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Abstract Background The prognostic value of circulating tumor cells (CTCs) in metastatic breast cancer (MBC) has been extensively studied and verified by the CellSearch® system. Varieties of microfluidic systems have been developed to improve capture efficiency with the lack of standardization and automation. This study systematically verified the positive threshold for prognosis and its guidance value in anti-HER2 therapy based on a novel automated microfluidic system OmiCell®. Methods CTCs isolation, enumeration and labeling were performed using the OmiCell® system. CTCs identification and reporting were performed using the DeepSight® scanning system. Results The capture efficiency and specificity of OmiCell® system was 91.9% and 90%, respectively. Then, 65 MBC patients with known HER2 status of their metastatic tumors were enrolled. In the cohort, we detected ≥ 1 CTCs in 59 patients (90.8%, range: 1–55 CTCs, median = 6),

[Introduction] Plasma disruption poses a significant threat to the tokamak nuclear device during its running and can cause damage to the device. Such damage can be reduced by adopting the disruption mitigation system, which has an action time highly dependent on the real-time running plasma disruption prediction system for predicting the plasma disruption moment. The deep-learning-based neural network has been used to train plasma disruption prediction models, and the real-time running of the deep-learning-based disruption prediction models requires a huge amount of real-time data from multiple diagnostics. [Method] The article proposed a design scheme for a real-time data acquisition system. The real-time data acquisition and transmission system was designed based on the modular structure and divided into the multiple channels acquisition module, ADC converting control and data reading module, data grouping and packing module and data transmission network module. The data transmission network module was developed on the hardware UDP network stack running on the FPGA at a speed of 10 G. This hardware UDP network stack featured a deterministic data transmission process, enabling a very low transmission latency of the system. [Result] The real-time data acquisition system has a sampling rate reaching 2 MSa/s, a data throughput rate exceeding 9.3 Gb/s, and a data transmission latency of less than 10 μs. [Conclusion] This data acquisition system facilitates the fast transmission of diagnostic data streams to disruption prediction models. The high sampling rates enable the system to perform real-time transmission of one-dimensional diagnostics such as radiation and electron temperature, improving the temporal resolution of data. The high data throughput rate can increase the transmission volume of diagnostic data, and the low data transmission latency can reduce the time required for disruption prediction models to obtain diagnostics data.

With the increasing number of distributed power sources such as photovoltaic power and wind power and electric vehicles connected to the grid, the structure and operation state of the traditional distribution network have undergone great changes. Therefore, through the establishment of a distributed power grid-connected evaluation system, it has become an important research topic to evaluate the access of distributed power and the carrying capacity of electric vehicles in the distribution network of new power systems. Firstly, the situation of distributed power supply and electric vehicles and the impact of grid connection are introduced. Secondly, the traditional distribution network carrying capacity evaluation method is studied and introduced. Then, the distribution network carrying capacity evaluation considering uncertainty is reviewed and investigated. Finally, in view of the lack of existing research, further research is needed, aiming to provide a reference for the realization of distributed power supply and grid-connected EV carrying capacity evaluation and a scientific basis for the future operation planning of distributed power supply and EV integration into the distribution network.

Abstract Tertiary lymphoid structures (TLSs) play a crucial role in determining prognosis and response to immunotherapy in several solid malignancies. Nevertheless, the effect of TLS-associated gene signature based on The Cancer Genome Atlas (TCGA) cohort in patients with breast cancer (BRCA) remains controversial. Based on TCGA-BRCA dataset (n = 866), 9-gene was identified to construct an TLS signature and further analyzed its prognostic value. Then, we explored the relationship of this TLS signature with molecular subtype, immune microenvironment, tumor mutational burden (TMB). High-TLS signature patients had a better overall survival (OS) than low-TLS signature patients, consistent with the results in the METABRIC cohort. Multivariate analysis revealed that TLS signature remained an independent prognostic indicator for OS. In addition, we established a nomogram with the integration of TLS signature and other independent variables to predict individual risk of death. The comprehensive results showed that patients with high TLS signature benefit from immunotherapy; the signature was also correlated with inhibition of cell proliferation pathways, low TP53 mutation rate, high infiltration of B cells, CD8 + T cells, CD4 + T cells, and M1 macrophages. Therefore, TLS signature is a promising biomarker to distinguish the prognosis and immune microenvironment in BRCA.

Abstract Background Previous studies have shown that high level of TILs in invasive lobular carcinoma (ILC) is associated with poor prognosis, contrary to that in TNBC and HER2‐positive breast cancer. Methods The densities of six immune cell markers and three immune checkpoints in the ILC microenvironment were detected by computational pathology analysis. Then, the LASSO cox regression model was used to construct an immune score (IS) and further evaluate its prognostic value. Results In our ILC cohort, the low density of CD4, CD8, CD20, CD56, CD68, FOXP3, PD‐1, and PD‐L1 had significantly longer disease‐free survival (DFS) and overall survival (OS); however, the low density of CTLA‐4 was associated with shorter DFS and OS. Based on this, an IS was constructed, and patients with low‐IS had significantly prolonged DFS (p

Since the distribution of plankton is always uneven, the nonlocal phytoplankton competition term indicates the spatial weighted mean of phytoplankton density, which is introduced into the plankton model with toxic substances effect to study the corresponding dynamic behavior. The stability of the positive equilibrium point and the existence of Hopf bifurcations are discussed by analysing the distribution of eigenvalues. The direction and stability of bifurcation periodic solution are researched based on an extended central manifold method and normal theory. Finally, spatially inhomogeneous oscillations are observed in the vicinity of the Hopf bifurcations. Through numerical simulation, we can observe that the system without nonlocal competition term only generates homogeneous periodic solution, and inhomogeneous periodic solution will produce only when both diffusion and nonlocal competition exist simultaneously. We can also see that when the toxin-producing rate of each phytoplankton is in an appropriate range, the system with nonlocal competition generates a stability switch with inhomogeneous periodic solution, when the value of time delay is in a certain interval, then Hopf bifurcations will appear, and with the increase of time delay, the quantity of plankton will eventually become stable.

