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Abstract The antitumor performance of PROteolysis-TArgeting Chimeras (PROTACs) is limited by its insufficient tumor specificity and poor pharmacokinetics. These disadvantages are further compounded by tumor heterogeneity, especially the presence of cancer stem-like cells, which drive tumor growth and relapse. Herein, we design a region-confined PROTAC nanoplatform that integrates both reactive oxygen species (ROS)-activatable and hypoxia-responsive PROTAC prodrugs for the precise manipulation of bromodomain and extraterminal protein 4 expression and tumor eradication. These PROTAC nanoparticles selectively accumulate within and penetrate deep into tumors via response to matrix metalloproteinase-2. Photoactivity is then reactivated in response to the acidic intracellular milieu and the PROTAC is discharged due to the ROS generated via photodynamic therapy specifically within the normoxic microenvironment. Moreover, the latent hypoxia-responsive PROTAC prodrug is restored in hypoxic cancer stem-like cells overexpressing nitroreductase. Here, we show the ability of region-confined PROTAC nanoplatform to effectively degrade BRD4 in both normoxic and hypoxic environments, markedly hindering tumor progression in breast and head-neck tumor models.

Chimeric antigen receptor T (CAR-T) cell therapy as a form of adoptive cell therapy (ACT) has shown significant promise in cancer treatment, demonstrated by the FDA-approved CAR-T cell therapies targeting CD19 or B cell maturation antigen (BCMA) for hematological malignancies, albeit with moderate outcomes in solid tumors. However, despite these advancements, the efficacy of CAR-T therapy is often compromised by T cell exhaustion, a phenomenon that impedes the persistence and effector function of CAR-T cells, leading to a relapse rate of up to 75% in patients treated with CD19 or CD22 CAR-T cells for hematological malignancies. Strategies to overcome CAR-T exhaustion employ state-of-the-art genomic engineering tools and single-cell sequencing technologies. In this review, we provide a comprehensive understanding of the latest mechanistic insights into T cell exhaustion and their implications for the current efforts to optimize CAR-T cell therapy. These insights, combined with lessons learned from benchmarking CAR-T based products in recent clinical trials, aim to address the challenges posed by T cell exhaustion, potentially setting the stage for the development of tailored next-generation approaches to cancer treatment.

Tumor neoantigen peptide vaccines hold potential for boosting cancer immunotherapy, yet efficiently co-delivering peptides and adjuvants to antigen-presenting cells in vivo remains challenging. Virus-like particle (VLP), which is a kind of multiprotein structure organized as virus, can deliver therapeutic substances into cells and stimulate immune response. However, the weak targeted delivery of VLP in vivo and its susceptibility to neutralization by antibodies hinder their clinical applications. Here, we first designed a novel protein carrier using the mammalian-derived capsid protein PEG10, which can self-assemble into endogenous VLP (eVLP) with high protein loading and transfection efficiency. Then, an engineered tumor vaccine, named ePAC, was developed by packaging genetically encoded neoantigen into eVLP with further modification of CpG-ODN on its surface to serve as an adjuvant and targeting unit to dendritic cells (DCs). Significantly, ePAC can efficiently target and transport neoantigens to DCs, and promote DCs maturation to induce neoantigen-specific T cells. Moreover, in mouse orthotopic liver cancer and humanized mouse tumor models, ePAC combined with anti-TIM-3 exhibited remarkable antitumor efficacy. Overall, these results support that ePAC could be safely utilized as cancer vaccines for antitumor therapy, showing significant potential for clinical translation.

SnTe has emerged as a non-toxic and environmentally friendly alternative to the high-performance thermoelectric material PbTe, attracting significant interest in sustainable energy applications. In our previous work, we successfully synthesized high-quality SnTe with reduced thermal conductivity under high-pressure conditions. Building on this, in this work, we introduced indium (In) doping to further decrease thermal conductivity under high pressure. By incorporating resonance doping into the SnTe matrix, we aimed to enhance the electrical transport properties while maintaining low thermal conductivity. This approach enhances the Seebeck coefficient to an impressive 153 μVK−1 at 735 K, marking a notable enhancement compared to undoped SnTe. Furthermore, we noted a substantial decrease in total thermal conductivity, dropping from 6.91 to 3.88 Wm−1K−1 at 325 K, primarily due to the reduction in electrical conductivity. The synergistic impact of decreased thermal conductivity and heightened Seebeck coefficient resulted in a notable improvement in the thermoelectric figure of merit (ZT) and average ZT, achieving approximately 0.5 and 0.22 in the doped samples, respectively. These advancements establish Sn1−xInxTe as a promising candidate to replace PbTe in thermoelectric applications, providing a safer and more environmentally sustainable option.

