly mediated by the inhibitory effect of NF-κB–mediated FLIP expression. Oncogene H19 lying in the upstream pathway of NF-κB played a vital role upon TNF-α exposure, and bioinformatics analysis proved that H19 participated in TP/TNF-α–induced apoptosis via binding of miR-204-5p. Lastly, a low dose of TP and TNF-α inhibited the tumor weight and tumor volume of AGS and MKN45 cells in vivo.Conclusion: TP pretreatment increased apoptosis in TNF-α–stimulated gastric cancer cells, which are dependent on the disruption of the H19/miR-204-5p/NF-κB/FLIP axis. Cotreatment of TP and TNF-α is a better option for enhancing the anticancer effect and lowering the side effect of TP.

In the published article [...]

Tianjin is a coastal city of China. However, the continuous rise of the relative sea-level has brought huge hidden danger to Tianjin’s economic and social development. The land subsidence is the most important factor that influences relative sea-level rise. By analyzing the current situation of subsidence in Tianjin through PS-InSAR, it was found that the subsidence rate of the southern plain of Tianjin is slowing down as a whole. In addition, Wuqing and Jinghai sedimentary areas as well as other several subsidence centers have been formed. By establishing a regular grid of land subsidence and ground water to construct a geo-weighted regression model (GWR), it was found that Wuqing sedimentary area as a whole is positively correlated with TCA. According to the relative sea-level change, it can be predicted that the natural coastline of Tianjin will recede by about 87 km2 in 20 years. Based on the research results above, this paper, by using machine-learning method (XGBoost), has evaluated Tianjin’s urban safety and analyzed high-risk areas and main contributing factors. Potential risks to urban safety brought about by relative sea-level rise have been analyzed, which will improve the resilience of coastal areas to disasters.

Rapid simulation of land subsidence can provide an effective means of facilitating its management and control. This paper innovatively introduced a back-propagation (BP) neural network subsidence simulation model which was optimized by the sparrow search algorithm (SSA), hereinafter referred to as the SSA-BP model, to simulate land subsidence in Tongzhou District, Beijing. First, based on the time series interferometric synthetic aperture radar (InSAR) monitoring, different technologies such as spatial analysis, Google Earth Engine (GEE), and machine learning were utilized together with a variety of multi-source spatial data, including groundwater level, compressible layer thickness, Visible Infrared Imager Radiometer Suite (VIIRS) nighttime light images, and the OpenStreetMap (OSM) road distribution. Furthermore, we determined the optimal grid scale for land subsidence research and worked out a multifactor-driven SSA-BP land subsidence simulation model for which sensitivity analysis was performed with great care. Main conclusions: (1) From November 2010 to January 2020, the average annual surface displacement rate in Beijing’s subcentre, Tongzhou, ranged from −133.9 to +3.9 mm/year. (2) Our SSA-BP land subsidence simulation model allows for a relatively high overall accuracy. The average root mean square error (RMSE) is 5.00 mm/year, the average mean absolute error (MAE) is 3.80 mm/year, and the average coefficient of determination (R2) is 0.83. (3) Sensitivity analysis shows that the SSA-BP model driven by multiple factors has a far better simulation performance than the model driven by any single weighting factor, and displays the highest sensitivity to the groundwater level factor among all the weighting factors. In terms of subdividing the study area, our SSA-BP land subsidence model runs with multifunctional zones displayed a higher accuracy than that without. This paper made use of a machine learning model to simulate land subsidence in Beijing’s Tongzhou District and explored the sensitivity of different factors to land subsidence, which is helpful for its scientific prevention.

Surface water bodies exhibit high dynamic variability on seasonal and interannual scales, and high spatiotemporal resolution water bodies extent data are crucial for studying surface water bodies’ evolution. Existing surface water bodies datasets are mainly based on optical data acquisition, which has the advantages of long temporal coverage and convenience but is susceptible to cloud contamination, leading to low spatiotemporal continuity. Although microwave remote sensing data are not affected by clouds, early SAR acquisition and short temporal coverage limit its use. Therefore, existing surface water bodies datasets face the problem of insufficient spatiotemporal resolution or low continuity. This research integrates Sentinel-2 optical data and Sentinel-1 Synthetic Aperture Radar (SAR) observations to reconstruct the surface water bodies dataset with a 6-day and 10-meter spatiotemporal resolution. Then, the proposed method introduces a spatiotemporal correlation model and predicts the land cover (water or land) of Sentinel-2 cloudy pixels, which improves the spatiotemporal continuity of the reconstructed surface water bodies dataset further. Based on the proposed method, we construct the Haihe River Water Dataset (HRWD) from 2016 to 2020 with a 6-day and 10-meter spatiotemporal resolution. Compared with the European Commission’s Joint Research Centre’s (JRC’s) Global Surface Water Explorer and Global Surface Water Extent Dataset (GSWED), the HRWD shows a rational accuracy (e.g., the overall accuracy of the HRWD is more than 93%) and a better spatiotemporal continuity, which provide an improved performance in identifying and monitoring surface water bodies in the Haihe River Basin. This indicates that the proposed method can improve the spatiotemporal continuity of surface water body mapping and meet the needs of accurate and long-term quantitative observation of the distribution of large-scale and high spatiotemporal continuity surface water bodies.