Challenges associated with topical analgesics and anti-inflammatory drugs include poor drug penetration and retention at the desired lesion site. Therefore, improving these challenges would help to reduce the toxic and side effects caused by drug absorption into the systemic circulation and improve the therapeutic efficacy of topical therapeutic drugs. Pentapeptide (KTTKS) is a signal peptide in skin tissue, it can be recognized and bound by signal recognition particles. In the current study, we successfully prepared novel indomethacin (IMC) loaded KTTKS-modified ethosomes (IMC-KTTKS-Es), and the physicochemical properties and topical efficacy were investigated. Results showed that the prepared IMC-KTTKS-Es displayed a particle size of about 244 nm, a negative charge, good deformability, and encapsulation efficiency (EE) exceeding 80% for IMC, with a sustained release pattern. In vitro percutaneous permeation studies revealed that the skin retention was increased after the drug was loaded in the IMC-KTTKS-Es. Confocal laser scanning microscopy also showed improved skin retention of IMC-KTTKS-Es. In addition, IMC-KTTKS-Es showed improved topical analgesic and anti-inflammatory activity with no potentially hazardous skin irritation. This study suggested that the IMC-KTTKS-Es might be an effective drug carrier for topical skin therapy with a good safety profile.

The J-TEXT capability is enhanced compared to two years ago with several upgrades of its diagnostics and the increase of electron cyclotron resonance heating (ECRH) power to 1 MW. With the application of electron cyclotron wave (ECW), the ECW assisted plasma startup is achieved; the tearing mode is suppressed; the toroidal injection of 300 kW ECW drives around 24 kA current; fast electrons are generated with toroidal injected ECW and the runaway current conversion efficiency increases with ECRH power. The mode coupling between 2/1 and 3/1 modes are extensively studied. The coupled 2/1 and 3/1 modes usually lead to major disruption. Their coupling can be either suppressed or avoided by external resonant magnetic perturbation fields and hence avoids the major disruption. It is also found that the 2/1 threshold of external field is significantly reduced by a pre-excited 3/1 mode, which can be either a locked island or an external kink mode. The disruption control is studied by developing prediction methods capable of cross tokamak application and by new mitigation methods, such as the biased electrode or electromagnetic pellet injector. The high-density operation and related disruptions are studied from various aspects. Approaching the density limit, the collapse of the edge shear layer is observed and such collapse can be prevented by applying edge biasing, leading to an increased density limit. The density limit is also observed to increase, if the plasma is operated in the poloidal divertor configuration or the plasma purity is increased by increasing the pre-filled gas pressure or ECRH power during the start-up phase.

IntroductionMedical image analysis is of tremendous importance in serving clinical diagnosis, treatment planning, as well as prognosis assessment. However, the image analysis process usually involves multiple modality-specific software and relies on rigorous manual operations, which is time-consuming and potentially low reproducible.MethodsWe present an integrated platform - uAI Research Portal (uRP), to achieve one-stop analyses of multimodal images such as CT, MRI, and PET for clinical research applications. The proposed uRP adopts a modularized architecture to be multifunctional, extensible, and customizable.Results and DiscussionThe uRP shows 3 advantages, as it 1) spans a wealth of algorithms for image processing including semi-automatic delineation, automatic segmentation, registration, classification, quantitative analysis, and image visualization, to realize a one-stop analytic pipeline, 2) integrates a variety of functional modules, which can be directly applied, combined, or customized for specific application domains, such as brain, pneumonia, and knee joint analyses, 3) enables full-stack analysis of one disease, including diagnosis, treatment planning, and prognosis assessment, as well as full-spectrum coverage for multiple disease applications. With the continuous development and inclusion of advanced algorithms, we expect this platform to largely simplify the clinical scientific research process and promote more and better discoveries.

The non-grain production rate (NGPR) of cropland is a grave threat to global grain and food supply, and has been a hot issue across the world. However, few scholars explored the impacts of the NGPRs of different cropland types, such as those of paddy land and irrigated land in the same region. Thus, according to the third land survey data, this research first estimated the NGPRs of cropland, paddy land, irrigated land, and dry land at different scales in Shandong Province, China in 2019. Then, their spatial characteristics at a county scale were identified by combining the standard deviation ellipse model and spatial autocorrelation analysis. Finally, the potential driving factors of the NGPR of cropland were explored with the geographical weight regression model. Results are as follows: (1) The NGPR of cropland is at relatively lower level in Shandong Province and is dominated by that of irrigated land, and the NGPR of dry land is higher than those of other cropland types; (2) Significant regional differences exist in the NGPR of cropland, with profound severity in the southeast and much lower in the northwest; (3) At the provincial scale, the total power of agricultural machinery per capita and utilization degree of cropland factors can relieve the NGPR of cropland in nearly the entire research area. The proportion of GDP of the primary industry in GDP, urban population rate, and DEM are the main obstacles for NGPR decrease. At the county scale, the influences of driving factors varied across regions. This research can provide targeted and regional differentiated references for policy improvement and NGPR management.

