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Abstract Background Erector spinae plane block (ESPB) is a novel fascial plane block technique that can provide effective perioperative analgesia for thoracic, abdominal and lumbar surgeries. However, the effect of cervical ESPB on postoperative analgesia after arthroscopic shoulder surgery is unknown. The aim of this study is to investigate the analgesic effect and safety of ultrasound-guided cervical ESPB in arthroscopic shoulder surgery. Methods Seventy patients undergoing arthroscopy shoulder surgery were randomly assigned to one of two groups: ESPB group (n = 35) or control group (n = 35). Patients in the ESPB group received an ultrasound-guided ESPB at the C7 level with 30 mL of 0.25% ropivacaine 30 min before induction of general anesthesia, whereas patients in the control group received no block. The primary outcome measures were the static visual analogue scale (VAS) pain scores at 4, 12, and 24 h after surgery. Secondary outcomes included heart rate (HR) and mean arterial pressure (MAP) before anesthesia (t1), 5 min after anesthesia (t2), 10 min after skin incision (t3), and 10 min after extubation (t4); intraoperative remifentanil consumption; the Bruggrmann comfort scale (BCS) score, quality of recovery-15 (QoR-15) scale score and the number of patients who required rescue analgesia 24 h after surgery; and adverse events. Results The static VAS scores at 4, 12 and 24 h after surgery were significantly lower in the ESPB group than those in the control group (2.17 ± 0.71 vs. 3.14 ± 1.19, 1.77 ± 0.77 vs. 2.63 ± 0.84, 0.74 ± 0.66 vs. 1.14 ± 0.88, all P 0.05). The intraoperative consumption of remifentanil was significantly less in the ESPB group compared to the control group (P

Abstract Cancer immunotherapy and vaccine development have significantly improved the fight against cancers. Despite these advancements, challenges remain, particularly in the clinical delivery of immunomodulatory compounds. The tumor microenvironment (TME), comprising macrophages, fibroblasts, and immune cells, plays a crucial role in immune response modulation. Nanoparticles, engineered to reshape the TME, have shown promising results in enhancing immunotherapy by facilitating targeted delivery and immune modulation. These nanoparticles can suppress fibroblast activation, promote M1 macrophage polarization, aid dendritic cell maturation, and encourage T cell infiltration. Biomimetic nanoparticles further enhance immunotherapy by increasing the internalization of immunomodulatory agents in immune cells such as dendritic cells. Moreover, exosomes, whether naturally secreted by cells in the body or bioengineered, have been explored to regulate the TME and immune-related cells to affect cancer immunotherapy. Stimuli-responsive nanocarriers, activated by pH, redox, and light conditions, exhibit the potential to accelerate immunotherapy. The co-application of nanoparticles with immune checkpoint inhibitors is an emerging strategy to boost anti-tumor immunity. With their ability to induce long-term immunity, nanoarchitectures are promising structures in vaccine development. This review underscores the critical role of nanoparticles in overcoming current challenges and driving the advancement of cancer immunotherapy and TME modification.

Copper, an indispensable micronutrient, is implicated in numerous vital biological processes and is essential for all physiological activities. Recently, the discovery of a novel type of copper-dependent cell death, known as cuproptosis, has shed light on its role in cancer development. Extensive research is currently underway to unravel the mechanisms underlying cuproptosis and its correlation with various cancer types. In this review, we summarize the findings regarding the roles and mechanisms of cuproptosis in various cancer types, including colorectal cancer, lung cancer, gastric cancer, breast cancer, liver cancer and cutaneous melanoma. Furthermore, the effects of copper-related agents such as copper chelators and copper ionophores on cell proliferation, apoptosis, angiogenesis, tumor immunity, and chemotherapy resistance have been explored in cancer preclinical and clinical trials. These insights provide promising avenues for the development of prospective anticancer drugs aimed at inducing cuproptosis.

Photocatalytic reduction of carbon dioxide (CO2) presents a pivotal solution to address meteorological and ecological challenges. Currently, metal-organic frameworks (MOFs) with their crystalline porosity, adjustable structures, and diverse chemical functionalities have garnered significant attention in the realm of photocatalytic CO2 reduction. This review provides a brief introduction to CO2 reduction and MOF material and their applications in CO2 reduction. Then, it undertakes a comprehensive examination of MOFs, summarizing their key attributes, including porosity, large surface area, structural multifunctionalities, and responsiveness to visible light, along with an analysis of heterojunctions and their methods of preparation. Additionally, it elucidates the fundamental principle of photocatalysis and CO2 reduction, encompassing both half and overall reactions. Furthermore, the classification of MOF-based materials is explored, along with the proposed mechanism for CO2 reduction and an update on recent developments in this field. Finally, this review outlines the challenges and potential opportunities for utilizing MOFs in CO2 reduction, offering valuable insights to scholars seeking innovative approaches not only to enhance CO2 reduction but also to advance other photocatalytic processes.

Abstract Extracellular vesicles (EVs) have gained increasing recognition as significant regulators of intercellular communication in various physiological and pathological processes. These vesicles play a pivotal role in cancer progression by facilitating the transfer of diverse cargoes, including lipids, proteins, and nucleic acids. Regulated cell death (RCD), the orderly and autonomous death of cells, is controlled by a variety of biomacromolecules and, in turn, influences various biological processes and cancer progression. Recent studies have demonstrated that EV cargoes regulate diverse oncogenes and tumor suppressors to mediate different nonapoptotic forms of RCD, notably ferroptosis, pyroptosis, and necroptosis. Nevertheless, comprehensive exploration of EV-mediated nonapoptotic RCD forms in the context of cancer has not been performed. This review summarizes the progress regarding the biological functions and underlying mechanisms of EVs in mediating nonapoptotic RCD by delivery of cargoes to regulate tumor progression. Additionally, the review delves into the potential clinical applications of EV-mediated cell death and its significance in the areas of cancer diagnosis and therapy.

Abstract Background Peripheral nerve block, including the quadratus lumborum block (QLB), has been used for postoperative analgesia in hip surgery. However, the effects of QLB on cognitive function after hip surgery remain unknown. This study aimed to assess the effects of the anterior approach to QLB on postoperative cognitive function in older people undergoing hip surgery. Methods Sixty older people who underwent hip surgery from May 2021 to May 2022 were randomly divided into the QLB (n = 30) and control groups (n = 30). The Montreal Cognitive Assessment (MoCA) score (mean ± SD) was measured one day preoperatively and seven and 30 days postoperatively. The frequency (%) of postoperative cognitive dysfunction (POCD) was examined seven and 30 days postoperatively. The visual analog scale (VAS) scores at rest and Bruggrmann comfort scale (BCS) scores [Median (IQR)] 6 h (t1), 12 h (t2), 24 h (t3), and 48 h (t4) after surgery were assessed. The plasma high mobility group box protein 1 (HMGB1) and levels of interleukin-6 (IL-6) (mean ± SD) were evaluated 1 h preoperatively (baseline) and 24 h postoperatively (day 1). The requirement for rescue analgesia [Median (IQR)], time to first off-bed activity (mean ± SD), and adverse effects after surgery were also recorded. Results Compared with the control group, the frequency of POCD was significantly lower in the QLB group seven days postoperatively (10.7% vs. 34.5%, P = 0.033), but no difference at 30 days postoperatively (3.6% vs. 10.3%, P = 0.319). There was no significant difference in MoCA scores between the two groups at one day preoperatively and 30 days postoperatively. However, the MoCA scores at seven days postoperatively were higher in the QLB group than in the control group (27.4 ± 1.81 vs. 26.4 ± 1.83, P = 0.043). In the QLB group, the VAS scores at t1, t2, and t3 were lower [3(2–4) vs. 4(3–4), P = 0.028; 3(2–3) vs. 4(3–5), P = 0.009; 2(1–3) vs. 2(2–3), P = 0.025], and the BCS scores at t1, t2, and t3 were higher than those in the control group [3(1–3) vs. 1(1–2), P = 0.006; 3(2–3) vs. 2(1–3), P = 0.011; 3(2–4) vs. 2(2–3), P = 0.041]. The patients in the QLB group reported significantly fewer requirements for rescue analgesia [0(0–1) vs. 1(0–2), P = 0.014]. The plasma levels of HMGB1 and IL-6 at 24 h postoperatively in the QLB group were significantly lower than in the control group (749.0 ± 185.7 vs. 842.1 ± 157.9, P = 0.046; 24.8 ± 8.1 vs. 31.9 ± 5.5, P

