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Objective Polycystic ovary syndrome (PCOS) is a prevalent cause of menstrual irregularities and infertility in women, impacting quality of life. Despite advancements, current understanding of PCOS pathogenesis and treatment remains limited. This study uses machine learning-based data mining to identify acetylation-related genetic markers associated with PCOS, aiming to enhance diagnostic precision and therapeutic efficacy.Methods Advanced machine learning techniques were used to improve the precision of key gene identification and reveal their biological mechanisms. Validation on an independent dataset (GSE48301) confirmed their diagnostic value, assessed through ROC curves and nomograms for PCOS risk prediction. Molecular mechanisms of acetylation-related gene regulation in PCOS were further examined through clustering, immune-environmental, and gene network analyses.Results Our analysis identified 15 key acetylation-regulated genes differentially expressed in PCOS, including SGF29, NOL6, KLF15, and INO80D, which are relevant to PCOS pathogenesis. ROC curve analyses on training and validation datasets confirmed the model’s high diagnostic accuracy. Additionally, these genes were associated with immune cell infiltration, offering insights into the inflammatory aspect of PCOS.Conclusion The identified acetylation gene markers offer novel insights into the molecular mechanisms underlying PCOS and hold promise for enhancing the development of precise diagnostic and therapeutic strategies.

Abstract Diabetic heart disease (DHD) is a serious complication in patients with diabetes. Despite numerous studies on the pathogenic mechanisms and therapeutic targets of DHD, effective means of prevention and treatment are still lacking. The pathogenic mechanisms of DHD include cardiac inflammation, insulin resistance, myocardial fibrosis, and oxidative stress. Macrophages, the primary cells of the human innate immune system, contribute significantly to these pathological processes, playing an important role in human disease and health. Therefore, drugs targeting macrophages hold great promise for the treatment of DHD. In this review, we examine how macrophages contribute to the development of DHD and which drugs could potentially be used to target macrophages in the treatment of DHD.

In order to evaluate the impact of traffic emissions on urban air quality, an increasing number of cities have established near-road air quality monitoring stations (hereafter referred to as roadside stations). This study reviews the system of roadside stations, the data application, and the evolution of air pollutant concentrations in the traffic environment in typical cities, and proposes optimization suggestions roadside stations in the future. The results show a steady increase in publications on roadside stations over the years, with the annual average number of publications after 2020 being approximately 10 times the annual mean during 1994–2001. The literature mainly focused on ‘air pollution’, ‘particulate matter’, ‘emission’, etc., highlighting the impact of traffic emissions on urban air quality and human health. The purpose and principles of setting up roadside stations vary from country to country, but they are mainly used to assess the impact of vehicle emissions on air quality and to protect human health in the vicinity of roads. Over the past decade, near-road NO2 concentrations in typical cities have decreased by 30%–50%, although they remain higher than those observed in the urban atmosphere. The comprehensive analysis based on long-term data from roadside stations can provide insight into the effectiveness of vehicle emission control measures, and serve as a scientific basis for the formulation of future public health protection policies.

Mobile edge computing is envisioned as a prospective technology for supporting time-sensitive and computation-intensive applications in marine vehicle systems. However, the offloading performance is highly impacted by the poor wireless channel. Recently, an Unmanned Aerial Vehicle (UAV) equipped with an Intelligent Reflecting Surface (IRS), i.e., UIRS, has drawn attention due to its capability to control wireless signals so as to improve the data rate. In this paper, we consider a multi-UIRS-assisted marine vehicle system where UIRSs are deployed to assist in the computation offloading of Unmanned Surface Vehicles (USVs). To improve energy efficiency, the optimization problem of the association relationships, computation resources of USVs, multi-UIRS phase shifts, and multi-UIRS trajectories is formulated. To solve the mixed-integer nonlinear programming problem, we decompose it into two layers and propose an integrated convex optimization and deep reinforcement learning algorithm to attain the near-optimal solution. Specifically, the inner layer solves the discrete variables by using the convex optimization based on Dinkelbach and relaxation methods, and the outer layer optimizes the continuous variables based on the Multi-Agent Twin Delayed Deep Deterministic Policy Gradient (MATD3). The numerical results demonstrate that the proposed algorithm can effectively improve the energy efficiency of the multi-UIRS-assisted marine vehicle system in comparison with the benchmarks.