Background: Nanocomposite Hydrogels (NHs) are 3D molecular networks formed by physically or covalently crosslinking polymer with nanoparticles or nanostructures, which are particularly suitable for serving as carriers for drug delivery systems. Many articles pertaining to the applications of Nanocomposite Hydrogels for drug delivery have been published, however, the use of bibliometric and visualized analysis in this area remains unstudied. The purpose of this bibliometric study intended to comprehensively analyze the knowledge domain, research hotspots and frontiers associated with the applications of Nanocomposite Hydrogels for drug delivery.Methods: We identified and retrieved the publications concerning the applications of NHs for drug delivery between 2003 and 2022 from Web of Science Core Collection Bibliometric and visualized analysis was utilized in this investigative study.Results: 631 articles meeting the inclusion criteria were identified and retrieved from WoSCC. Among those, 2,233 authors worldwide contributed in the studies, accompanied by an average annual article increase of 24.67%. The articles were co-authored by 764 institutions from 52 countries/regions, and China published the most, followed by Iran and the United States. Five institutions published more than 40 papers, namely Univ Tabriz (n = 79), Tabriz Univ Med Sci (n = 70), Islamic Azad Univ (n = 49), Payame Noor Univ (n = 42) and Texas A&M Univ (n = 41). The articles were published in 198 journals, among which the International Journal of Biological Macromolecules (n = 53) published the most articles, followed by Carbohydrate Polymers (n = 24) and ACS Applied Materials and Interfaces (n = 22). The top three journals most locally cited were Carbohydrate Polymers, Biomaterials and Advanced materials. The most productive author was Namazi H (29 articles), followed by Bardajee G (15 articles) and Zhang J (11 articles) and the researchers who worked closely with other ones usually published more papers. “Doxorubicin,” “antibacterial” and “responsive hydrogels” represent the current research hotspots in this field and “cancer therapy” was a rising research topic in recent years. “(cancer) therapeutics” and “bioadhesive” represent the current research frontiers.Conclusion: This bibliometric and visualized analysis offered an investigative study and comprehensive understanding of publications regarding the applications of Nanocomposite Hydrogels for drug delivery from 2003 to 2022. The outcome of this study would provide insights for researchers in the field of Nanocomposite Hydrogels applications for drug delivery.

The purpose of this study was to evaluate L-cysteine-modified transfersomes as the topical carrier for enhanced epidermal delivery of podophyllotoxin (POD). L-cysteine-deoxycholic acid (LC-DCA) conjugate was synthesized via an amidation reaction. POD-loaded L-cysteine-modified transfersomes (POD-LCTs) were prepared via a thin membrane dispersion method and characterized for their particle size, zeta potential, morphology, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and in vitro release. Subsequently, in vitro skin permeation and retention, fluorescence distribution in the skin, hematoxylin–eosin staining and in vivo skin irritation were studied. The POD-LCTs formed spherical shapes with a particle size of 172.5 ± 67.2 nm and a zeta potential of −31.3 ± 6.7 mV. Compared with the POD-Ts, the POD-LCTs provided significantly lower drug penetration through the porcine ear skin and significantly increased the skin retention (p < 0.05). Meaningfully, unlike the extensive distribution of the POD-loaded transfersomes (POD-Ts) throughout the skin tissue, the POD-LCTs were mainly located in the epidermis. Moreover, the POD-LCTs did not induce skin irritation. Therefore, the POD-LCTs provided an enhanced epidermal delivery and might be a promising carrier for the topical delivery of POD.

Curcumin (Cur) is a kind of polyphenol with a variety of topical pharmacological properties including antioxidant, analgesic and anti-inflammatory activities. However, its low water solubility and poor skin bioavailability limit its effectiveness. In the current study, we aimed to develop microemulsion-based keratin–chitosan gel for the improvement of the topical activity of Cur. The curcumin-loaded microemulsion (CME) was formulated and then loaded into the keratin–chitosan (KCS) gel to form the CME-KCS gel. The formulated CME-KCS gel was evaluated for its characterization, in vitro release, in vitro skin permeation and in vivo activity. The results showed that the developed CME-KCS gel had an orange-yellow and gel-like appearance. The particle size and zeta potential of the CME-KCS gel were 186.45 ± 0.75 nm and 9.42 ± 0.86 mV, respectively. The CME-KCS gel showed desirable viscoelasticity, spreadability, bioadhesion and controlled drug release, which was suitable for topical application. The in vitro skin permeation and retention study showed that the CME-KCS gel had better in vitro skin penetration than the Cur solution and achieved maximum skin drug retention (3.75 ± 0.24 μg/cm2). In vivo experimental results confirmed that the CME-KCS gel was more effective than curcumin-loaded microemulsion (Cur-ME) in analgesic and anti-inflammatory activities. In addition, the CME-KCS gel did not cause any erythema or edema based on a mice skin irritation test. These findings indicated that the developed CME-KCS gel could improve the skin penetration and retention of Cur and could become a promising formulation for topical delivery to treat local diseases.

Objective: Current evidence on the immunogenicity of influenza vaccination in patients with chronic obstructive pulmonary disease (COPD) is limited. To address this need for additional knowledge, we conducted a study on the immunogenicity of trivalent seasonal influenza vaccine (TIV) in COPD patients. Methods: We recruited patients from respiratory outpatient clinics of three hospitals in Tangshan, Hebei province who had stable confirmed COPD, were less than 80 y old, and reported not having had influenza or receiving TIV during the study season prior to enrollment. Patients who had a history of allergy to any TIV component or were classified as having very severe COPD were excluded from the study. Eligible and consenting participants were given one dose of TIV after obtaining a baseline blood sample. A second blood sample was obtained 5 weeks later. We used hemagglutination inhibition (HI) assays to measure antibody responses. We considered seropositive to be an HI titer ≥1:10. We considered seroprotection to be an HI titer ≥1:40 and seroconversion to be either a change from seronegative to a post-vaccination titer of ≥1:40 or a fourfold rise in antibody titer among baseline seropositive subjects. Each subject was followed for 1 month to assess the frequency and type of adverse events. Results: Eighty-eight subjects completed our study; the median age was 64 y; most (62.5%) had moderately severe COPD; 48.9% of the subjects had comorbid conditions in addition to COPD. Post–vaccination seropositive rates for influenza H1N1, H3N2, and B were all 100%; corresponding seroprotection rates were 96.6%, 93.2%, and 98.9%; seroconversion rates were 81.8%, 87.5%, and 75.0%. There were no statistical differences in seroconversion (P = .10) and seroprotection (P = .30) among the three types of influenza virus. Geometric mean titers (1:) of HI antibodies to H1N1, H3N2, and B were 18.8 (95% CI: 14.0–25.1), 12.2 (95% CI: 9.6–15.4), and 31.8 (95% CI: 26.1–38.8) at baseline, and 267.0 (95% CI: 213.8–333.4), 190.3 (95% CI: 151.7–238.6), and 201.1 (95% CI: 166.5-242.8) after vaccination. Conclusion: The immunogenicity of one dose of influenza vaccine was excellent in COPD patients. Our study supports recommending influenza vaccination for COPD patients to provide protection from influenza and its complications.