Aldo-Keto Reductase Family 1 Member C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase (17β-HSD5) or prostaglandin F (PGF) synthase, functions as a pivotal enzyme in androgen biosynthesis. It catalyzes the conversion of weak androgens, estrone (a weak estrogen), and PGD2 into potent androgens (testosterone and 5α-dihydrotestosterone), 17β-estradiol (a potent estrogen), and 11β-PGF2α, respectively. Elevated levels of AKR1C3 activate androgen receptor (AR) signaling pathway, contributing to tumor recurrence and imparting resistance to cancer therapies. The overexpression of AKR1C3 serves as an oncogenic factor, promoting carcinoma cell proliferation, invasion, and metastasis, and is correlated with unfavorable prognosis and overall survival in carcinoma patients. Inhibiting AKR1C3 has demonstrated potent efficacy in suppressing tumor progression and overcoming treatment resistance. As a result, the development and design of AKR1C3 inhibitors have garnered increasing interest among researchers, with significant progress witnessed in recent years. Novel AKR1C3 inhibitors, including natural products and analogues of existing drugs designed based on their structures and frameworks, continue to be discovered and developed in laboratories worldwide. The AKR1C3 enzyme has emerged as a key player in carcinoma progression and therapeutic resistance, posing challenges in cancer treatment. This review aims to provide a comprehensive analysis of AKR1C3’s role in carcinoma development, its implications in therapeutic resistance, and recent advancements in the development of AKR1C3 inhibitors for tumor therapies.

Conflict over land use is an issue that all countries are experiencing in the accelerated process of urbanization and industrialization. Research on the identification and characterization of land-use conflicts is an important basis for promoting the sustainable development of regional land use. Taking Hebei Province under the background of Beijing–Tianjin–Hebei integration as the research object, this article combines the SCCI model and the LUF model to study the land-use flush in the process of rapid urbanization from the dimensions of land-use landscape conflict and land-use function conflict. The results of this study point out that land-use conflicts in the region have gone through a developmental course of intensification of heavy conflicts, slowing down, and then smoothing out. The exacerbation of land-use conflicts is synchronized with the time pattern of construction and development in the accelerated industrialization and urbanization of Hebei, while the activities of arable land occupation and compensation balance and land ecological management produce lagging land-use conflicts. The spatial pattern is characterized by dispersed and random conflicts in the plains, concentrated conflicts in the mountain stream zones, and stable conflicts in the ecological zones within the mountains in the mountainous areas. The role of externalities and internalities from within the region and in the coordinated development of the region has led to the coexistence of developmental and governance land-use conflicts in Hebei Province, and the geographic environment has a constraining effect on the spatial differentiation of these conflicts. Along with the strong implementation of China’s eco-governance and use-control systems, developmental land-use conflicts from the region will be effectively curbed, but the risk of overlapping developmental conflicts and lagging governance conflicts from coordinated regional development is a key focus for conflict prevention in the future.

Exploring the evolution of the production patterns of major crops and their driving factors can provide new ideas to ensure the security of supply of important agricultural products. This study selected four major crop types in Jilin Province—grain, oil crop, vegetable, and fruit—as research subjects. Using the center of gravity migration model, spatial autocorrelation analysis, and comparative advantage index, the spatial and temporal evolution of these crops’ production patterns from 2000 to 2020 was examined. A geographically weighted regression model was employed to analyze driving factors. The results showed that the planting area of grain was the most extensive; the percentage of production of grain, oil crop, and fruit increased to different degrees; the unit area yield of the four crops increased. The centers of gravity of all four crops’ productions were located in the central-northwestern region of Jilin Province. The global Moran’s I was positive for all four crops’ productions. The comparative advantage characteristics of the four crops were closely related to the natural geographical environment. Grain, vegetable, and fruit production were significantly and positively correlated with fertilizer application, and the most significant factor affecting oil crop production was land input intensity.

We present early-time, hour-to-day cadence spectroscopy of the nearby Type II supernova (SN II) 2024ggi, which was discovered at a phase when the SN shock had just emerged from the red supergiant (RSG) progenitor star. Over the first few days after the first light, SN 2024ggi exhibited prominent narrow emission lines formed through intense and persistent photoionization of the nearby circumstellar material (CSM). In the first 63 hr, spectral lines of He, C, N, and O revealed a rapid rise in ionization as a result of the progressive sweeping up of the CSM by the shock. The duration of the IIn-like spectra indicates a dense and relatively confined CSM distribution extending up to ∼4 × 10 ^14 cm. Spectral modeling reveals that a CSM mass-loss rate at this region exceeding 5 × 10 ^−3 M _⊙ yr ^−1 is required to reproduce low-ionization emissions, which dramatically exceeds that of an RSG. Analyzing the H α emission shift implies the velocity of the unshocked outer CSM to be between 20 and 40 km s ^−1 , matching the typical wind velocity of an RSG. The differences between the inner and outer layers of the CSM and an RSG progenitor highlight a complex mass-loss history before the explosion of SN 2024ggi.

We present a detailed analysis of the progenitor and its local environment for the recently discovered Type II supernova (SN) 2024ggi at a distance of about 6.7 Mpc, by utilizing the pre-explosion images from the Hubble Space Telescope and Spitzer Space Telescope. The progenitor is identified as a red bright variable star, with absolute F814W-band magnitudes being −6.2 mag in 1995 to −7.2 mag in 2003, respectively, consistent with that of a normal red supergiant star. Combining with the historical mid-infrared light curves, a pulsational period of about 379 days can be inferred for the progenitor star. Fitting its spectral energy distribution with stellar spectral models yields the stellar parameters of temperature, radius, and bolometric luminosity as ${T}_{* }={3290}_{-27}^{+19}$ K, ${R}_{* }={887}_{-51}^{+60}$ R _⊙ , and log( L / L _⊙ ) $\,=\,{4.92}_{-0.04}^{+0.05}$ , respectively. The above parameters indicate that the progenitor of SN 2024ggi is consistent with the stellar evolutionary track of a solar-metallicity massive star with an initial mass of ${13}_{-1}^{+1}$ M _⊙ . Moreover, our analysis indicates a relatively low mass-loss rate (i.e.,

Abstract The theoretical model of a Galfenol cantilever energy harvester is investigated for vibration energy harvesting. Compared with the numerical solution, the analytical solution can better capture the intrinsic effects of the physical parameters on the performance of the harvester. In this work, an electromechanical coupled distributed-parameter model of the Galfenol cantilever energy harvester is established based on Hamilton’s principle, linear constitutive equations of magnetostrictive material, and Faraday’s law of electromagnetic induction. The definitions and expressions of the electric damping and modified frequency are proposed due to the electromechanical coupling. The explicit analytical expressions of the average harvested power across the load resistance and tip vibration displacement of the Galfenol energy harvesting model are derived using the methods of Galliakin decomposition and electromechanical decoupling. The accuracy of the derived analytical results is verified by the experimental data and numerical solutions. The vibration response and energy harvesting performance of the Galfenol energy harvesting model are investigated by varying the excitation frequency, external resistance, and excitation acceleration amplitude. The analytical results show that, with the increase of the external load resistance and excitation frequency, the harvested power increases first and then decreases, indicating the existence of the optimal resistance and excitation frequency. From the explicit analytical expressions of the average harvested power, the optimal external load resistance or excitation frequency could be easily found to achieve the maximum harvested power for any fixed excitation frequency or external load resistance. The concept of proposing the electric damping and modified frequency for the Galfenol cantilever energy harvester simplifies the solution process for the output performances benefiting from the exact relationship between the output performances and the electromechanical coupling parameter derived in this work.