Abstract mRNA therapeutics have emerged as powerful tools for cancer immunotherapy in accordance with their superiority in expressing all sequence‐known proteins in vivo. In particular, with a small dosage of delivered mRNA, antigen‐presenting cells (APCs) can synthesize mutant neo‐antigens and multi‐antigens and present epitopes to T lymphocytes to elicit antitumor effects. In addition, expressing receptors like chimeric antigen receptor (CAR), T‐cell receptor (TCR), CD134, and immune‐modulating factors including cytokines, interferons, and antibodies in specific cells can enhance immunological response against tumors. With the maturation of in vitro transcription (IVT) technology, large‐scale and pure mRNA encoding specific proteins can be synthesized quickly. However, the clinical translation of mRNA‐based anticancer strategies is restricted by delivering mRNA into target organs or cells and the inadequate endosomal escape efficiency of mRNA. Recently, there have been some advances in mRNA‐based cancer immunotherapy, which can be roughly classified as modifications of the mRNA structure and the development of delivery systems, especially the lipid nanoparticle platforms. In this review, the latest strategies for overcoming the limitations of mRNA‐based cancer immunotherapies and the recent advances in delivering mRNA into specific organs and cells are summarized. Challenges and opportunities for clinical applications of mRNA‐based cancer immunotherapy are also discussed.

Abstract Background Prophylactic irradiation of supraclavicular lymph node drainage areas can improve the regional control rate of lymph node-positive or lymph node-negative disease but a locally-advanced stage breast cancer, and it can reduce breast cancer-related mortality. However, many controversies exist in the clinical target volume delineation of supraclavicular lymph node drainage in patients with breast cancer. Methods We retrospectively analyzed 42 patients with breast cancer and supraclavicular lymph node metastasis at our hospital between January 2017 and December 2021. Among these cases, 32 were locally advanced and 10 were stage IV at initial treatment. A patient with breast cancer who did not undergo dissection of the supraclavicular and infraclavicular lymph nodes at our hospital was selected as a standard patient. A contrast-enhanced computed tomography (CT) scan for positioning was used as a template image, and blood vessels, muscles, and bony landmarks were used as references for positioning. The metastatic supraclavicular lymph nodes were identified in all enrolled patients and projected into the template CT images. Results The metastastic pattern of supraclavicular lymph node in breast cancer was proposed: distribution along the posterolateral border of the internal jugular vein (medial supraclavicular group) and along the transverse jugular vein (lateral supraclavicular group). We theorized that the lateral and posterior borders of the clinical target volume in the supraclavicular region should include the lymph nodes in the posterior triangle of the neck (level V) in high-risk individuals. If the metastatic axillary lymph node is extensive, then the superior border of the supraclavicular region should be moved upward appropriately. Conclusions This study analyzed patients with breast cancer and supraclavicular lymph node metastasis at initial treatment, explored the metastastic pattern of supraclavicular lymph node, and applied anatomical knowledge to further optimize the target volume delineation of supraclavicular lymph node drainage area in high-risk breast cancer.

Abstract The global increase of cutaneous wounds imposes huge health and financial burdens on patients and society. Despite improved wound healing outcomes, conventional wound dressings are far from ideal, owing to the complex healing process. Smart wound dressings, which are sensitive to or interact with changes in wound condition or environment, have been proposed as appealing therapeutic platforms to effectively facilitate wound healing. In this review, the wound healing processes and features of existing biomaterials are firstly introduced, followed by summarizing the mechanisms of smart responsive materials. Afterwards, recent advances and designs in smart and versatile materials of extensive applications for cutaneous wound healing were submarined. Finally, clinical progresses, challenges and future perspectives of the smart wound dressing are discussed. Overall, by mapping the composition and intrinsic structure of smart responsive materials to their individual needs of cutaneous wounds, with particular attention to the responsive mechanisms, this review is promising to advance further progress in designing smart responsive materials for wounds and drive clinical translation. Graphical Abstract