The present study focused on the development of Cur-loaded SOHA nanogels (Cur-SHNGs) to enhance the topical administration of Cur. The physiochemical properties of Cur-SHNGs were characterized. Results showed that the morphology of the Cur-SHNGs was spherical, the average size was 171.37 nm with a zeta potential of −13.23 mV. Skin permeation experiments were carried out using the diffusion cell systems. It was found that the skin retention of Cur-SHNGs was significantly improved since it showed the best retention value (0.66 ± 0.17 μg/cm2). In addition, the hematoxylin and eosin staining showed that the Cur-SHNGs improved transdermal drug delivery by altering the skin microstructure. Fluorescence imaging indicated that Cur-SHNGs could effectively deliver the drug to the deeper layers of the skin. Additionally, Cur-SHNGs showed significant analgesic and anti-inflammatory activity with no skin irritation. Taken together, Cur-SHNGs could be effectively used for the topical delivery of therapeutic drugs.

Objective: Two-photon polymerization (TPP) utilizes an optical nonlinear absorption process to initiate the polymerization of photopolymerizable materials. To date, it is the only technique capable of fabricating complex 3D microstructures with finely adjusted geometry on the cell and sub-cell scales. TPP shows a very promising potential in biomedical applications related to high-resolution features, including drug delivery, tissue engineering, microfluidic devices, and so forth. Therefore, it is of high significance to grasp the global scientific achievements in this field. An analysis of publications concerning the applications of TPP in the biomedical field was performed, and the knowledge domain, research hotspots, frontiers, and research directions in this topic were identified according to the research results.Methods: The publications concerning TPP applications in biomedical field were retrieved from WoSCC between 2003 and 2022, Bibliometrics and visual analysis employing CiteSpace software and R-language package Bibliometrix were performed in this study.Results: A total of 415 publications regarding the TPP applications in the biomedical field were retrieved from WoSCC, including 377 articles, and 38 review articles. The studies pertaining to the biomedical applications of TPP began back in 2003 and showed an upward trend constantly. Especially in the recent 5 years, studies of TPP in biomedical field have increased rapidly, with the number of publications from 2017 to 2021 accounting for 52.29% of the total. In terms of output, China was the leading country and Chinese Acad Sci, Tech Inst Phys and Chem was the leading institution. The United States showed the closest cooperation with other countries. ACS applied materials and interfaces was the most prolific journal (n = 13), followed by Biofabrication (n = 11) and Optics express (n = 10). The journals having the top cited papers were Biomaterials, Advanced materials, and Applied physic letters. The most productive author was Aleksandr Ovsianikov (27 articles). Meanwhile, researchers who had close cooperation with other researchers were also prolific authors. “cell behavior”, " (tissue engineering) scaffolds”, “biomaterials,” and “hydrogel” were the main co-occurrence keywords and “additional manufacturing”, “3D printing,” and “microstructures” were the recent burst keywords. The Keyword clusters, “stem cells,” and “mucosal delivery”, appeared recently. A paper reporting unprecedented high-resolution bull models fabricated by TPP was the most locally cited reference (cited 60 times). “Magnetic actuation” and “additive manufacturing” were recently co-cited reference clusters and an article concerning ultracompact compound lens systems manufactured by TPP was the latest burst reference.Conclusion: The applications of TPP in biomedical field is an interdisciplinary research topic and the development of this field requires the active collaboration of researchers and experts from all relevant disciplines. Bringing up a better utilization of TPP as an additive manufacturing technology to better serve the biomedical development has always been the research focus in this field. Research on stem cells behaviors and mucosal delivery based on microstructures fabricated using TPP were becoming new hotspots. And it can be predicted that using TPP as a sourcing technique to fabricate biomedical-related structures and devices is a new research direction. In addition, the research of functional polymers, such as magnetic-driven polymers, was the frontier topic of TPP biomedical applications.

The needs for high-resolution, well-defined and complex 3D microstructures in diverse fields call for the rapid development of novel 3D microfabrication techniques. Among those, two-photon polymerization (TPP) attracted extensive attention owing to its unique and useful characteristics. As an approach to implementing additive manufacturing, TPP has truly 3D writing ability to fabricate artificially designed constructs with arbitrary geometry. The spatial resolution of the manufactured structures via TPP can exceed the diffraction limit. The 3D structures fabricated by TPP could properly mimic the microenvironment of natural extracellular matrix, providing powerful tools for the study of cell behavior. TPP can meet the requirements of manufacturing technique for 3D scaffolds (engineering cell culture matrices) used in cytobiology, tissue engineering and regenerative medicine. In this review, we demonstrated the development in 3D microfabrication techniques and we presented an overview of the applications of TPP as an advanced manufacturing technique in complex 3D biomedical scaffolds fabrication. Given this multidisciplinary field, we discussed the perspectives of physics, materials science, chemistry, biomedicine and mechanical engineering. Additionally, we dived into the principles of tow-photon absorption (TPA) and TPP, requirements of 3D biomedical scaffolders, developed-to-date materials and chemical approaches used by TPP and manufacturing strategies based on mechanical engineering. In the end, we draw out the limitations of TPP on 3D manufacturing for now along with some prospects of its future outlook towards the fabrication of 3D biomedical scaffolds.