Cultivated land plays a crucial role as the basis of grain production, and it is essential to effectively manage the unregulated expansion of non-grain production (NGP) on cultivated land in order to safeguard food security. The study of NGP has garnered significant attention from scholars, but the prediction of NGP trends is relatively uncommon. Therefore, we focused on Jiangsu Province, a significant grain production region in China, as the study area. We extracted data on cultivated land for non-grain production (NGPCL) in 2000, 2005, 2010, 2015, and 2019, and calculated the ratio of non-grain production (NGPR) for each county unit in the province. On this basis, Kernel Density Estimation (KDE) and spatial autocorrelation analysis tools were utilized to uncover the spatio-temporal evolution of NGP in Jiangsu Province. Finally, the Patch-Generating Land Use Simulation (PLUS) model was utilized to predict the trend of NGP in Jiangsu Province in 2038 under the three development scenarios of natural development (NDS), cultivated land protection (CPS), and food security (FSS). After analyzing the results, we came to the following conclusions:(1) During the period of 2000–2019, the NGPCL area and NGPR in Jiangsu Province exhibited a general decreasing trend. (2) The level of NGP displayed a spatial distribution pattern of being “higher in the south and central and lower in the north”. (3) The results of multi-scenario simulation show that under the NDS, the area of NGPCL and cultivated land for grain production (GPCL) decreases significantly; under the CPS, the decrease in NGPCL and GPCL is smaller than that of the NDS. Under the FSS, NGPCL decreases, while GPCL increases. These results can provide reference for the implementation of land use planning, the delineation of the cultivated land protection bottom line, and the implementation of thee cultivated land use control system in the study area.

The nonlinear energy sink (NES) and Galfenol material can achieve vibration suppression and energy harvesting of the structure, respectively. Compared with a linear structure, the geometric nonlinearity can affect the output performances of the cantilever beam structure. This investigation aims to present a coupled system consisting of a nonlinear energy sink (NES) and a cantilever Galfenol energy harvesting beam with geometric nonlinearity. Based on Hamilton’s principle, linear constitutive equations of magnetostrictive material, and Faraday’s law of electromagnetic induction, the theoretical dynamic model of the coupled system is proposed. Utilizing the Galliakin decomposition method and Runge–Kutta method, the harvested power of the external load resistance, and tip vibration displacements of the Galfenol energy harvesting model are analyzed. The influences of the external excitation, external resistance, and NES parameters on the output characteristic of the proposed coupling system have been investigated. Results reveal that introducing NES can reduce the cantilever beam’s vibration while considering the geometric nonlinearity of the cantilever beam can induce a nonlinear softening phenomenon for the output behaviors. Compared to the linear system without NES, the coupling model proposed in this work can achieve dual efficacy goals over a wide range of excitation frequencies when selecting appropriate parameters. In general, large excitation amplitude and NES stiffness, small external resistance, and small or large NES damping values can achieve the effect of broadband energy harvesting.

Abstract The growing prevalence of counterfeit products worldwide poses serious threats to economic security and human health. Developing advanced anti-counterfeiting materials with physical unclonable functions offers an attractive defense strategy. Here, we report multimodal, dynamic and unclonable anti-counterfeiting labels based on diamond microparticles containing silicon-vacancy centers. These chaotic microparticles are heterogeneously grown on silicon substrate by chemical vapor deposition, facilitating low-cost scalable fabrication. The intrinsically unclonable functions are introduced by the randomized features of each particle. The highly stable signals of photoluminescence from silicon-vacancy centers and light scattering from diamond microparticles can enable high-capacity optical encoding. Moreover, time-dependent encoding is achieved by modulating photoluminescence signals of silicon-vacancy centers via air oxidation. Exploiting the robustness of diamond, the developed labels exhibit ultrahigh stability in extreme application scenarios, including harsh chemical environments, high temperature, mechanical abrasion, and ultraviolet irradiation. Hence, our proposed system can be practically applied immediately as anti-counterfeiting labels in diverse fields.

Abstract Photocatalytic methane conversion requires a strong polarization environment composed of abundant activation sites with the robust stretching ability for C-H scissoring. High-density frustrated Lewis pairs consisting of low-valence Lewis acid Nb and Lewis base Nb-OH are fabricated on lamellar Nb2O5 through a thermal-reduction promoted phase-transition process. Benefitting from the planar atomic arrangement of lamellar Nb2O5, the frustrated Lewis pairs sites are highly exposed and accessible to reactants, which results in a superior methane conversion rate of 1456 μmol g−1 h−1 for photocatalytic non-oxidative methane coupling without the assistance of noble metals. The time-dependent DFT calculation demonstrates the photo-induced electron transfer from LA to LB sites enhances their intensities in a concerted way, promoting the C-H cleavage through the coupling of LA and LB. This work provides in-depth insight into designing and constructing a polarization micro-environment for photocatalytic C-H activation of methane without the assistance of noble metals.

In order to explore the feasibility of impedance spectroscopy in the application of online diagnosis of aging and deterioration of medium voltage (MV) three-core cables, based on the theory of transmission line equation, an aging and deterioration model of the MV three-core cable has been established. The impedance spectroscopy of the cable head-end under healthy and different aging and degradation states has been simulated and analyzed. Further, the effects the extent of aging, local deterioration size and position, line length, load rate and other factors on the impedance spectroscopy have been studied. According to the influence of the various factors on the impedance spectroscopy, a set of aging and deterioration diagnosis procedures and methods are proposed. The simulation results indicate that the state of the cable can be divided into 4 categories of “healthy,” “overall aging,” “large-size deterioration” and “small-size deterioration.” The impedance spectroscopies of different states have certain characteristics. These characteristics can be determined by specific criterion indicators such as the monotonous decrease of the value of the resonance peaks and the phase amplitudes, the value of the resonance peaks, and the eigen propagation frequency, etc. Therefore, impedance spectroscopy has broad application prospects for online diagnosis of aging and deterioration of MV three-core cable.

The sustainable utilization of regional cultivated land systems in the Yangtze River Delta (YRD) region over the past 40 years has been severely impacted by rapid urbanization processes. Improving the eco-efficiency of cultivated land use (ECLU) plays a significant role in achieving the sustainable utilization of farmland and high-quality development of agriculture and rural areas. In this study, the spatial–temporal features and influencing factors of the ECLU in the YRD are investigated by various methods, such as a super-efficient SBM model, hot spot analysis, Dagum Gini coefficient, and panel tobit model. The findings indicate the following: the ECLU showed an overall high level from 2000 to 2020; the ECLU varied significantly over time and space in the YRD. The ECLU presented obvious spatial agglomeration in the YRD: southern regions exhibited a concentration of cold spots, while hot spots were primarily found in the east and north of the YRD. The trend of regional differences in ECLU during the research period fluctuated upwards in the YRD, and the density difference super-variable was the main source of regional differences. Increases in urbanization level and GDP per capita contributed to ECLU enhancement in the YRD, and agricultural intensity levels and agricultural industrial structures played a negative role in ECLU improvement. Finally, we suggest that different regions should adapt to local conditions, scientifically and reasonably allocate cultivated land production resources, and promote the coordinated improvement of ECLU. This study could provide a reference for policymakers to formulate better decisions on cultivated land utilization and management.

Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer, representing approximately 85% of cases. The diagnosis is often made in the middle and late stages, necessitating systemic treatment as the primary therapeutic option. Despite sorafenib being the established standard of care for advanced HCC in the past decade, the efficacy of systemic therapy remains unsatisfactory, highlighting the need for novel treatment modalities. Recent breakthroughs in immunotherapy have shown promise in HCC treatment, particularly with immune checkpoint inhibitors (ICIs). However, the response rate to ICIs is currently limited to approximately 15%–20% of HCC patients. Recently, ICIs demonstrated greater efficacy in “hot" tumors, highlighting the urgency to devise more effective approaches to transform “cold" tumors into “hot" tumors, thereby enhancing the therapeutic potential of ICIs. This review presented an updated summary of the factors influencing the effectiveness of immunotherapy in HCC treatment, identified potential combination therapies that may improve patient response rates to ICIs, and offered an overview of ongoing clinical trials focusing on ICI-based combination therapy.

Summary: Most gastric cancer (GC) patients with early stage often have no lymph node (LN) metastases, while LN metastases appear in the advanced stage. However, there are some patients who present with early stage LN metastases and no LN metastases in the advanced stage. To explore the deeper molecular mechanisms involved, we collected clinical samples from early and advanced stage GC with and without LN metastases, as well as metastatic lymph nodes. Herein, we identified a key target, HOXA11, that was upregulated in GC tissues and closely associated with lymphatic metastases. HOXA11 transcriptionally regulates TGFβ1 expression and activates the TGFβ1/Smad2 pathway, which not only promotes EMT development but also induces VEGF-C secretion and lymphangiogenesis. These findings provide a plausible mechanism for HOXA11-modulated tumor in lymphatic metastasis and suggest that HOXA11 may represent a potential therapeutic target for clinical intervention in LN-metastatic gastric cancer.

ABSTRACTLactate plays an important role in shaping immune tolerance in tumor microenvironment (TME) and correlates with poor prognosis in various solid tumors. Overcoming the immune resistance in an acidic TME may improve the anti-tumor immunity. Here, this study elucidated that via G-protein-coupled receptor 81 (GPR81), lactate could modulate immune tolerance in TME by recruiting regulatory T cells (Tregs) in vitro and in vivo. A high concentration of lactate was detected in cell supernatant and tissues of gastric cancer (GC), which was modulated by lactic dehydrogenase A (LDHA). GPR81 was the natural receptor of lactate and was overexpressed in different GC cell lines and samples, which correlated with poor outcomes in GC patients. Lactate/GPR81 signaling could promote the infiltration of Tregs into TME by inducing the expression of chemokine CX3CL1. GPR81 deficiency could decrease the infiltration of Tregs into TME, thereby inhibiting GC progression by weakening the inhibition of CD8+T cell function in a humanized mouse model. In conclusion, targeting the lactate/GPR81 signaling may potentially serve as a critical process to overcome immune resistance in highly glycolytic GC.

ABSTRACTThe gut microbiota and Short-chain fatty acids (SCFAs) can influence the progression of diseases, yet the role of these factors on gastric cancer (GC) remains uncertain. In this work, the analysis of the gut microbiota composition and SCFA content in the blood and feces of both healthy individuals and GC patients indicated that significant reductions in the abundance of intestinal bacteria involved in SCFA production were observed in GC patients compared with the controls. ABX mice transplanted with fecal microbiota from GC patients developed more tumors during the induction of GC and had lower levels of butyric acid. Supplementation of butyrate during the induction of gastric cancer along with H. pylori and N-methyl-N-nitrosourea (MNU) in WT in GPR109A−/−mice resulted in fewer tumors and more IFN-γ+ CD8+ T cells, but this effect was significantly weakened after knockout of GPR109A. Furthermore, In vitro GC cells and co-cultured CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells, as well as in vivo tumor-bearing studies, have indicated that butyrate enhanced the killing function of CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells against GC cells through G protein-coupled receptor 109A (GPR109A) and homologous domain protein homologous box (HOPX). Together, these data highlighted that the restoration of gut microbial butyrate enhanced CD8+ T cell cytotoxicity via GPR109A/HOPX, thus inhibiting GC carcinogenesis, which suggests a novel theoretical foundation for GC management against GC.

Volatility is an inherent characteristic of wind power. The normal, Weibull, and other distributions are commonly used to describe the characteristics of wind power. However, many of these single distribution models are not suitable to characterize wind power, particularly those converging from multiple wind farm groups. In this study, the maximum entropy distribution model is utilized as probability density function to fit wind power fluctuations. To evaluate the effectiveness and performance of the model, we compared the probability density function curve and cumulative distribution function curve fitting with the mixed Gaussian, the mixed logistic, and the mixed Weibull distribution models using simulation experiments. We developed four scenarios with different numbers of wind farm groups and calculated the fitting error, determination coefficient, and K–S test value for the four models. The simulation results show that the maximum entropy distribution model has the best fitting effect in all four scenarios. Compared with the other three distribution models, the maximum entropy distribution model has clear advantages and is more suitable to describe the fluctuation characteristics of wind power. The parameter estimation of the maximum entropy distribution model can be transformed into a linear optimization problem to significantly reduce calculation complexity.

Extracellular vesicles (EVs) are membrane-encapsulated vesicles released by almost all cell types, which participate in intercellular communication by delivering different types of molecular cargoes, such as non-coding RNAs (ncRNAs). Accumulating evidence suggests that tumor-derived EVs act as a bridge for intercellular crosstalk between tumor cells and surrounding cells, including immune cells. Tumor-derived EVs containing ncRNAs (TEV-ncRNAs) mediate intercellular crosstalk to manipulate immune responses and affect the malignant phenotypes of cancer cells. In this review, we summarize the double-edged roles and the underlying mechanisms of TEV-ncRNAs in regulating innate and adaptive immune cells. We also highlight the advantages of using TEV-ncRNAs in liquid biopsies for cancer diagnosis and prognosis. Moreover, we outline the use of engineered EVs to deliver ncRNAs and other therapeutic agents for cancer therapy.

Introduction: Spinocerebellar ataxia type 3 (SCA3) is a common autosomal dominant hereditary ataxia, which is caused by a cytosine-adenine-guanine (CAG) repeat expansion on the causative gene ATXN3, usually with lower extremity ataxia as the first symptom, and effective treatment is scarce. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that regulates the cerebellum and the neural network connected to it. Methods: Herein, we report familial cases of SCA3 in two nephews and their aunt, each of whom was treated with high-frequency (5 Hz) rTMS. The rTMS treatment lasted 2 weeks, once daily for 5 consecutive days a week, about 20 minutes each session. The Scale for the Assessment and Rating of Ataxia (SARA), the International Cooperative Ataxia Rating Scale (ICARS), and proton magnetic resonance spectroscopy (1H-MRS) examination were evaluated before and after rTMS treatment. Results: We found that the ICARS scores improved significantly (p = 0.04), and the NAA/Cr values were elevated in vermis and both cerebellar hemispheres after rTMS treatment. Conclusion: Our study suggested that high-frequency rTMS therapy can contribute to the improvement of cerebellar NAA/Cr value of SCA3 patients, and improve posture and gait as well as limb kinetic function in SCA3 patients.

An electrically controlled rotor (ECR) is a kind of swashplateless rotor that implements the primary control via the trailing-edge flap system instead of a swashplate and demonstrates great potential in vibration reduction and noise alleviation. In this paper, the mesoscopic numerical simulation method known as the lattice Boltzmann method (LBM) is employed to investigate the aerodynamic characteristics of an ECR. In the LBM, the discretized Boltzmann transport equation is solved to simulate the macroscopic motion of the fluid, and the D3Q27 model is applied for this study. The effects of the flap deflection on the ECR aerodynamic characteristics can be accurately included with the appropriate refined wall lattice resolution. On this basis, the adaptive wake-refinement strategy is applied to track the evolution of the wake and adequately capture details of the wake structure in the wake flow field. Based on this method, an aerodynamic analysis model for the ECR can be established on the XFlow simulation platform. The aerodynamic analysis model is validated, and the results indicate that the LBM can accurately capture the details of the rotor flow field and calculate blade aerodynamic load, as well as predict the downwash of the rotor. Therefore, based on this model, the ECR aerodynamic characteristics under hovering and forward flight conditions are analyzed, and the effects of the flap deflection on the wake structure, induced inflow, and disc load can be captured. The results indicate that a relatively large flap deflection required to trim the rotor will cause the additional intense flap wake vortex in the ECR wake flow field, apart from the concentrated vorticity at the blade tip and root demonstrated in the conventional rotor wake flow field, and thus significantly change the distributions of the disc-induced inflow and aerodynamic load.