There is always a lack of effective treatment for highly active refractory generalized myasthenia gravis (GMG). Recently, telitacicept combined with efgartigimod significantly reduces circulating B cells, plasma cells, and immunoglobulin G, which brings promising therapeutic strategies. We report a case of a 37-year-old female patient with refractory GMG, whose condition got significant improvement and control with this latest treatment after multiple unsuccessful therapies of immunosuppressants. The new combination deserves further attention in the therapeutic application of myasthenia gravis.

Abstract The efficacy of neoadjuvant chemotherapy (NACT) in patients with advanced gastric cancer (GC) varies greatly. Thus, we aimed to verify the predictive value of tumor‐infiltrating immune cells (TIICs) on the treatment response to NACT and the prognosis of patients with advanced GC, and to explore the impact of NACT on the tumor immune microenvironment (TIME). Paired tumor tissues (pre‐ and post‐NACT) from patients with advanced GC were collected for this study. TIICs were assessed using immunohistochemistry staining and analyzed using logistic regression to establish an immune microenvironment score for GC (ISGC score) and predict NACT efficacy. Kaplan–Meier curves were used to evaluate the survival outcome of patients. The results showed that TIME was dramatically heterogeneous between NACT response and nonresponse patients. In the validation cohort, the ISGC score demonstrated good predictive performance for treatment response to NACT. Moreover, high ISGC indicated better long‐term survival in patients with advanced GC. Furthermore, tumor‐infiltrated T cells (CD3+ and CD8+) and CD11c+ macrophages were significantly increased in the response group, while CD163+ macrophages and FOXP3+ Treg cells were decreased after NACT. However, opposite results were exhibited in the nonresponse group. Finally, we found that the percentage of programmed cell death ligand 1 (PD‐L1)‐positive tumors was 31% (32/104) pre‐NACT and 49% (51/104) post‐NACT, and almost all patients with elevated PD‐L1 were in the NACT response group. The ISGC model accurately predicted NACT efficacy and classified patients with GC into different survival groups. NACT regulates the TIME in GC, which may provide strategies for personalized immunotherapy.

BackgroundPrevious studies have shown that alterations in the gut microbiota are closely associated with Acute Coronary Syndrome (ACS) development. However, the value of gut microbiota for early diagnosis of ACS remains understudied.MethodsWe recruited 66 volunteers, including 29 patients with a first diagnosis of ACS and 37 healthy volunteers during the same period, collected their fecal samples, and sequenced the V4 region of the 16S rRNA gene. Functional prediction of the microbiota was performed using PICRUSt2. Subsequently, we constructed a nomogram and corresponding webpage based on microbial markers to assist in the diagnosis of ACS. The diagnostic performance and usefulness of the model were analyzed using boostrap internal validation, calibration curves, and decision curve analysis (DCA).ResultsCompared to that of healthy controls, the diversity and composition of microbial community of patients with ACS was markedly abnormal. Potentially pathogenic genera such as Streptococcus and Acinetobacter were significantly increased in the ACS group, whereas certain SCFA-producing genera such as Blautia and Agathobacter were depleted. In addition, in the correlation analysis with clinical indicators, the microbiota was observed to be associated with the level of inflammation and severity of coronary atherosclerosis. Finally, a diagnostic model for ACS based on gut microbiota and clinical variables was developed with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.963 (95% CI: 0.925–1) and an AUC value of 0.948 (95% CI: 0.549–0.641) for bootstrap internal validation. The calibration curves of the model show good consistency between the actual and predicted probabilities. The DCA showed that the model had a high net clinical benefit for clinical applications.ConclusionOur study is the first to characterize the composition and function of the gut microbiota in patients with ACS and healthy populations in Southwest China and demonstrates the potential effect of the microbiota as a non-invasive marker for the early diagnosis of ACS.