Based on paleogeomorphology, drilling and seismic data, this paper systematically studies the structural and sedimentary evolution, source rock characteristics, reservoir characteristics and formation mechanism, hydrocarbon accumulation model and enrichment law in the Linhe Depression of the Hetao Basin, NW China. The Hetao Basin mainly experienced three stages of evolution, namely, weak extensional fault depression, strong extensional fault depression and strike-slip transformation, giving rise to four positive structural belts (Jilantai, Shabu, Nalinhu and Xinglong), which are favorable areas for oil and gas accumulation. The two main saline lacustrine source rocks, Lower Cretaceous Guyang Formation and Oligocene Linhe Formation, are characterized by high sulfur content, rich algae, early maturity, early expulsion, and wide oil generation window. The large structural transition belt in the intermountain area around the Hetao Basin controls the formation of large-scale braided river delta deposits, which are characterized by high quartz content (50%–76%), long-term shallow burial and weak compaction, low cement content, and good reservoir properties in delta front sandbody. The burial depth of the effective Paleogene reservoirs is predicted to reach 8000 m. Three hydrocarbon accumulation models, nose-uplift near sag, buried hill surrounding sag, fault nose near source rock, are constructed. The law of hydrocarbon accumulation in the Linhe Depression is finally clarified as follows: near-source around the depression is the foundation, high-quality thick reservoir is the premise, good tectonic setting and trap conditions are the key.

Abstract The immune-excluded tumors (IETs) show limited response to current immunotherapy due to intrinsic and adaptive immune resistance. In this study, it is identified that inhibition of transforming growth factor-β (TGF-β) receptor 1 can relieve tumor fibrosis, thus facilitating the recruitment of tumor-infiltrating T lymphocytes. Subsequently, a nanovesicle is constructed for tumor-specific co-delivery of a TGF-β inhibitor (LY2157299, LY) and the photosensitizer pyropheophorbide a (PPa). The LY-loaded nanovesicles suppress tumor fibrosis to promote intratumoral infiltration of T lymphocytes. Furthermore, PPa chelated with gadolinium ion is capable of fluorescence, photoacoustic and magnetic resonance triple-modal imaging-guided photodynamic therapy, to induce immunogenic death of tumor cells and elicit antitumor immunity in preclinical cancer models in female mice. These nanovesicles are further armored with a lipophilic prodrug of the bromodomain-containing protein 4 inhibitor (i.e., JQ1) to abolish programmed death ligand 1 expression of tumor cells and overcome adaptive immune resistance. This study may pave the way for nanomedicine-based immunotherapy of the IETs.

Nano-drug delivery strategies have been highlighted in cancer treatment, and much effort has been made in the optimization of bioavailability, biocompatibility, pharmacokinetics profiles, and in vivo distributions of anticancer nano-drug delivery systems. However, problems still exist in the delicate balance between improved anticancer efficacy and reduced toxicity to normal tissues, and opportunities arise along with the development of smart stimuli-responsive delivery strategies. By on-demand responsiveness towards exogenous or endogenous stimulus, these smart delivery systems hold promise for advanced tumor-specificity as well as controllable release behavior in a spatial-temporal manner. Meanwhile, the blossom of nanotechnology, material sciences, and biomedical sciences has shed light on the diverse modern drug delivery systems with smart characteristics, versatile functions, and modification possibilities. This review summarizes the current progress in various strategies for smart drug delivery systems against malignancies and introduces the representative endogenous and exogenous stimuli-responsive smart delivery systems. It may provide references for researchers in the fields of drug delivery, biomaterials, and nanotechnology.

Background: This study aims to evaluate the overall and breast cancer-specific survival (BCSS) after breast-conserving surgery (BCS) plus radiotherapy (RT) compared with mastectomy plus RT in resectable breast cancer. Moreover, the aim is to also identify the subgroups who benefit from BCS plus RT and establish a predictive nomogram for stage II patients. Methods: Stage I–III breast cancer patients were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 1990 and 2016. Patients with available clinical information were split into two groups: BCS plus RT and mastectomy plus RT. Kaplan–Meier survival analysis, univariate and multivariate regression analysis, and propensity score matching were used in the study. Hazard ratio (HR) was calculated based on stratified Cox univariate regression analyses. A prognostic nomogram by multivariable Cox regression model was developed for stage II patients, and consistency index (C-index) and calibration curve were used to evaluate the accuracy of the nomogram in the training and validation set. Results: A total of 24,590 eligible patients were enrolled. The difference in overall survival (OS) and BCSS remained significant in stage II patients both before and after PSM (after PSM: OS: HR = 0.8536, p = 0.0115; BCSS: HR = 0.7803, p = 0.0013). In stage II patients, the survival advantage effect of BCS plus RT on OS and BCSS was observed in the following subgroups: any age, smaller tumor size (Conclusions: BCS plus RT significantly improved the survival rates for patients of stage IIA (T2N0, T0–1N1), ER (+). For stage II patients, the nomogram was a good predictor of 5-, 10-, and 15-year BCSS. Our study may help guide treatment decisions and prolong the survival of stage II breast cancer patients.