Jilin Province is an important commercial grain production base in northeast China, and it has seen significant transition in cultivated land use in recent years. This study constructed a measurement system for the recessive transition of cultivated land use in Jilin Province based on the perspective of “three-function synergy” (productive, living, and ecological functions). It discussed the temporal and spatial evolution characteristics of the recessive transition of cultivated land use from 1990 to 2020, identified the turning point of the cultivated land transition trend, and built a model of recessive transition of cultivated land in Jilin Province. After analyzing the results, we came to the following conclusions: (1) The turning point of the “three-function synergy” of the recessive morphology of cultivated land in Jilin Province occurred earlier than the mutation point of the recessive transition of cultivated land, and there was a certain temporality in the recessive transition of cultivated land compared with the functional change of cultivated land; (2) the degree of recessive transition of cultivated land in Jilin Province showed a spatial distribution characteristic of being higher in the west and lower in the east; (3) the recessive transition of cultivated land use in Jilin Province could be divided into transition stages characterized by “low stage slow rise period”, “middle stage significant increase period”, and “high stage steady growth period”; (4) Jilin Province should adopt differentiated and diversified management of cultivated land to achieve a comprehensive management model that emphasizes quantity, quality, and ecology.

Abstract Multiple three-dimensional (3D) tumour organoid models assisted by multi-omics and Artificial Intelligence (AI) have contributed greatly to preclinical drug development and precision medicine. The intrinsic ability to maintain genetic and phenotypic heterogeneity of tumours allows for the reconciliation of shortcomings in traditional cancer models. While their utility in preclinical studies have been well established, little progress has been made in translational research and clinical trials. In this review, we identify the major bottlenecks preventing patient-derived tumour organoids (PDTOs) from being used in clinical setting. Unsuitable methods of tissue acquisition, disparities in establishment rates and a lengthy timeline are the limiting factors for use of PDTOs in clinical application. Potential strategies to overcome this include liquid biopsies via circulating tumour cells (CTCs), an automated organoid platform and optical metabolic imaging (OMI). These proposed solutions accelerate and optimize the workflow of a clinical organoid drug screening. As such, PDTOs have the potential for potential applications in clinical oncology to improve patient outcomes. If remarkable progress is made, cancer patients can finally benefit from this revolutionary technology.

ObjectiveTo investigate the effect of aerobic exercise on five dimensions of physical self-worth, exercise capacity, physical condition, physical attractiveness, and physical quality in body self-esteem of Chinese college students.MethodsBy searching PubMed, Web of Science, Cochrane Library, CNIK database, VIP database, WANFANG database platform, we searched for the subject terms or keywords "body self-esteem", "Chinese college students", "Systematic evaluation", "Aerobic exercise", "Exercise intervention", "Meta-Analysis". The search method was a combination of subject terms and keywords and title, and the search period was from database creation to The search was conducted from database creation to May 2022. A total of 3221 articles were searched, and 9 articles were included in the study through repeated screening. Risk of bias was assessed with Cochrane and the quality of studies in the literature was assessed using Grade pro software. The outcome indicators of the included literature were analysed using review manager 5.4 software and StataMP 17.0 software.ResultsNine papers including 1613 subjects were included. results of Meta-analysis showed that aerobic exercise was effective in improving physical self-worth (WMD = 1.46, 95% CI: 1.08-1.83, pConclusionAerobic exercise can effectively improve the body self-esteem of Chinese college students. In exercise, male students pursue is athletic ability and physical fitness, and female students pursue is the sense of physical self-worth and physical attractiveness. Aerobic exercise has a greater increase in body self-esteem for obese or Obese college students. Aerobics and physical dance are the most cost-effective for improving body self-esteem. Medium-intensity relative to low-intensity exercise was effective for body self-esteem intervention. A single exercise session of 90 minutes was more effective than a single 30-minute session in boosting body self-esteem, and the overall intervention duration of 16 weeks was more effective than 10 weeks.

Abstract Urological cancers are among the most common malignancies around the world. In particular, bladder cancer severely threatens human health due to its aggressive and heterogeneous nature. Various therapeutic modalities have been considered for the treatment of bladder cancer although its prognosis remains unfavorable. It is perceived that treatment of bladder cancer depends on an interdisciplinary approach combining biology and engineering. The nanotechnological approaches have been introduced in the treatment of various cancers, especially bladder cancer. The current review aims to emphasize and highlight possible applications of nanomedicine in eradication of bladder tumor. Nanoparticles can improve efficacy of drugs in bladder cancer therapy through elevating their bioavailability. The potential of genetic tools such as siRNA and miRNA in gene expression regulation can be boosted using nanostructures by facilitating their internalization and accumulation at tumor sites and cells. Nanoparticles can provide photodynamic and photothermal therapy for ROS overgeneration and hyperthermia, respectively, in the suppression of bladder cancer. Furthermore, remodeling of tumor microenvironment and infiltration of immune cells for the purpose of immunotherapy are achieved through cargo‐loaded nanocarriers. Nanocarriers are mainly internalized in bladder tumor cells by endocytosis, and proper design of smart nanoparticles such as pH‐, redox‐, and light‐responsive nanocarriers is of importance for targeted tumor therapy. Bladder cancer biomarkers can be detected using nanoparticles for timely diagnosis of patients. Based on their accumulation at the tumor site, they can be employed for tumor imaging. The clinical translation and challenges are also covered in current review.

BackgroundImmune checkpoint inhibitors (ICIs) have been increasingly used for the treatment of advanced gastric cancer (AGC). However, the safety and the short-term outcomes of laparoscopic gastrectomy for patients with AGC after neoadjuvant immunotherapy (NAI) remain unknown.MethodsWe retrospectively analyzed the patients with AGC who underwent laparoscopic surgery after neoadjuvant therapy between 1 January 2019 and 31 October 2021. We further compared the differences in postoperative complications, overall response rate, adverse events, surgical parameters, and postoperative recovery between two cohorts: the NAI group (NAI plus chemotherapy) and the neoadjuvant chemotherapy (NAC) group. Multivariable regression analyses were used to determine the risk factors for the overall response rate.ResultsOverall, 80 patients were enrolled, of whom 30 cases were included in the NAI cohort and 50 were included in the NAC cohort. The overall rate of postoperative complications was 30.0% in both groups (p = 1.000). The overall response rate was 70.0% in the NAI cohort and 40% in the NAC cohort (p = 0.012). The adverse effects were found in 16 cases (53.3%) of the NAI cohort and 23 cases (46.0%) of the NAC cohort (p = 0.645). There was no statistical difference in intraoperative bleeding (50 ml vs. 50 ml, p = 0.983), operation time (320.9 min vs. 303.5 min, p = 0.382), dissected lymph node count (43.5 vs. 40.0, p = 0.364), first postoperative anal aerofluxus (3 days vs. 3 days, p = 0.091), first liquid diet (4 days vs. 5 days, p = 0.213), and postoperative length of stay in the hospital (8 days vs. 7 days, p = 0.508) between the two groups. NAI was estimated to be the independent protective factor [odds ratio (OR) 4.931, 95% confidence interval (CI) (1.385–17.559), p = 0.014] for odds to overall response rate, whereas vessel invasion was found to be the significant risk factor [OR 0.113, 95% CI (0.027–0.475), p = 0.003].ConclusionsLaparoscopic surgery after NAI combined with chemotherapy is a safe therapeutic choice for AGC and may bring better short-term outcomes due to a higher overall response rate.