IntroductionSalt stress is a major constraint affecting crop productivity worldwide. Investigation of halophytes could provide valuable information for improving economically important crops to tolerate salt stress and for more effectively using halophytes to remediate saline environments. Sesuvium portulacastrum L. is a halophyte species widely distributed in tropical and subtropical coastal regions and can absorb a large amount of sodium (Na). This study was to analyze S. portulacastrum responses to salt stress at morphological, physiological, proteomic, and metabolomic levels and pursue a better understanding of mechanisms behind its salt tolerance. MethodsThe initial experiment evaluated morphological responses of S. portulacastrum to different concentrations of NaCl in a hydroponic system, and subsequent experiments compared physiological, proteomic, and metabolomic changes in S. portulacastrum after being exposed to 0.4 M NaCl for 24 h as immediate salt stress (IS) to 14 days as adaptive salt stress (AS). Through these analyses, a working model to illustrate the integrative responses of S. portulacastrum to salt stress was proposed.ResultsPlants grown in 0.4 M NaCl were morphologically comparable to those grown in the control treatment. Physiological changes varied in control, IS, and AS plants based on the measured parameters. Proteomic analysis identified a total of 47 and 248 differentially expressed proteins (DEPs) in leaves and roots, respectively. KEGG analysis showed that DEPs, especially those occurring in roots, were largely related to metabolic pathways. Root metabolomic analysis showed that 292 differentially expressed metabolites (DEMs) occurred in IS plants and 371 in AS plants. Among them, 20.63% of upregulated DEMs were related to phenolic acid metabolism. DiscussionBased on the integrative analysis of proteomics and metabolomics, signal transduction and phenolic acid metabolism appeared to be crucial for S. portulacastrum to tolerate salt stress. Specifically, Ca2+, ABA, and JA signalings coordinately regulated salt tolerance in S. portulacastrum. The stress initially activated phenylpropanoid biosynthesis pathway through Ca2+ signal transduction and increased the content of metabolites, such as coniferin. Meanwhile, the stress inhibited MAPK signaling pathway through ABA and JA signal transduction, which promoted Na sequestration into the vacuole to maintain ROS homeostasis and enhanced S. portulacastrum tolerance to salt stress.

Electric field treatment is a new method to improve the cold flowability of waxy crude oil. Its basic principle is electrorheological behaviors of waxy oil, and its mechanism is the interfacial polarization of wax particles. So far, researchers have found that the effect of electric field treatment varies greatly among different crude oils, yet the mechanism is unclear. Herein, the effect of electric field treatment on improving flowability was tested using 8 waxy crude oils with various resin and asphaltene contents ranging within 4% to 23%. The results show that: under the experimental conditions, the crude oils with lower resin and asphaltene content (of which the total mass fraction is less than 5%) have the viscosity reduction effect induced by electric field increase first and then decrease with the increasing of cumulative amount of wax precipitated; the crude oils with medium resin and asphaltene content (of which the total mass fraction is about 10%) have the viscosity reduction effect induced by electric field increase monotonically with the increasing of precipitated wax; the crude oils with high resin and asphaltene content (of which the total mass fraction is above 15%) have unobvious viscosity reduction effect induced by electric field. It is concluded according to the mechanism of interfacial polarization of wax crystal particles of flowability improvement by electric field treatment is closely related to the abundance and aggregation degree of rein and asphaltene in crude oil.