Abstract Background Denitrifying phosphorus removal sludge (DPRS) is widely adopted for nitrogen and phosphorus removal in wastewater treatment but faces threats from heavy metals. However, a lack of understanding of the taxon-specific heavy metal-resistance mechanisms hinders the targeted optimization of DPRS’s robustness in nutrient removal. Results We obtained 403 high- or medium-quality metagenome-assembled genomes from DPRS treated by elevating cadmium, nickel, and chromium pressure. Then, the proteomic responses of individual taxa under heavy metal pressures were characterized, with an emphasis on functions involving heavy metal resistance and maintenance of nutrient metabolism. When oxygen availability was constrained by high-concentration heavy metals, comammox Nitrospira overproduced highly oxygen-affinitive hemoglobin and electron-transporting cytochrome c-like proteins, underpinning its ability to enhance oxygen acquisition and utilization. In contrast, Nitrosomonas overexpressed ammonia monooxygenase and nitrite reductase to facilitate the partial nitrification and denitrification process for maintaining nitrogen removal. Comparisons between phosphorus-accumulating organisms (PAOs) demonstrated different heavy metal-resistance mechanisms adopted by Dechloromonas and Candidatus Accumulibacter, despite their high genomic similarities. In particular, Dechloromonas outcompeted the canonical PAO Candidatus Accumulibacter in synthesizing polyphosphate, a potential public good for heavy metal detoxification. The superiority of Dechloromonas in energy utilization, radical elimination, and damaged cell component repair also contributed to its dominance under heavy metal pressures. Moreover, the enrichment analysis revealed that functions involved in extracellular polymeric substance formation, siderophore activity, and heavy metal efflux were significantly overexpressed due to the related activities of specific taxa. Conclusions Our study demonstrates that heavy metal-resistance mechanisms within a multipartite community are highly heterogeneous between different taxa. These findings provide a fundamental understanding of how the heterogeneity of individual microorganisms contributes to the metabolic versatility and robustness of microbiomes inhabiting dynamic environments, which is vital for manipulating the adaptation of microbial assemblages under adverse environmental stimuli. Video abstract

Abstract Background The introductions of anti‐ human epidermal growth factor receptor‐2 (HER2) agents have significantly improved the treatment outcome of patients with HER2‐positive breast cancer. BAT8001 is a novel antibody‐drug conjugate targeting human epidermal growth factor receptor‐2 (HER2)‐expressing cells composed of a trastuzumab biosimilar linked to the drug‐linker Batansine. This dose‐escalation, phase I study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary anti‐tumor activity of BAT8001 in patients with HER2‐positive locally advanced or metastatic breast cancer. Methods This trial was conducted in subjects with histologically confirmed HER2‐positive breast cancer (having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1) using a 3 + 3 design of escalating BAT8001 doses. Patients received BAT8001 intravenously in a 21‐day cycle, with dose escalation in 5 cohorts: 1.2, 2.4, 3.6, 4.8, and 6.0 mg/kg. The primary objective was to evaluate the safety and tolerability of BAT8001. Preliminary activity of BAT8001 was also assessed as a secondary objective. Results Between March 2017 to May 2018, 29 HER2‐positive breast cancer patients were enrolled. The observed dose‐limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase. The maximum tolerated dose was determined to be 3.6 mg/kg. Grade 3 or greater adverse events (AEs) occurred in 14 (48.3%) of 29 patients, including thrombocytopenia in 12 (41.4%) patients, aspartate aminotransferase increased in 4 (13.8%) patients, γ‐glutamyl transferase increased in 2 (6.9%) patients, alanine aminotransferase increased in 2 (6.9%) patients, diarrhea in 2 (6.9%) patients. Objective response was observed in 12 (41.4%; 95% confidence interval [CI] = 23.5%‐61.1%) and disease control (including patients achieving objective response and stable disease) was observed in 24 (82.8%; 95% CI = 64.2%‐94.2%) patients. Conclusions BAT8001 demonstrated favorable safety profiles, with promising anti‐tumor activity in patients with HER2‐positive locally advanced or metastatic breast cancer. BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2‐positive breast cancer.

AbstractBackground Triple-negative breast cancer (TNBC) represents about 19% of all breast cancer cases in the Chinese population. Lack of targeted therapy contributes to the poorer outcomes compared with other breast cancer subtypes. Comprehensive genomic profiling helps to explore the clinically relevant genomic alterations (CRGAs) and potential therapeutic targets in very-early-relapsed TNBC patients.Methods Formalin-fixed paraffin-embedded (FFPE) tumour tissue specimens from 23 patients with very-early-relapsed TNBC and 13 patients with disease-free survival (DFS) more than 36 months were tested by FoundationOne CDx (F1CDx) in 324 genes and select gene rearrangements, along with genomic signatures including microsatellite instability (MSI) and tumour mutational burden (TMB).Results In total, 137 CRGAs were detected in the 23 very-early-relapsed TNBC patients, averaging six alterations per sample. The mean TMB was 4 Muts/Mb, which was higher than that in non-recurrence patients, and is statistically significant. The top-ranked altered genes were TP53 (83%), PTEN (35%), RB1 (30%), PIK3CA (26%) and BRCA1 (22%). RB1 mutation carriers had shorter DFS. Notably, 100% of these patients had at least one CRGA, and 87% of patients had at least one actionable alteration. In pathway analysis, patients who carried a mutation in the cell cycle pathway were more likely to experience very early recurrence. Strikingly, we detected one patient with ERBB2 amplification and one patient with ERBB2 exon20 insertion, both of which were missed by immunohistochemistry (IHC). We also detected novel alterations of ROS1–EPHA7 fusion for the first time, which has not been reported in breast cancer before.Conclusions The comprehensive genomic profiling can identify novel treatment targets and address the limited options in TNBC patients. Therefore, incorporating F1CDx into TNBC may shed light on novel therapeutic opportunities for these very-early-relapsed TNBC patients.

A clear understanding of cropland expansion dynamics and their effects is vital for cropland protection and food security. However, the trajectories of cropland expansion have been less discussed. This study referred to the modes of landscape expansion and assessed the cropland expansion trajectory in three urban agglomerations in the Yangtze River Economic Belt and its impact on cropland fragmentation. Specifically, we identified three cropland expansion trajectories using the landscape expansion index, namely, infilling, edge-expansion, and outlying. Moreover, the surface relief amplitude model was employed to characterize the relief amplitude effect on cropland expansion trajectories. By coupling landscape metrics (e.g., patch density, landscape shape index, the largest patch index, and aggregation index) and Spearman correlation analysis, the relationship between cropland expansion trajectories and cropland fragmentation was assessed. Results show that (1) three urban agglomerations experience cropland expansion, in which the edge-expansion trajectory is primary, followed by infilling and outlying trajectories; (2) the cumulative frequency curve indicates that infilling and edge-expansion trajectories are likely to be distributed in low topographic relief amplitude regions, while the outlying trajectory is located in relatively higher topographic relief amplitude regions; and (3) infilling and edge-expansion trajectories contribute to a significantly positive relationship with the decrease of cropland fragmentation, while the outlying trajectory has a negative relationship with cropland fragmentation. This research highlights that cropland protection policies should considerably focus on the trajectory of cropland expansion, not only request the total area of cropland in a dynamic balance.