Nonylphenol (NP) is a typical environmental endogenous disrupter with low concentration and high toxicity. This paper describes the mechanism of NP degradation in solution by strong ionization dielectric barrier discharge (SIDBD). Furthermore, the degradation performance of NP by SIDBD was tested by changing the equipment voltage, the initial concentration of NP in aqueous solution, pH, and inorganic ions. Degradation pathways of NP were detected using a high-performance liquid chromatography-mass spectrometer. The biological effects of NP degradation were assessed by detecting indicators of embryonic development in zebrafish (survival rate, fetal movement, heartbeat, the body length, behavior, deformity) and adult fish (sex differentiation, weight, ovarian testes pathological section analysis). The results showed when the input O2 was 5 L/min and the voltage was 3.2 kV, the degradation efficiency of NP can reach 99.0% after 60 min of experiment. Equipment voltage, initial concentration of NP in solution, pH, inorganic ions and other factors can influence the degradation efficiency of NP by DBD. At the higher concentration of NP, the greater influence on embryonic development in zebrafish was noticed. Although the effects of NP on zebrafish sex differentiation were not obvious, it showed significant male weight inhibition and decrease in sperm number. HIGHLIGHTS The possible pathways and mechanisms for degradation of NP by strong ionization discharge were studied.; The higher formation of ·OH was favorable for NP degradation by strong ionization discharge.; Zebrafish was used as a biological model to evaluate the toxicity of strong ionization discharge degraded water.;

Proteolysis targeting chimeras (PROTACs) have emerged as promising cancer therapy agents but have suffered from systemic toxicity issues. Here, the authors report on the creation of polymeric PROTAC nanoparticles for tumour targeting delivery and demonstrate protein degradation in vivo, in combination with photodynamic therapy.

Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance. Herein, a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms. A disulfide bond-linked bispecific prodrug of NLG919 and JQ1 (namely NJ) was synthesized and self-assembled into a prodrug nanoparticle, which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ. Upon tumor accumulation via passive tumor targeting, the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug. NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond. JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1. In contrast, NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment, which thus restores robust antitumor immune responses. Photodynamic therapy (PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells. The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.

Abstract Solid‐state lithium metal batteries (SSLMBs) have attracted considerable attention as one of the most promising energy storage systems owing to their high safety and energy density. Solid electrolytes, particularly polymer‐based composite solid electrolytes (CSEs), are considered promising electrolyte candidates for SSLMBs. However, their wide application is inhibited by various electrochemical issues, such as low ionic conductivity, the growth of lithium dendrites, and poor cycling stability, which are related to interface issues within SSLMBs. In this review, the parameters related to various interfaces in the CSE of SSLMBs, including the interfaces between the polymer matrix and inorganic fillers, between the CSEs and the cathode, and between the CSEs and the lithium metal anode, are examined. Relevant issues and corresponding remediation strategies are proposed. Finally, future perspectives based on interfacial engineering and the characterization of polymer/inorganic filler interactions are proposed for building high‐performance CSEs for use in SSLMBs.