Objective: The morbidity of malignant melanoma keeps increasing annually. It has high risks of metastasis, drug resistance, and poor prognosis in clinics. Moreover, the available medicines used commonly, such as dacarbazine, temozolomide, the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor vemurafenib, and the programmed cell death protein 1 inhibitor pembrolizumab, have some limitations at some extent. Therefore, a more effective therapeutic strategy is still urgently necessary. Methods: In this study, Brucea javanica(L.)Merr. globulins were hydrolyzed with pepsin, then ultra-filtrated to collect small molecular peptides (≤3 kDa). The peptides were then analyzed by anti-proliferative assay, cell-cycle distribution, apoptosis assay, and in vitro wound-scratch assay. Finally, western blotting was conducted to elucidate the underlying anti-melanoma mechanism. Results: The small molecular peptide from B. javanica significantly inhibited malignant melanoma cell proliferation with the IC50 of 2.72 μg/mL for 72 h. Further analysis indicated that B. javanica peptides arrested cell cycle at the S and G2/M phases and induced apoptosis by upregulating p21, p53, Bax, caspase-3, and cleaved PARP while downregulating Bcl-2 expression. The inhibitory migration effects were also confirmed by wound-healing assay. Conclusion: The small molecular biopeptides from B. javanica may be a promising bioactive agent candidate for melanoma treatment.

Abstract Clinical trials repurposing peroxisome proliferator-activated receptor-gamma (PPARγ) agonists as anticancer agents have exhibited lackluster efficacy across a variety of tumor types. Here, we report that increased PPARG expression is associated with a better prognosis but is anticorrelated with histone deacetylase (HDAC) 1 and 2 expressions. We show that HDAC overexpression blunts anti-proliferative and anti-angiogenic responses to PPARγ agonists via transcriptional and post-translational mechanisms, however, these can be neutralized with clinically approved and experimental HDAC inhibitors. Supporting this notion, concomitant treatment with HDAC inhibitors was required to license the tumor-suppressive effects of PPARγ agonists in triple-negative and endocrine-refractory breast cancer cells, and combination therapy also restrained angiogenesis in a tube formation assay. This combination was also synergistic in estrogen receptor-alpha (ERα)–positive cells because HDAC blockade abrogated ERα interference with PPARγ-regulated transcription. Following a pharmacokinetics optimization study, the combination of rosiglitazone and a potent pan-HDAC inhibitor, LBH589, stalled disease progression in a mouse model of triple-negative breast cancer greater than either of the monotherapies, while exhibiting a favorable safety profile. Our findings account for historical observations of de-novo resistance to PPARγ agonist monotherapy and propound a therapeutically cogent intervention against two aggressive breast cancer subtypes.

BackgroundThe COVID-19 pandemic had a major impact on people's mental health. As the SAS-Cov-2 evolves to become less virulent, the number of asymptomatic patients increases. It remains unclear if the mild symptoms are associated with mild perceived stress and mental illness, and the interventions to improve the mental health of the patients are rarely reported.MethodsThis cross-sectional study investigated the level of depression, anxiety and perceived stress of 1,305 COVID-19 patients who received treatment in the Fangcang shelter hospitals in Shanghai, China. Network analysis was used to explore the relationship among depression, anxiety and perceived stress.ResultsThe prevalence of depression, anxiety and perceived stress in the patients with Omicron infection were 9.03, 4.60, and 17.03%, respectively, lower than the prevalence reported during the initial outbreak of COVID-19. “Restlessness (A5),” “Uncontrollable worry (A2),” “Trouble relaxing (A4)” and “Fatigue (D4)” had the highest expected influence values. “Irritability (A6)” and “Uncontrollable (S1)” were bridge symptoms in the network. Comparative analysis of the network identified differences in the network structures between symptomatic and asymptomatic patients.ConclusionThis study investigated the prevalence of depression, anxiety and perceived stress and the correlation among them in Omicron-infected patients in Fangcang shelter hospital, in Shanghai, China. The core symptoms identified in the study provide insight into targeted clinical prevention and intervention of mental health in non-severe Omicron-infected patients.

ObjectiveTo investigate whether postoperative anion gap (AG) is associated with short- and long-term mortality in patients following cardiac surgery.Materials and methodsWe conducted a retrospective cohort study of adults who underwent cardiac surgery from the Medical Information Mart for Intensive Care - III database. The generalized additive model (GAM), logistic regression, and Cox regression were performed to assess the correlations between AG levels and in-hospital, 90-day, and 4-year mortality. Linear regression was used to evaluate the associations between AG and length of stay (LOS).ResultsTotally, 6,410 subjects were enrolled in this study and classified into tertiles based on the initial AG levels. The GAM indicated a positive association between initial AG and in-hospital mortality after adjusting for potential confounders. Multivariate logistic analysis revealed that the risk of in-hospital mortality was higher among patients in tertile 2 (OR 2.05, 95% CI 1.11–3.76, P = 0.021) and tertile 3 (OR 4.51, 95% CI 2.57–7.91, P < 0.001) compared with those in tertile 1. For 90-day and 4-year mortality, multivariate Cox regression found similar associations between AG tertiles and mortality. The LOS in ICU and hospital also increased as AG tertiles increased. The E-value indicated robustness to unmeasured confounders.ConclusionThis study found a positive association between postoperative AG levels and short- and long-term mortality among patients after cardiac surgery. This relationship warrants further research.

Objective: To explore the role of Wnt/β-catenin signaling pathway in the pathogenesis and progression of temporomandibular joint osteoarthritis (TMJ OA) caused by overloaded force. Materials and methods: We generated a rat model of forward mandibular extension device to induce TMJ OA by overloaded force. Condylar cartilage samples were collected at 2wk, 4wk, and 8wk after appliances were installed. Changes of the condylar cartilage and subchondral bone were evaluated by hematoxylin and eosin (HE), Safranin O and Fast Green staining (SO&FG), micro-CT, tartrate resistant acid phosphatase (TRAP) staining. The expression levels of β-catenin, COL-2, MMP3 and sclerostin (SOST) were detected by immunohistochemistry (IHC) and PCR. Results: HE, SO&FG, micro-CT, OARSI and Mankin scores showed that the condyle cartilage layer was significantly thinner and proteoglycan loss in the overloded group. TRAP staining exhibited that the number of positive osteoclasts increased and OPG level decreased in the overload group. IHC, PCR showed that the expression of COL2 and SOST decreased, while MMP3 and β-catenin increased in the overload group. Conclusion: Wnt/β-catenin signaling pathway is activated in the progress of mandibular condylar cartilage degeneration and subchondral bone loss induced by overloaded functional orthopedic force (OFOF)

As the world continues to urbanize, the eco-environment of many countries is facing great pressure. The pressure of eco-environment is particularly serious in China, where urbanization is developing rapidly. At present, the interaction between urbanization and eco-environment, the characteristics of coupling coordination degree (CCD) and its driving factors are not clear. Correctly understanding the relationship between urbanization and eco-environment and coordinating the relationship between the two are the key to achieve sustainable development. This study took the Harbin-Changchun urban agglomeration (HCUA) from 2000 to 2019 as the research object. Applied “Urban Society - Ecosystem” (USEs) theory to build a set of indicators for urbanization and eco-environment. Using the CCD model, improved environmental Kuznets curve (EKC) model and geographic detector to analyze the relationship between urbanization and eco-environment from the subsystem level. The results indicated that, the urbanization level of HCUA showed a low starting point (less than 0.2) and an increasing trend, with a relatively stable spatial pattern. The leading factor of urbanization has changed from population to social urbanization. The eco-environment quality of HCUA fluctuated frequently and the spatial pattern was unstable. With the development of urbanization, the rising rate of eco-environment slowed down and even showed a downward trend. There is an inverted-U curve between urbanization and eco-environment. Before the inflection point of the curve, the degree of impact on the eco-environment is positively correlated with urbanization, while after the inflection point, it’s negatively correlated. When the inflection point appeared, the urbanization level of each city was basically 0.77 ± 0.05. The more developed the economy, the closer the urbanization level at the inflection point is to 0.77. The CCD kept an upward trend. And its level of northwest and southeast was relatively high and rose rapidly, while the middle development lagged behind. The characteristics of the CCD presented a process of “urbanization lag, mutual detriment, synchronous development, urbanization or eco-environment lag, synchronous development”. Urbanization in line with the carrying capacity of eco-environment can avoid the mutual detriment between urbanization and eco-environment. Economic, social, spatial urbanization and resources were the common factors that affect the CCD. This study analyzed the interaction between urbanization and eco-environment, the CCD between urbanization and eco-environment and its driving factors from the subsystem level. It provides an important reference for realizing sustainable development.