Soil erosion is a land degradation process that may threaten the sustainability of ecosystem as well as cause severe social and economic problems. The studies on the effect of ecological restoration policies on soil erosion have been well documented, while the spatial relationships and spillover effects of the policies on soil erosion have been rarely scrutinized, though it is of great policy implications in soil erosion control. Based on the analysis of the spatio-temporal evolution of soil erosion in 107 counties of Shaanxi Province with Revised Universal Soil Loss Equation, this study employs a panel spatial Durbin model (SDM) with multi-source data for 107 counties from 2000 to 2015 to investigate the spatial effects of the Sloping Land Conversion Program (SLCP) on soil erosion control with investment data of SLCP. The results show that during 2000–2015, the average amount of soil erosion exhibited a significant downtrend contributed by the continuous investment of SLCP. The spatial economic results demonstrate that the own effect, as well as the spillover effect of investment on soil erosion control, is significant and positive. A 0.1 billion CNY increase in investment in a county will result in a reduction of the total soil erosion by 288.69 thousand t/a, of which 63% is contributed to the own direct effect on local soil erosion control and the 37% of it is contributed to the spillover effect on the neighbors. Moreover, rainfall has a significant and positive moderating effect on the mitigation effect of SLCP on soil erosion at county scale; the marginal contribution of investment of SLCP on soil erosion control in the county with less rainfall is greater than that with more rainfall. These findings contribute to further our understanding of the long-term effects of ecological restoration policies and transboundary ecological governance.

Nowadays, both urbanization and cropland expansion are hot issues. However, research related to the spatiotemporal interaction between urbanization and cropland expansion and their socioeconomic determinants remains scarce. Accordingly, this research takes the urban agglomeration in the middle reaches of the Yangtze River (MRUA) as the research area by combining spatial analysis, sensitivity analysis, and the spatial gravity model. To achieve this goal, we identified the area of the construction land expansion and cropland expansion, the sensitivity of cropland expansion to construction land expansion, and the shifting trajectory of gravity centers of construction land expansion and cropland expansion and their interaction during 2000–2020, respectively. Additionally, the geographically weighted regression model was utilized to explore the spatiotemporal heterogeneity of four socioeconomic determinants of the interaction between construction land expansion and cropland expansion. The results are as follows: 1) the area of the expanded construction land and the expanded cropland and the sensitivity of cropland expansion to construction land expansion show an overall increasing pattern; 2) the gravity center of the expanded construction land shifted toward the northeast, whereas that of the expanded cropland moved to the southeast but with similar moving distances (17.83 and 15.37 km, respectively); 3) the GDP has an increasing positive effect on the interaction of the construction land expansion and cropland expansion, whereas the investment in fixed assets shows an increasing negative effect during 2000–2020. The GDP in the agricultural sector and population displays a stable influence. This article offers a solution for decision makers to promote the interaction between construction land and cropland.

Diagnosing degradation risks of ecosystem services (ESs) is a cornerstone for achieving sustainable development of the ecosystem and promote human well-being. In this study, we constructed and applied a diagnostic framework for degradation risks of ecosystem services (ESDRs) in Wuhan City, China. First, the risk receptors and risk sources were spatially overlaid to identify and measure the ESDRs. Second, a multiscale geographically weighted regression (MGWR) model was applied to identify land development factors that could be used to regulate ESDRs. Finally, the high value areas of ESDRs were clustered and the regression results were used to propose regulatory measures for each clustered zone. Our study showed that the uncontrolled expansion of construction land in Wuhan might weaken the functions of water retention, habitat maintenance and carbon sequestration services, while the functions of habitat maintenance and soil conservation services might be weakened by the expansion of farmland. The five ESDRs identified based on the above results had significant spatial clustering characteristics and spatial heterogeneity. The visual results of the MGWR model suggested that factors of land development could effectively mitigate conflicts between construction or farming activities and ESs. Ultimately, the spatial clusters of ESDRs were scientifically delimited and differentiated regulatory measures were developed simultaneously. Therefore, we argue that land use planning and environmental management in rapidly urbanizing areas should take into account the diagnostic framework of ESDRs in order to protect natural ecosystems.

Diaveridine (DVD) is widely used for the prevention and treatment of coccidiosis and leucocytozoonosis infections in food-producing animals. To gain a better understanding of DVD metabolism and pharmacokinetics in healthy Landrace/Doric Cross castrated male pigs and both female and male Cobb 500 broiler chickens, a method involving radioactive tracing coupled with LC/MS-IT-TOF was developed for the identification and quantitation of DVD and its metabolites in pig and chicken plasma, and then was applied to investigate DVD pharmacokinetics. A simple MCX solid phase extraction procedure was adopted for sample preparation. After a single oral administration of 3H-DVD (10 mg/kg BW), three radioactive compounds (D0: DVD; D1: 3′-desmethyl-DVD; and D2: monoglucuronide of 3′-desmethyl-DVD) were identified in pig plasma, while only two radioactive compounds (D0 and D2) were identified in chicken plasma. In both species, the Cmax values for all detected compounds were reached at 2 h after dosing. The Cmax order was D2 (1.38 μg/ml) > D0 (0.49 μg/ml) > D1 (0.24 μg/ml) in pigs and D0 (1.55 μg/ml) > D2 (0.27 μg/ml) in chickens. The longer t1/2 (elimination half-life) of D0 contributed to the slow elimination of DVD-related compounds. The t1/2β of D0 in pigs (66.41 h) was significantly longer than that in chickens (48.30 h), but the t1/2 of total DVD-related metabolites in pigs (42.86 h) was lower than that in chickens (56.11 h). These findings suggested that the metabolism and pharmacokinetics of DVD in pigs and chickens were significantly different, and that this would affect its effectiveness, toxicology, and food safety in these animals.