Because of the lack of hydrological monitoring facilities and methods in many areas, basic hydrological elements cannot be obtained directly. In that case, the reverse flow routing method is frequently used, which allows for the simulation of hydraulic elements upstream using downstream data, and is of great significance for river and reservoir joint regulation, flood disaster management, flood control evaluation, and flood forecasting. The hydrological and hydrodynamic methods are the two main approaches to reverse flow routing. The hydrological method is mainly realized by constructing a distributed or lumped hydrological model based on rainfall, soil type, terrain slope, and other data. A distributed hydrological model focuses on the physical mechanism of runoff yield and flow concentration, the spatial variability of model input, and the hydraulic connection between different units. The solution of the hydrological method is relatively simple, but it requires a large amount of measured data, which limits the applicability of this method. The other method builds a hydrodynamic model by solving shallow water equations for reverse flow routing. This method has definite physical significance, higher accuracy, and obvious advantages of simple and fast calculations. It can not only simulate one-dimensional but also two-dimensional flood routing processes. In addition, the slope-area method is frequently used for flood reverse routing in many areas in China without relevant hydrological data, and can calculate the peak discharge, maximum water level, flood recurrence interval, and other information by the hydrodynamic formula, along with the cross-section and the measured flood mark water level. Due to the influence of extreme weather, a heavy rainstorm and flood occurred in the Luxi river basin in China on 16 August 2020, resulting in severe flood disasters in this area and causing significant economic losses. Moreover, due to the lack and damage of hydrological monitoring equipment, hydrological information such as flood hydrographs and peak discharges of this flood could not be recorded. To reduce the uncertainty of a single method for reverse flow routing, we integrated and applied the hydrodynamic, hydrological, and slope-area methods to reverse flow routing in the Luxi river basin on 16 August 2020. The simulation accuracy of the three methods was verified in terms of the measured flood mark water level, and the simulation results of the three methods were analyzed and compared. The results are as follows: 1) The hydrological method can better simulate flood hydrographs and durations, especially for flood hydrographs with multiple peaks, and is more applicable than the other two methods. However, the hydrodynamic and slope-area methods have better accuracy in the reverse simulation of flood peaks. Therefore, through the comprehensive comparative analysis of these three methods, flood elements such as flood hydrographs, peak discharges, and durations can be simulated more accurately, and the problem of large errors caused by a single method can be avoided; 2) The simulation results of the hydrodynamic and slope-area methods are similar, and the maximum error of the peak discharge calculated using the two methods is within 10%. According to the simulation results, the peak discharge reached 2,920 m3/s downstream of Luxi river basin, which is a flood having more than 100-year recurrence interval; 3) The simulation results of the hydrological method show that the flow hydrograph is a double-peak, and the two peaks occurred at 17:00 on August 16 and 6:00 on 17 August 2020, respectively.

Abstract Lithium‐rich layered oxides (LLOs) with high energy density and low cost are regarded as promising candidates for the next‐generation cathode materials for lithium‐ion batteries (LIBs). However, there are still some drawbacks of LLOs such as oxygen instability and irreversible structure reconstruction, which seriously limit their electrochemical performance and practical applications. Herein, the high‐valence Ta doping is proposed to adjust the electronic structures of transition metals, which form strong Ta‐O bonds and reduce the covalency of Ni‐O bonds, thereby stabilizing the lattice oxygen and enhancing the structural/thermal stabilities of LLOs during electrochemical cycling. As a result, the optimized Ta‐doped LLO can deliver a capacity retention of 80% and voltage decay of 0.34 mV cycle−1 after 650 cycles at 1C. This study enriches the fundamental understanding of the electronic structure adjustment of LLOs and contributes to the optimization of LLOs for high‐energy LIBs.

In recent years, reactive species-based cancer therapies have attracted tremendous attention due to their simplicity, controllability, and effectiveness. Herein, we overviewed the state-of-art advance for photo-controlled generation of highly reactive radical species with nanomaterials for cancer therapy. First, we summarized the most widely explored reactive species, such as singlet oxygen, superoxide radical anion (O2●-), nitric oxide (●NO), carbon monoxide, alkyl radicals, and their corresponding secondary reactive species generated by interaction with other biological molecules. Then, we discussed the generating mechanisms of these highly reactive species stimulated by light irradiation, followed by their anticancer effect, and the synergetic principles with other therapeutic modalities. This review might unveil the advantages of reactive species-based therapeutic methodology and encourage the pre-clinical exploration of reactive species-mediated cancer treatments.

Abstract Chemoradiotherapy is the standard of care for the clinical treatment of locally advanced head and neck cancers. However, the combination of ion radiation with free chemotherapeutics yields unsatisfactory therapeutic output and severe side effects due to the nonspecific biodistribution of the anticancer drugs. Herein, a self‐cooperative prodrug nanovesicle is reported for highly tumor‐specific chemoradiotherapy. The nanovesicles integrating a prodrug of oxaliplatin (OXA) can passively accumulate at the tumor site and penetrate deep into the tumor mass via matrix metalloproteinase 2‐mediated cleavage of the polyethylene glycol corona. The OXA prodrug can be restored inside the tumor cells with endogenous glutathione to trigger immunogenic cell death (ICD) of the tumor cells and sensitize the tumor to ion radiation. The nanovesicles can be further loaded with the JAK inhibitor ruxolitinib to abolish chemoradiotherapy‐induced programmed death ligand 1 (PD‐L1) upregulation on the surface of the tumor cells, thereby prompting chemoradiotherapy‐induced immunotherapy by blocking the interferon gamma‐Janus kinase‐signal transducer and activator of transcription axis. The prodrug nanoplatform reported herein might present a novel strategy to cooperatively enhance chemoradiotherapy of head and cancer and overcome PD‐L1‐dependent immune evasion.