Fucoidan has been reported to present diverse bioactivities, but each extract has specific features from which a particular biological activity, such as immunomodulation, must be confirmed. In this study a commercially available pharmaceutical-grade fucoidan extracted from Fucus vesiculosus, FE, was characterized and its anti-inflammatory potential was investigated. Fucose was the main monosaccharide (90 mol%) present in the studied FE, followed by uronic acids, galactose, and xylose that were present at similar values (3.8–2.4 mol%). FE showed a molecular weight of 70 kDa and a sulfate content of around 10%. The expression of cytokines by mouse bone-marrow-derived macrophages (BMDMs) revealed that the addition of FE upregulated the expression of CD206 and IL-10 by about 28 and 22 fold, respectively, in respect to control. This was corroborated in a stimulated pro-inflammatory situation, with the higher expression (60 fold) of iNOS being almost completely reversed by the addition of FE. FE was also capable of reverse LPS-caused inflammation in an in vivo mouse model, including by reducing macrophage activation by LPS from 41% of positive CD11C to 9% upon fucoidan injection. Taken together, the potential of FE as an anti-inflammatory agent was validated, both in vitro and in vivo.

Cancer metastasis is a significant challenge in cancer treatment, and most existing drugs are designed to inhibit tumor growth but are often ineffective in treating metastatic cancer, which is the leading cause of cancer-related deaths. Resveratrol, a polyphenol found in grapes, berries, and peanuts, has shown potential in preclinical studies as an anticancer agent to suppress metastasis. However, despite positive results in preclinical studies, little progress has been made in clinical trials. To develop resveratrol as an effective anticancer agent, it is crucial to understand its cellular processes and signaling pathways in tumor metastasis. This review article evaluates the current state and future development strategies of resveratrol to enhance its potency against cancer metastasis within its therapeutic dose. In addition, we critically evaluate the animal models used in preclinical studies for cancer metastasis and discuss novel techniques to accelerate the translation of resveratrol from bench to bedside. The appropriate selection of animal models is vital in determining whether resveratrol can be further developed as an antimetastatic drug in cancer therapy.

This Special Issue of Cancers (two original articles, five reviews), presented by international experts in tumor hypoxia, focuses on the role of hypoxia, or low oxygen levels, in the development and progression of cancer [...]

In this paper, we developed a probability density function (PDF) shape control method for non-linear stochastic systems using a hybrid logistic function (HLF) as an approximate PDF of the state variable. First, the functional relationship between the hybrid logistic probability density function and the controller was established based on the Fokker–Planck–Kolmogorov (FPK) equation. Then, the optimal PDF shape controller derivation was completed using the optimization method and the inner product definition of Hilbert space. This approach is suitable for any non-linear stochastic system. To evaluate the effectiveness and performance of the proposed method, we conducted a comparison experiment with the multi-Gaussian closure (MGC) method and the exponential polynomial (EP) method. The experimental results show that, for different types of targeted PDFs (symmetric unimodal, asymmetric unimodal, bimodal, and trimodal shapes), the PDF shape controller obtained using the HLF approach can make the PDF shape of the state variable track the targeted PDF effectively. In particular, when the targeted PDF has an asymmetric or complex trimodal shape, the proposed technique has comparatively better control effects. Compared with the EP method, our method requires a much smaller number of parameters, greatly reducing the computational complexity while achieving the same control effects. This study provides another approach for controlling the PDF shape of state variables in non-linear stochastic systems, which has important research significance.

Abstract The RIG‐I pathway can be activated by RNA containing 5′ triphosphate, leading to type I interferon release and immune activation. Hence, RIG‐I agonists have been used to induce immune responses against cancer as potential immunotherapy. However, delivery of 5′ triphosphorylated RNA molecules as RIG‐I agonists to tumour cells in vivo is challenging due to the susceptibility of these molecules to degradation. In this study, we demonstrate the use of extracellular vesicles (EVs) from red blood cells (RBCs), which are highly amenable for RNA loading and taken up robustly by cancer cells, for RIG‐I agonist delivery. We evaluate the anti‐cancer activity of two novel RIG‐I agonists, the immunomodulatory RNA (immRNA) with a unique secondary structure for efficient RIG‐I activation, and a 5′ triphosphorylated antisense oligonucleotide with dual function of RIG‐I activation and miR‐125b inhibition (3p‐125b‐ASO). We find that RBCEV‐delivered immRNA and 3p‐125b‐ASO trigger the RIG‐I pathway, and induce cell death in both mouse and human breast cancer cells. Furthermore, we observe a significant suppression of tumour growth coupled with increased immune cell infiltration mediated by the activation of RIG‐I cascade after multiple intratumoral injections of RBCEVs loaded with immRNA or 3p‐125b‐ASO. Targeted delivery of immRNA using RBCEVs with EGFR‐binding nanobody administrated via intrapulmonary delivery facilitates the accumulation of RBCEVs in metastatic cancer cells, leading to potent tumour‐specific CD8+ T cells immune response. This contributes to prominent suppression of breast cancer metastasis in the lung. Hence, this study provides a new strategy for efficient RIG‐I agonist delivery using RBCEVs for immunotherapy against cancer and cancer metastasis.

Van der Waals heterostructures (vdWHs) are showing considerable potential in both fundamental exploration and practical applications. Built upon the synthetic successes of (two-dimensional) 2D materials, several synthetic strategies of vdWHs have been developed, allowing the convenient fabrication of diverse vdWHs with decent controllability, quality, and scalability. This review first summarizes the current state of the art in synthetic strategies of vdWHs, including physical combination, deposition, solvothermal synthesis, and synchronous evolution. Then three major applications and their representative vdWH devices have been reviewed, including electronics (tunneling field effect transistors and 2D contact), optoelectronics (photodetector), and energy conversion (electrocatalysts and metal ion batteries), to unveil the potentials of vdWHs in practical applications and provide the general design principles of functional vdWHs for different applications. Besides, moiré superlattices based on vdWHs are discussed to showcase the importance of vdWHs as a platform for novel condensed matter physics. Finally, the crucial challenges towards ideal vdWHs with high performance are discussed, and the outlook for future development is presented. By the systematical integration of synthetic strategies and applications, we hope this review can further light up the rational designs of vdWHs for emerging applications.