Lysozymes are naturally occurring enzymes present in a variety of biological organisms, such as bacteria, fungi, and animal bodily secretions and tissues. It is also the main ingredient of many ethnomedicines. It is well known that lysozymes and lysozyme-like enzymes can be used as anti-bacterial agents by degrading bacterial cell wall peptidoglycan that leads to cell death, and can also inhibit fungi, yeasts, and viruses. In addition to its direct antimicrobial activity, lysozyme is also an important component of the innate immune system in most mammals. Increasing evidence has shown the immune-modulatory effects of lysozymes against infection and inflammation. More recently, studies have revealed the anti-cancer activities of lysozyme in multiple types of tumors, potentially through its immune-modulatory activities. In this review, we summarized the major functions and underlying mechanisms of lysozymes derived from animal and plant sources. We highlighted the therapeutic applications and recent advances of lysozymes in cancers, hypertension, and viral diseases, aiming toseeking alternative therapies for standard medical treatment bypassing side effects. We also evaluated the role of lysozyme as a promising cancer marker for prognosis to indicate the outcomes recurrence for patients.

IntroductionHR+/HER2− breast cancer (BC) has a much lower pathological complete response (pCR) rate to neoadjuvant chemotherapy (NAC). Therefore, to better stratify the relapse risk for HR+/HER2− non-pCR populations, it is essential to accurate identification new prognostic markers.Materials and MethodsThe study retrospectively analyzed 105 stage II–III patients who were diagnosed with HR+/HER2− BC and received NAC followed by breast and axilla surgery between 2013 and 2019 in Sun Yat-Sen University Cancer Center. The Miller–Payne (MP) grading system was used to evaluate pathological responses to NAC. The 70-gene signature was used to classify the prognosis signatures.ResultsAmong the 105 patients, the study demonstrated that larger tumor size and lower progesterone receptor level at baseline and larger tumor size postoperative were statistically significantly associated with worse disease-free survival (DFS) (p = 0.004, p = 0.021, and p = 0.001, respectively). Among 54 patients who underwent the 70-gene assays, 26 (48.1%) had a low-risk signature; 28 (51.9%) patients had a high-risk signature. Patients with poor response (MP grades 1–2) were more likely to with a high-risk 70-gene signature than those with good response (MP grades 4–5). The final analysis showed that DFS was longer in the low-risk group than in the high-risk group [52.4 vs. 36.1 months of the median DFS, hazard ratio (HR) for recurrence, 0.29; 95% confidence interval (CI), 0.10–0.80; p = 0.018]. DFS was longer in the good response (MP grades 3–4) group than in the poor response (MP grades 1–2) group (94.7% vs. 60% of the patients free from recurrence; HR, 0.16; 95% CI, 0.05–0.47; p = 0.037). When stratified by MP grades combined with the 70-gene signature, subgroup analyses showed the good-response low-risk group with the best DFS, whereas the poor-response high-risk group showed the worst DFS (p = 0.048). Due to the short median follow-up time of 34.5 months (5.9–75.1 months), MP grades and the 70-gene signature did not show significant prognostic value for overall survival.ConclusionThe study showed that analysis of MP grades combined with the 70-gene signature with residual NAC-resistant breast samples has a significant correlation with DFS.

Electroencephalograph (EEG) plays a significant role in the diagnostics process of epilepsy, but the detection rate is unsatisfactory when the length of interictal EEG signals is relatively short. Although the deliberate attacking theories for undirected brain network based on node removal method can extract potential network features, the node removal method fails to sufficiently consider the directionality of brain electrical activities. To solve the problems above, this study proposes a feature tensor-based epileptic detection method of directed brain networks. First, a directed functional brain network is constructed by calculating the transfer entropy of EEG signals between different electrodes. Second, the edge removal method is used to imitate the disruptions of brain connectivity, which may be related to the disorder of brain diseases, to obtain a sequence of residual networks. After that, topological features of these residual networks are extracted based on graph theory for constructing a five-way feature tensor. To exploit the inherent interactions among multiple modes of the feature tensor, this study uses the Tucker decomposition method to get a core tensor which is finally reshaped into a vector and input into the support vectors machine (SVM) classifier. Experiment results suggest that the proposed method has better epileptic screening performance for short-term interictal EEG data.

We analysed Natality data obtained from the National Vital Statistics System from 1971 through 2018. Overall, the rates of singletons declined among all racial groups over the five decades of the study. However, the rates of twins and higher-order multiples increased over the same period although for the past two decades, the rates of higher-order multiples had substantially plummeted. The global health implication of these findings is that policy changes in the US in the form of professional practice guidelines have succeeded in reducing the birth of vulnerable populations (i.e., higher-order multiples) who are predominantly created using assisted reproductive technology. Key words: • Trends in Multiple Gestations • US • Black • White • Singletons • Twins • Higher-order multiples Copyright © 2020 Wang et al. Published by Global Health and Education Projects, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in this journal, is properly cited.

In this paper, we studied a nutrient–phytoplankton model with time delay and diffusion term. We studied the Turing instability, local stability, and the existence of Hopf bifurcation. Some formulas are obtained to determine the direction of the bifurcation and the stability of periodic solutions by the central manifold theory and normal form method. Finally, we verify the above conclusion through numerical simulation.

Power battery is the core component of electric vehicles, and its characteristics determine the performance of electric vehicles. Lithium-ion power battery is a kind of time-varying nonlinear system, which has different external features under different application conditions and aging state. In order to implement the optimized charging method under changeable application conditions, the estimation of the internal states is extremely necessary. For this purpose, this paper studies the multiple states joint estimation based on the accurate and reliable battery modeling method. First, the modeling of lithium-ion battery and the parameter identification of the models are studied. A parameter identification method is proposed based on forgetting factor recursive extended least square. The battery model’s order is based on Bayesian information criterions. Second, multiple states joint estimation algorithm for power battery under charging mode is studied. For the estimated accuracy of the battery’s state of charge is associated with the battery usable capacity, state of charge and usable capacity joint estimation algorithm, based on several different order battery models is proposed. State of power estimation algorithm of the battery under multiple factors constraints is proposed based on the solution discrete analysis of the continuous time traction battery differential state equation. Finally, multiple states joint estimation algorithm is achieved. Validation results show that the proposed estimation algorithm can achieve high accuracy.