BackgroundTo explore the underlying mechanism of programmed cell death (PCD)-related genes in patients with endometrial cancer (EC) and establish a prognostic model.MethodsThe RNA sequencing data (RNAseq), single nucleotide variation (SNV) data, and corresponding clinical data were downloaded from TCGA. The prognostic PCD-related genes were screened and subjected to consensus clustering analysis. The two clusters were compared by weighted correlation network analysis (WGCNA), immune infiltration analysis, and other analyses. The least absolute shrinkage and selection operator (LASSO) algorithm was used to construct the PCD-related prognostic model. The biological significance of the PCD-related gene signature was evaluated through various bioinformatics methods.ResultsWe identified 43 PCD-related genes that were significantly related to prognoses of EC patients, and classified them into two clusters via consistent clustering analysis. Patients in cluster B had higher tumor purity, higher T stage, and worse prognoses compared to those in cluster A. The latter generally showed higher immune infiltration. A prognostic model was constructed using 11 genes (GZMA, ASNS, GLS, PRKAA2, VLDLR, PRDX6, PSAT1, CDKN2A, SIRT3, TNFRSF1A, LRPPRC), and exhibited good diagnostic performance. Patients with high-risk scores were older, and had higher stage and grade tumors, along with worse prognoses. The frequency of mutations in PCD-related genes was correlated with the risk score. LRPPRC, an adverse prognostic gene in EC, was strongly correlated with proliferation-related genes and multiple PCD-related genes. LRPPRC expression was higher in patients with higher clinical staging and in the deceased patients. In addition, a positive correlation was observed between LRPPRC and infiltration of multiple immune cell types.ConclusionWe identified a PCD-related gene signature that can predict the prognosis of EC patients and offer potential targets for therapeutic interventions.

Abstract Background Owing to the low ratio of patients benefitting from immunotherapy, patient stratification becomes necessary. An accurate patient stratification contributes to therapy for different tumor types. Therefore, this study aimed to subdivide colon cancer patients for improved combination immunotherapy. Methods We characterized the patients based on urea cycle metabolism, performed a consensus clustering analysis and constructed a risk model in the cancer genome atlas cohort. Colon cancer patients were further categorized into two tags: clusters, and risk groups, for the exploration of combination immunotherapy. In addition to external validation in the Gene Expression Omnibus datasets, several images of immunohistochemistry were used for further validation. Results Patient characterization based on urea cycle metabolism was related to immune infiltration. An analysis of consensus clustering and immune infiltration generated a cluster distribution and identified patients in cluster 1 with high immune infiltration levels as hot tumors for immunotherapy. A risk model of seven genes was constructed to subdivide the patients into low- and high-risk groups. Validation was performed using a cohort of 731 colon cancer patients. Patients in cluster 1 had a higher immunophenoscore (IPS) in immune checkpoint inhibitor therapy, and those other risk groups displayed varying sensitivities to potential combination immunotherapeutic agents. Finally, we subdivided the colon cancer patients into four groups to explore combination immunotherapy. Immunohistochemistry analysis showed that protein expression of two genes were upregulated while that of other two genes were downregulated or undetected in cancerous colon tissues. Conclusion Using subdivision to combine chemotherapy with immunotherapy would not only change the dilemma of immunotherapy in not hot tumors, but also promote the proposition of more rational personalized therapy strategies in future.

The autophagy-lysosomal pathway (ALP) is the major biological pathway responsible for clearing intracellular protein aggregates, therefore a promising target for treating diseases featuring the accumulation of aggregation-prone proteins, such as Huntington disease (HD). However, accumulating evidence indicated that targeting ALP to treat HD is pharmacologically challenging due to the complexity of autophagy and the autophagy defects in HD cells. Here in this mini-review, we summarized the current challenges in targeting ALP in HD and discussed a number of latest findings on aggrephagy and targeted protein degradation, which we believe will provide potential new targets and new strategies for treating HD via ALP.

The shade avoidance syndrome (SAS) is a collective adaptive response of plants under shade highlighted by characteristic phenotypes such as hypocotyl elongation, which is largely mediated by concerted actions of auxin and GA. We identified ATHB2, a homeodomain-leucine zipper (HD-Zip) domain transcription factor known to be rapidly induced under shade condition, as a positive regulator of GA biosynthesis necessary for the SAS by transactivating the expression of GA20ox2, a key gene in the GA biosynthesis pathway. Based on promoter deletion analysis, EMSA and ChIP assay, ATHB2 appears to regulate the GA20ox2 expression as a direct binding target. We also found that the GA20ox2 expression is under negative control by TCP13, the effect of which can be suppressed by presence of ATHB2. Considering a rapid induction kinetics of ATHB2, this relationship between ATHB2 and TCP13 may allow ATHB2 to play a shade-specific activator for GA20ox by derepressing a pre-existing activity of TCP13.