Abstract Background We previously reported that low-dose, short-course sunitinib prior to neoadjuvant doxorubicin-cyclophosphamide (AC) normalised tumour vasculature and improved perfusion, but resulted in neutropenia and delayed subsequent cycles in breast cancer patients. This study combined sunitinib with docetaxel, which has an earlier neutrophil nadir than AC. Methods Patients with advanced solid cancers were randomized 1:1 to 3-weekly docetaxel 75 mg/m2, with or without sunitinib 12.5 mg daily for 7 days prior to docetaxel, stratified by primary tumour site. Primary endpoints were objective-response (ORR:CR + PR) and clinical-benefit rate (CBR:CR + PR + SD); secondary endpoints were toxicity and progression-free-survival (PFS). Results We enrolled 68 patients from 2 study sites; 33 received docetaxel-sunitinib and 35 docetaxel alone, with 33 breast, 25 lung and 10 patients with other cancers. There was no difference in ORR (30.3% vs 28.6%, p = 0.432, odds-ratio [OR] 1.10, 95% CI 0.38–3.18); CBR was lower in the docetaxel-sunitinib arm (48.5% vs 71.4%, p = 0.027 OR 0.37, 95% CI 0.14–1.01). Median PFS was shorter in the docetaxel-sunitinib arm (2.9 vs 4.9 months, hazard-ratio [HR] 2.00, 95% CI 1.15–3.48, p = 0.014) overall, as well as in breast (4.2 vs 5.6 months, p = 0.048) and other cancers (2.0 vs 5.3 months, p = 0.009), but not in lung cancers (2.9 vs 4.1 months, p = 0.597). Median OS was similar in both arms overall (9.9 vs 10.5 months, HR 0.92, 95% CI 0.51–1.67, p = 0.789), and in the breast (18.9 vs 25.8 months, p = 0.354), lung (7.0 vs 6.7 months, p = 0.970) and other cancers (4.5 vs 8.8 months, p = 0.449) subgroups. Grade 3/4 haematological toxicities were lower with docetaxel-sunitinib (18.2% vs 34.3%, p = 0.132), attributed to greater discretionary use of prophylactic G-CSF (90.9% vs 63.0%, p = 0.024). Grade 3/4 non-haematological toxicities were similar (12.1% vs 14.3%, p = 0.792). Conclusions The addition of sunitinib to docetaxel was well-tolerated but did not improve outcomes. The possible negative impact in metastatic breast cancer patients is contrary to results of adding sunitinib to neoadjuvant AC. These negative results suggest that the intermittent administration of sunitinib in the current dose and schedule with docetaxel in advanced solid tumours, particularly breast cancers, is not beneficial. Trial registration The study was registered ( NCT01803503 ) prospectively on clinicaltrials.gov on 4th March 2013.

Abstract The quantum defects in nanodiamonds, such as nitrogen‐vacancy (NV) centers, are emerging as a promising candidate for nanoscale sensing and imaging, and the controlled placement with respect to target locations is vital to their practical applications. Unfortunately, this prerequisite continues to suffer from coarse positioning accuracy, low throughput, and process complexity. Here, it is reported on direct, on‐demand electrohydrodynamic printing of nanodiamonds containing NV centers with high precision control over quantity and position. After thorough characterizations of the printing conditions, it is shown that the number of printed nanodiamonds can be controlled at will, attaining the single‐particle level precision. This printing approach, therefore, enables positioning NV center arrays with a controlled number directly on the universal substrate without any lithographic process. The approach is expected to pave the way toward new horizons not only for experimental quantum physics but also for the practical implementation of such quantum systems.

Cancer has become a global health problem, accounting for one out of six deaths. Despite the recent advances in cancer therapy, there is still an ever-growing need for readily accessible new therapies. The process of drug discovery and development is arduous and takes many years, and while it is ongoing, the time for the current lead compounds to reach clinical trial phase is very long. Drug repurposing has recently gained significant attention as it expedites the process of discovering new entities for anticancer therapy. One such potential candidate is the antimalarial drug, artemisinin that has shown anticancer activities in vitro and in vivo. In this review, major molecular and cellular mechanisms underlying the anticancer effect of artemisinin and its derivatives are summarised. Furthermore, major mechanisms of action and some key signaling pathways of this group of compounds have been reviewed to explore potential targets that contribute to the proliferation and metastasis of tumor cells. Despite its established profile in malaria treatment, pharmacokinetic properties, anticancer potency, and current formulations that hinder the clinical translation of artemisinin as an anticancer agent, have been discussed. Finally, potential solutions or new strategies are identified to overcome the bottlenecks in repurposing artemisinin-type compounds as anticancer drugs.

Codon 158 gain-of-function mutant p53 (158-mutp53) promotes tumourigenesis in lung cancer. Here, the authors show that 158-mutp53 render cancers sensitive to cisplatin and p53 acetylation agents through a mechanism where acetylated mutant p53 upregulates TRAIP and inhibits NF-ĸB signaling.

Steep-wavefront impulse overvoltages may be generated, including fast-front overvoltage (FFO) with wavefront time of 0.1~20 μs, during the operations of disconnector switch in gas insulated equipment (GIE), threatening its insulation. To study the breakdown characteristics of SF6 alternative C4F7N/CO2 mixtures under FFO, the influence of FFO wavefront time, pressures and polarities on the breakdown characteristics of C4F7N/CO2 in slightly non-uniform and extremely non-uniform electric field were investigated. The results show that the effects of FFO wavefront time, polarities and pressures on the insulation properties of C4F7N/CO2 and SF6 are similar. In the slightly non-uniform electric field, the insulation performance of 9%C4F7N/91% CO2 reaches 78% SF6 under the same conditions. The 50% breakdown voltage of gas under impulse voltage (U50%) of the C4F7N/CO2 decreases first then rise with the FFO wavefront time showing a U-curve. It is also found that the voltage polarity has little effect on the trend of the 50% breakdown voltage curve with wavefront time of impulse voltage (U50%-Tf) and the 50% breakdown voltage curve with gas pressure (U50%-P) in the slightly non-uniform electric field. In the extremely non-uniform electric field, the U50% of the C4F7N/CO2 tends to decrease first and then stabilize with the increase of wavefront time. With the increase of pressure, the U50% of C4F7N/CO2 increases linearly in the slightly non-uniform electric field. Under the positive FFO, in the extremely non-uniform electric field, the U50% of the C4F7N/CO2 changes with the rise in pressure showed a tendency to increases first, then decreases and rises again, resembling the N letter. Under the negative FFO, the U50% of C4F7N/CO2 rises with the increase of pressure and tends to be saturated.

Abstract Background Ovarian cancer is the leading cause of gynecological cancer-related mortality. The novel oncogene S100A10 has been reported to be involved in cancer cell proliferation, invasion and metastasis. The role of S100A10 in ovarian cancer has not been well studied and the effect of S100A10 on chemotherapy remains unclear. The aims of the present study were to investigate the functional role of S100A10 in the progression and carboplatin sensitivity of ovarian cancer. Methods We examined the expression levels in tissues of S100A10 in 138 cases of ovarian cancer by IHC. To determine the functional roles of downregulated S100A10 in ovarian cancer, cell proliferation, colony formation, cell migration and invasion assays were performed. Chemoresistance was analyzed by apoptosis assay. A xenograft tumor model was established to confirm the role of S100A10 in carboplatin resistance in vivo. Using Western blot assays, we also explored the possible mechanisms of S100A10 in ovarian cancer. Results The results showed that increased expression of S100A10 was positively associated with carboplatin resistance (P

Extracellular vesicles (EVs) are heterogeneous membrane-encapsulated vesicles released by most cells. They act as multifunctional regulators of intercellular communication by delivering bioactive molecules, including non-coding RNAs (ncRNAs). Metastasis is a major cause of cancer-related death. Most cancer cells disseminate and colonize a specific target organ via EVs, a process known as “organ-specific metastasis”. Mounting evidence has shown that EVs are enriched with ncRNAs, and various EV-ncRNAs derived from tumor cells influence organ-specific metastasis via different mechanisms. Due to the tissue-specific expression of EV-ncRNAs, they could be used as potential biomarkers and therapeutic targets for the treatment of tumor metastasis in various types of cancer. In this review, we have discussed the underlying mechanisms of EV-delivered ncRNAs in the most common organ-specific metastases of liver, bone, lung, brain, and lymph nodes. Moreover, we summarize the potential clinical applications of EV-ncRNAs in organ-specific metastasis to fill the gap between benches and bedsides.