Cyclooxygenase-2 (COX-2) imaging agents are potent tools for early cancer diagnosis. Almost all of the COX2 imaging agents using celecoxib as backbone were chemically modified in the position of N-atom in the sulfonamide group. Herein, a novel COX-2 probe (CCY-5) with high targeting ability and a near-infrared wavelength (achieved by attaching a CY-5 dye on the pyrazole ring of celecoxib using a migration strategy) was evaluated for its ability to probe COX-2 in human cancer cells. CCY-5 is expected to have high binding affinity for COX-2 based on molecular docking and enzyme inhibition assay. Meanwhile, CCY-5 caused stronger fluorescence imaging of COX-2 overexpressing cancer cells (Hela and SCC-9 cells) than that of normal cell lines (RAW 264.7 cells). Lipopolysaccharide (LPS) treated RAW264.7 cells revealed an enhanced fluorescence as LPS was known to induce COX-2 in these cells. In inhibitory studies, a markedly reduced fluorescence intensity was observed in cancer cells, when they were co-treated with a COX-2 inhibitor celecoxib. Therefore, CCY-5 may be a selective bioimaging agent for cancer cells overexpressing COX-2 and could be useful as a good monitoring candidate for effective diagnosis and therapy in cancer treatment.

Over the past few decades urbanization and population growth have been the main trend all over the world, which brings the increase of economic benefits (EB) and the decrease of cropland. Cropland protection policies play an important role in the urbanization progress. In this study, we assess the trade-offs between EB and ecosystem services value (ESV) under three cropland protection policy scenarios using the LAND System Cellular Automata for Potential Effects (LANDSCAPE) model. The empirical results reveal that trade-offs between EB and ESV in urbanizing areas are dynamic, and that they considerably vary under different cropland protection policy scenarios. Especially, the results identify certain “turning points” for each policy scenario at which a small to moderate growth in EB would result in greater ESV losses. Among the three scenarios, we found that the cropland protection policy has the most adverse effect on trade-offs between EB and ESV and the results in the business as usual scenario have the least effect on the trade-offs. Furthermore, the results show that a strict balance between requisition and compensation of cropland is an inappropriate policy option in areas where built-up areas are increasing rapidly from the perspective of mitigating conflict between EB and ESV and the numbers of cropland protection that restrained by land use planning policy of Wuhan is a better choice.

Xinnao shutong (XNST) capsules have been clinically used in China to treat cerebrovascular diseases. Previous studies have demonstrated that XNST has significant neuroprotective effects against acute cerebral ischemic stroke. The present study investigated the effects and mechanisms of XNST treatment following chronic cerebral hypoperfusion. Thirty-six adult male Sprague-Dawley rats were treated with XNST or vehicle following permanent bilateral common carotid artery (BCCA) ligation. Body weight was recorded on days 0, 3, 7, 14, 28, and 42 post-surgery. The Morris water maze (MWM) test was used to assess cognitive function in rats. Immunofluorescent staining and western blot were used to assess the severity of neuronal plasticity, white matter injury, and the numbers and/or phenotypic changes incurred to microglia. Protein levels of p-AKT (Thr308) and p-ERK (Thr202/Tyr204) were detected 42 days after BCCA ligation was performed. The results indicate that XNST treatment significantly reduced escape latency, decreased the frequency of platform crossing compared to the vehicle group. Synaptophysin, protein levels improved and white matter injury ameliorated following XNST treatment. Meanwhile, XNST reduced the number of M1 microglia and increased the number of M2 microglia. Furthermore, p-AKT (Thr308) and p-ERK (Thr202/Tyr204) levels were increased 42 days following BCCA ligation. In summary, our results suggest that XNST mitigates memory impairments by restoration of neuronal plasticity and by modulation of microglial polarization following chronic cerebral hypoperfusion in rats.

In this paper, we propose a novel framework for IQ estimation using Magnetic Resonance Imaging (MRI) data. In particular, we devise a new feature selection method based on an extended dirty model for jointly considering both element-wise sparsity and group-wise sparsity. Meanwhile, due to the absence of large dataset with consistent scanning protocols for the IQ estimation, we integrate multiple datasets scanned from different sites with different scanning parameters and protocols. In this way, there is large variability in these different datasets. To address this issue, we design a two-step procedure for 1) first identifying the possible scanning site for each testing subject and 2) then estimating the testing subject's IQ by using a specific estimator designed for that scanning site. We perform two experiments to test the performance of our method by using the MRI data collected from 164 typically developing children between 6 and 15 years old. In the first experiment, we use a multi-kernel Support Vector Regression (SVR) for estimating IQ values, and obtain an average correlation coefficient of 0.718 and also an average root mean square error of 8.695 between the true IQs and the estimated ones. In the second experiment, we use a single-kernel SVR for IQ estimation, and achieve an average correlation coefficient of 0.684 and an average root mean square error of 9.166. All these results show the effectiveness of using imaging data for IQ prediction, which is rarely done in the field according to our knowledge.

To explore the deformation behavior and failure strength of sulfate saline silty clay at a temperature of -10℃ and confining pressures of 6~10 MPa, we have performed low-temperature triaxial shear tests on sulfate saline silty clay in Hexi region of Gansu province, China. The variation trend of deviatoric stress, volumetric strain and initial deformation modulus with confining pressure were analyzed. The results demonstrated that the stress-strain curve of frozen sulfate saline silty clay was hyperbolic and the deviatoric stress increased as the axial strain increased and was eventually constant. Owing to particle breakage and melting of ice, when the confining pressure, σ3>6 the strength decreased as the confining pressure increased and the sample exhibited volumetric shrinkage throughout the entire confining-pressure range. A constitutive model of frozen sulfate saline silty clay under high confining pressure has been proposed in combination with the Duncan Chang model and the validity of the model has been confirmed by comparison with test data. [ABSTRACT FROM AUTHOR]