Modification of crude oil is a basic method to improve the safety and economy of pipeline transportation. Definitely, high-voltage electric field treatment is a new approach to modify the crude oil based on its electrorheological effect. Herein, the progress of research on electric field treatment for modification of crude oil was summarized systematically, and the law of the electrorheological effect of crude oil was also concluded. The research results indicate that: applying an electric field (with an intensity of 0.2-5 kV/mm) to crude oil for several seconds can obtain the significant immediate modification effect. Specifically, the viscosity and yield stress can be reduced at a rate of 80% or higher, but the energy consumption is only 1% of that required for the same viscosity reduction rate by heating. After the removal of electric field, the viscosity and yield stress will recover gradually. The effect of viscosity reduction will disappear after about one day of placement. But the yield stress recovers slowly (at 90% of the reduction rate of yield stress two days later). The modification effect of electric field treatment is closely related to the composition of crude oil, and the presence of wax crystal, resin and asphaltene in the crude oil is essential for electric field treatment. In addition, the existing issues of the current research on electric field treatment technology were analyzed, and the development direction of the technology in the future was also proposed.

Soil salinity is an important environmental problem that seriously affects plant growth and crop productivity. Phytoremediation is a cost-effective solution for reducing soil salinity and potentially converting the soils for crop production. Sesuvium portulacastrum is a typical halophyte which can grow at high salt concentrations. In order to explore the salt tolerance mechanism of S. portulacastrum, rooted cuttings were grown in a hydroponic culture containing ½ Hoagland solution with or without addition of 400 mM Na for 21 days. Root and leaf samples were taken 1 h and 21 days after Na treatment, and RNA-Seq was used to analyze transcript differences in roots and leaves of the Na-treated and control plants. A large number of differentially expressed genes (DEGs) were identified in the roots and leaves of plants grown under salt stress. Several key pathways related to salt tolerance were identified through KEGG analysis. Combined with physiological data and expression analysis, it appeared that cyclic nucleotide gated channels (CNGCs) were implicated in Na uptake and Na+/H+ exchangers (NHXs) were responsible for the extrusion and sequestration of Na, which facilitated a balance between Na+ and K+ in S. portulacastrum under salt stress. Soluble sugar and proline were identified as important osmoprotectant in salt-stressed S. portulacastrum plants. Glutathione metabolism played an important role in scavenging reactive oxygen species. Results from this study show that S. portulacastrum as a halophytic species possesses a suite of mechanisms for accumulating and tolerating a high level of Na; thus, it could be a valuable plant species used for phytoremediation of saline soils.

Lithium–sulfur batteries (LSBs) with high energy density have the potential to replace current commercial lithium-ion batteries. However, the shuttle effect and the low conversion kinetics of lithium polysulfide (LiPS) remain the main challenges in the development of LSBs. In this study, a metal-free and simple-to-prepare carbon nitride with a high surface area and tubular morphology (CN-nt) is used as the sulfur host for LSBs. Due to its unique nanostructure and rich active sites, it not only effectively disperses the active sulfur material and anchors soluble polysulfide species, but it also promotes the nucleation process of Li2S, thus achieving fast and sustainable Li-S redox reactions. Experimental results show that the obtained S@CN-nt electrodes exhibit a high sulfur utilization of 1296.2 mAh g−1 at 0.1 C and a significant rate capability of 689.4 mAh g−1 at the high current rate of 3C. More importantly, the capacity retention reaches 87.7% after 500 cycles. This simple strategy of engineering unique carbon-based nanostructured hosts can inspire new ideas for developing cost-effective and metal-free host materials for sulfur-based batteries.