Abstract Radiotherapy-related caries is a complication of radiotherapy for nasopharyngeal carcinoma; however, factors influencing the occurrence, accurate prediction of onset, and protective factors of radiotherapy-related caries remain unclear. This study analyzed risk factors, disease predictors, and protective factors for radiotherapy-related caries in nasopharyngeal carcinoma. This prospective study included 138 nasopharyngeal carcinoma patients receiving radical radiotherapy at our hospital during June 2012–December 2016 and were followed up for dental caries. Patients’ clinical data on radiotherapy were collected, dynamic monitoring was performed to assess changes in oral pH values, and a questionnaire survey was administered to collect patients’ lifestyle habits. Time-dependent cox regression trees, event-free Kaplan–Meier curve, Mann–Whitely U test were used to analysis the results. The median follow-up time was 30 (12–60) months. Radiotherapy-related caries occurred in 28 cases (20.3%). Univariate analyses showed that radiotherapy-related caries was associated with patient’s age, oral saliva pH value, green tea consumption, and radiation dose to sublingual glands, but not with the radiation dose to the parotid and submandibular glands. Multivariate analysis showed that oral saliva pH value [hazard ratio (HR) = 0.390, 95% confidence interval = 0.204–0.746] was an independent prognostic factor for radiotherapy-related caries. Patients with oral saliva pH values ≤ 5.3 in the 9th month after radiotherapy represented a significantly higher risks for radiotherapy-related caries (p

Abstract Background BLCA is a common cancer worldwide, and it is both aggressive and fatal. Immunotherapy (ICT) has achieved an excellent curative effect in BLCA; however, only some BLCA patients can benefit from ICT. MT1L is a pseudogene, and a previous study suggested that MT1L can be used as an indicator of prognosis in colorectal cancer. However, the role of MT1L in BLCA has not yet been determined. Methods Data were collected from TCGA, and logistic regression, Kaplan-Meier plotter, and multivariate Cox analysis were performed to demonstrate the correlation between the pseudogene MT1L and the prognosis of BLCA. To identify the association of MT1L with tumor-infiltrating immune cells, TIMER and TISIDB were utilized. Additionally, GSEA was performed to elucidate the potential biological function. Results The expression of MT1L was decreased in BLCA. Additionally, MT1L was positively correlated with immune cells, such as Tregs (ρ = 0.708) and MDSCs (ρ = 0.664). We also confirmed that MT1L is related to typical markers of immune cells, such as PD-1 and CTLA-4. In addition, a high MT1L expression level was associated with the advanced T and N and high grade in BLCA. Increased expression of MT1L was significantly associated with shorter OS times of BLCA patients (p < 0.05). Multivariate Cox analysis revealed that MT1L expression could be an independent prognostic factor in BLCA. Conclusion Collectively, our findings demonstrated that the pseudogene MT1L regulates the immune microenvironment, correlates with poor survival, and is an independent prognostic biomarker in BLCA.

High-capacity and structural stable cathode materials are challenges for sodium-ion batteries. Here, the authors report a layered P2-Na0.612K0.056MnO2 with large-sized K+ riveted in the Na-layers to enable 0.9 Na+ (de)insertion with a reversible phase transition of P2-P’2.

Targeting regulatory T cells (Treg) represents a therapeutic option to abrogate tumor-associated immune suppression. Here the authors show that pharmacological degradation of BCL-XL preferentially induces apoptosis of tumor-infiltrating Treg, promoting CD8 T cell activation and anti-tumor immune responses in preclinical cancer models.

End of life vehicle (ELV) is a significant renewable resource with enormous economic value and environmental value. New regulation promulgated by the State Council of PRC has been implemented since June 2019, allows main assemblies of ELV can be sold to remanufacture enterprises, which dramatically prompts more enterprises to invest in the recycling industry. According to the technological recovery characteristics of ELV, the system layout design (SLP) method is briefly applied to arrange the plant facility layout of ELV recycling and disassembly enterprise. The relationship between logistics and non-logistics was firstly analyzed, and the operating unit correlation diagram of location and area were presented correspondingly. Then, through further modification and adjustment, the feasible layout scheme was obtained, and the reasonable general layout of the plant area was determined by using the weighted factor method. As a critical functional unit of the factory area, the detailed planning and design of the disassembly and shredding workshop were further presented. A detailed facility layout and logistics route of the disassembly and shredding workshop are finally proposed according to the obtained correlation diagram of the operating unit area based SLP, which has been implemented in a recycling company in Changsha, a typical case in China. Combined with the theoretical techniques of statistics, intelligent algorithms, and logistics analysis under the background of modern green production and sustainable manufacturing, this work can provide a new approach for plant layout design and optimization for ELV recycling and disassembly industry.

Abstract Immunotherapy has been a new standard for recurrent/metastatic head and neck cancers (R/M HNC). One of the prominent characteristics of cancer immunotherapy is the induction of immune memory followed by endured treatment response. However, whether and how a treatment delay would impact on the efficacy of immunotherapy has not been well determined. During the outbreak of COVID-19, a number of cancer patients in Wuhan, the epicenter of the pandemic in China, had experienced long-lasting city lockdown and delay of immunotherapies. Here, we retrospectively analyzed 24 HNC patients treated with immune checkpoint inhibitors in our cancer institute prior to the outbreak of COVID-19 who were re-evaluated after the restoration of regular medical care. Of these 24 patients, 10 patients had achieved complete response (CR) or partial response (PR), 12 patients had achieved stable disease (SD), and 2 patients had received just one cycle treatment without efficacy evaluation before treatment delay. The median delay was 3.75 months (range 1.73–8.17 months). Re-evaluation after treatment delay revealed that ten patients (10/10) who achieved CR or PR, two patients (2/2) who received just one cycle treatment without efficacy evaluation and seven patients (7/12) who achieved SD before outbreak of COVID-19 maintained tumor response after treatment delay. Among the rest five patients who had achieved SD, four patients were re-evaluated as progressive disease (PD) due to treatment delay and one patient died after treatment interruption without re-evaluation. Our results from a small cohort of R/M HNC patients showed that treatment delay of three to four months might have mild, if any, impact on the efficacy of immunotherapy for patients with controlled disease.

This paper presents a Laguerre homotopy method for quadratic optimal control problems in semi-infinite intervals (LaHOC), with particular interests given to nonlinear interconnected large-scale dynamic systems. In LaHOC, the spectral homotopy analysis method is used to derive an iterative solver for the nonlinear two-point boundary value problem derived from Pontryagin's maximum principle. A proof of local convergence of the LaHOC is provided. Numerical comparisons are made between the LaHOC, Matlab BVP5C generated results and results from the literature for two nonlinear optimal control problems. The results show that LaHOC is superior in both accuracy and efficiency.

Zinc pyrithione (ZPT) is widely used as an antimicrobial. Zinc is a necessary trace element of the human whose homeostasis associated with several cancers. However, the anticancer effect of increased Zinc in ovarian cancer is still unclear. This study focussed on the anti-tumour effects of ZPT combined with Zinc in SKOV3 and SKOV3/DDP cells. The cell viability, apoptosis, migration, and invasion assays were detected by CCK-8, flow cytometry, wound healing and transwell assay, respectively. The distribution of Zinc in cells was monitored by staining of Zinc fluorescent dye and lysosome tracker. The changes in lysosomal membrane stability were reflected by acridine orange fluorescence and cathepsin D reposition. Expression of the proteins about invasion and apoptosis was evaluated by western blot. The results indicated that ZPT combined with Zinc could notably reduce cell viability, inhibit migration and invasion in SKOV3 and SKOV3/DDP cells. Besides, ZPT performed as a Zinc carrier targeted lysosomes, caused the increase of its membrane permeability and the release of cathepsin D accompanied by mitochondrial apoptosis in SKOV3/DDP cells. In conclusion, our work suggests that ZPT combined with Zinc could inhibit proliferation, migration, invasion, and promote apoptosis by trigger the lysosome-mitochondrial apoptosis pathway in ovarian carcinoma.

This paper focuses on the principal problems in the actual transaction of decommissioned power batteries such as the asymmetry of information, huge risk and difficult is sues such as recovery and trace. And constructed a new energy vehicle decommissioned power battery recycling platform based on the big data technology. Integrated characteristics of big data information, this paper analyzes the operating mechanism of the Big-Data-Based power battery recovery platform. The functional module on this platform is designed and investigated for the functional requirements of users and shared in formation based on big data. Based on the analysis of traffic big data, a traction battery dangerous goods transportation optimization system is established by using Baidu map application program interface (API). The improved ant algorithm was used to obtain the shortest path model and decrease the transportation costs and risks, besides, it boosts the value of information resources maximum and gives impetus to the power battery recycling industrial transformation and upgrading.