Multiple unmanned aerial vehicle (multi-UAV) cooperative air combat, which is an important form of future air combat, has high requirements for the autonomy and cooperation of unmanned aerial vehicles. Therefore, it is of great significance to study the decision-making method of multi-UAV cooperative air combat since the conventional methods are challenging to solve the high complexity and highly dynamic cooperative air combat problems. This paper proposes a multi-agent double-soft actor-critic (MADSAC) algorithm for solving the cooperative decision-making problem of multi-UAV. The MADSAC achieves multi-UAV cooperative air combat by treating the problem as a fully cooperative game using a decentralized partially observable Markov decision process and a centrally trained distributed execution framework. The use of maximum entropy theory in the update process makes the method more exploratory. Meanwhile, MADSAC uses double-centralized critics, target networks, and delayed policy updates to solve the overestimation and error accumulation problems effectively. In addition, the double-centralized critics based on the attention mechanism improve the scalability and learning efficiency of MADSAC. Finally, multi-UAV cooperative air combat experiments validate the effectiveness of MADSAC.

This paper introduces physical models of drill string whirling and torsional vibrations and analyses the physical models in V.I. Gulyayev's three papers on drill string whirling and torsional vibrations: “V.I. Gulyayev, L.V. Shevchuk, Drill string bit whirl simulation with the use of frictional and nonholonomic models, Journal of Vibration and Acoustics 138(1) (2016) 011021”, “V.I. Gulyayev, L.V. Shevchuk, Nonholonomic dynamics of drill string bit whirling in a deep bore-hole, J Multi-body Dynamics 227(3) (2013) 234–244” and “V.I. Gulyayev, SN Hudoliy, O.V. Glushakova, Simulation of torsion relaxation auto-oscillations of drill string bit with viscous and coulombic friction moment models, J Multi-body Dynamics 225 (2011) 139–152”. This work finds that the physical models described in these three papers are clearly incorrect. Keywords: Drill string, Vibration, Lateral, Torsion, Whirl

A hydrothermal alkali modification method was used to produce geopolymer (BFA-GP) from biofuel ash (BFA). The product was characterized by scanning electron microscopy with energy dispersive spectrometry (SEM-EDS), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared reflection (FTIR), and X-ray photoelectron spectroscopy (XPS). Significant amount of geopolymer and gismondine was produced by this modification. The surface area increased from 20.41 m2 g−1 to 56.63 m2 g−1. The adsorption capacity of BFA-GP can reach 29.92 and 137.49 mg g−1 for Cd2+ and Pb2+, respectively, in a pure solution at 298 K, which is about triple of that by the original BFA. Competitive adsorption of Cd2+ and Pb2+ showed that the binding affinity is Pb2+> Cd2+. Chemical sorption including electrostatic attraction, chelate reaction, and ion-exchange is the dominant mechanism of heavy metal adsorption on BFA-GP. And the adsorption thermodynamics indicates that adsorption reaction of heavy metal ions by BFA-GP is spontaneous and endothermic. This modification provided a cost-effective and environmentally friendly way to change BFA to adsorbent for heavy metals with promising application prospects.

Plant-based removal of nitrogen (N) and phosphorus (P) from water bodies is an important method for remediation of aquaculture wastewater. In order to acquire knowledge as to how antibiotic residues in wastewater might affect the microbial community and plant uptake of N and P, this study investigated N and P removal by a coastal plant Sesuvium portulacastrum L. grown in aquaculture wastewater treated with 0, 1, 5, or 50 mg/L sulfonamide antibiotics (sulfadiazine, SD) for 28 days and compared the microbial community structure between the water and rhizosphere. Results showed that SD significantly decreased N removal rates from 87.5% to 22.1% and total P removal rates from 99.6% to 85.5%. Plant fresh weights, root numbers, and moisture contents as well as activities of some enzymes in leaves were also reduced. SD changed the microbial community structure in water, but the microbial community structure in the rhizosphere was less affected by SD. The microbial diversity in water was higher than that in the rhizosphere, indicating microbial community differences. Our results showed that the commonly used antibiotic, SD, in aquaculture can inhibit plant growth, change the structure of microbial community, and reduce the capacity of S. portulacastrum plants to remove N and P from wastewater, and also raised alarm about detrimental effects of antibiotic residues in phytoremediation of wastewater.

During extended-reach well drilling, the torque of a rotary drill string is too large in the horizontal section, which results in the failure of the drill string. The effect of radial vibration on the friction and torque of the rotary drill string is unclear. In this work, first, the principle of the impact of radial vibration on the friction and torque of the rotary drill string in the horizontal section is analysed. Then, joints with an elliptical outer edge of the section are designed, which can generate low-amplitude vibration as the drill string rotates owing to the interaction with the wellbore wall. The radial vibration characteristics can be tuned by changing the major to minor radius ratio of the ellipse. A self-developed experimental device was designed to test the performance of tools with reduced friction and torque. The drill string torque with different penetration rates, rotation speeds, and ratios of the major radius to minor radius of the ellipse were systematically studied. The experimental results show that the average and the maximum amplitudes of the torque fluctuation first decrease to the lowest value and then increase with the increase of the ratio. When the ratio reaches 1.065, the average and the maximum amplitudes of the torque fluctuation evidently reduce; therefore, a joint with a ratio of 1.065 can effectively reduce frictional torque. The average torque reduces when the penetration rate and rotation speed decrease. At rotation speeds of 45 and 60 r/min, the maximum amplitude of torque fluctuation increases first and then decreases with an increase in penetration rate, and it reaches a maximum value at a penetration rate of 22.5 m/h. The fundamental frequency of torque fluctuation is almost linearly related to rotation speed, which is irrelevant to the penetration rate and the ratio of major to minor radius of the ellipse.

Abstract A chitosan-based microsphere delivery system has been fabricated for controlled release of alendronate (AL). The present study aimed to incorporate the chitosan/hydroxyapatite microspheres-loaded with AL (CH/nHA-AL) into poly(L-lactic acid)/nanohydroxyapatite (PLLA/nHA) matrix to prepare a novel microspheres-scaffold hybrid system (CM-ALs) for drug delivery and bone tissue engineering application. The characteristics of CM-ALs scaffolds containing 10% and 20% CH/nHA-AL were evaluated in vitro, including surface morphology and porosity, mechanical properties, drug release, degradation, and osteogenic differentiation. The in vivo bone repair for large segmental radius defects (1.5 cm) in a rabbit model was evaluated by radiography and histology. In vitro study showed more sustained drug release of CM-AL-containing scaffolds than these of CM/nHA-AL and PLLA/nHA/AL scaffolds, and the mechanical and degradation properties of CM-ALs (10%) scaffolds were comparable to that of PLLA/nHA control. The osteogenic differentiation of adipose-derived stem cells (ASCs) was significantly enhanced as indicated by increased alkaline phosphates (ALP) activity and calcium deposition. In vivo study further showed better performance of CM-ALs (10%) scaffolds with complete repair of large-sized bone defects within 8 weeks. A microspheres-scaffold-based release system containing AL-encapsulated chitosan microspheres was successfully fabricated in this study. Our results suggested the promising application of CM-ALs (10%) scaffolds for drug delivery and bone tissue engineering.

Pulmonary metastases are the major cause of death of osteosarcoma (OS) patients. Endothelin-1 (ET-1) reportedly plays an important role in OS metastasis. In the present study, we for the first time explored the association of ET-1 SNPs with the risk of pulmonary metastatic OS. We genotyped three SNPs (rs1800541, rs2070699 and rs5370) in the ET-1 gene in a case-control study, using 260 pairs of age-, sex-, residence area- and tumor location-matched subjects. Patients with pulmonary metastatic OS and patients with localized high-grade (stage IIB) OS were enrolled as cases and controls, respectively. The G allele at rs1800541 was found associated with reduced risk of pulmonary metastatic OS after adjustment for body mass index, systolic blood pressure, diastolic blood pressure and the plasma ET-1 level (P=10(-4); adjusted OR, 0.55; 95% CI, 0.42-0.70), while the G allele at rs2070699 was not significantly associated with the risk of pulmonary metastatic OS (P=0.15; adjusted OR, 1.15; 95% CI, 0.87-1.50). The mRNA and the secreted protein levels of ET-1 in primary OS cell cultures (POCCs) established from surgically resected primary OS in the rs1800541 TT homozygotes were higher than those from the TG heterozygotes (P