As a new generation computed tomography (CT) technology, spectral CT has great potential in many aspects, especially in the identification and decomposition of materials. To achieve higher accuracy of materials decomposition, we propose a multi-constraint based nonlocal total variation (NLTV) method, named as MCNLTV. Because image-domain based material decomposition belongs to the two-step material decomposition method, the Filter Back-Projection (FBP) algorithm or SART algorithm is used to reconstruct spectral CT images in the first step. Then the material attenuation coefficient matrix is obtained from the reconstruction results. In the second step, MCNLTV regularization is utilized to obtain the material decomposition image. Both simulation experiments and real data experiments are carried out. Experiment results show that the proposed method can obtain higher accuracy of material decomposition than traditional total variation based material decomposition (TVMD), ROF-LLT regularization and direct inverse transformation (DI) for spectral CT.

Maintaining the stability of the surrounding rock is an important prerequisite in ensuring the safe and efficient construction of underground mines—in particular, the surrounding rock of the cross-layer roadway, which is a combination of different media with different lithologies. Numerical models were established to investigate the effects of the different lateral pressure coefficients (λ), the angle (α) between the roadway and the maximum horizontal principal stress, and typical lithological combinations on the deformation of the surrounding rock of weakly cemented roadways. The main outcomes obtained from our research indicated the following: (1) under the action of tectonic stress, the focus should be on strengthening the roof of the roadway support of the slab, which is conducive to the stability of the surrounding rock; (2) roadway deformation and failure for the cases λ < 1.5 are approximately symmetrically distributed, whereas those for the cases λ > 1.5 are asymmetric; (3) roadway deformation and failure for the cases α < 45° are approximately symmetrically distributed, whereas those for the cases α > 45° are asymmetric; (4) tectonic stress has an important influence on stress redistribution, deformability, and damage in cross-layer roadways; and (5) when excavating cross-layer roadways under the action of tectonic stress, the concentrated stress around the end of the working face (especially the bottom corner) should be reduced. The research results provide insights for the roadway layout through coal seam and cross-layer excavation and deepen the understanding of the deformation mechanism of weakly cemented cross-layer roadway under tectonic stress.

Drug delivery systems (DDS) are defined as methods by which drugs are delivered to desired tissues, organs, cells and subcellular organs for drug release and absorption through a variety of drug carriers. Its usual purpose to improve the pharmacological activities of therapeutic drugs and to overcome problems such as limited solubility, drug aggregation, low bioavailability, poor biodistribution, lack of selectivity, or to reduce the side effects of therapeutic drugs. During 2015–2018, significant progress in the research on drug delivery systems has been achieved along with advances in related fields, such as pharmaceutical sciences, material sciences and biomedical sciences. This review provides a concise overview of current progress in this research area through its focus on the delivery strategies, construction techniques and specific examples. It is a valuable reference for pharmaceutical scientists who want to learn more about the design of drug delivery systems. KEY WORDS: Pharmaceutics, Drug delivery system, Basic research, Application, Delivery strategy

Abstract The low immunogenicity, insufficient infiltration of T lymphocytes, and dismal response to immune checkpoint blockade therapy pose major difficulties in immunotherapy of pancreatic cancer. Photoimmunotherapy by photodynamic therapy (PDT) can induce an antitumor immune response by triggering immunogenic cell death in the tumor cells. Notwithstanding, PDT‐driven oxygen consumption and microvascular damage can further aggravate hypoxia to exaggerates glycolysis, leading to lactate accumulation and immunosuppressive tumor microenvironment. Herein, a supramolecular prodrug nanoplatform codelivering a photosensitizer and a prodrug of bromodomain‐containing protein 4 inhibitor (BRD4i) JQ1 for combinatory photoimmunotherapy of pancreatic cancer are demonstrated. The nanoparticles are fabricated by host–guest complexation between cyclodextrin‐grafted hyaluronic acid (HA‐CD) and adamantine‐conjugated heterodimers of pyropheophorbide a (PPa) and JQ1, respectively. HA can achieve active tumor targeting by recognizing highly expressed CD44 on the surface of pancreatic tumors. PPa‐mediated PDT can enhance the immunogenicity of the tumor cells and promote intratumoral infiltration of the cytotoxic T lymphocytes. Meanwhile, JQ1 combats PDT‐mediated immune evasion through inhibiting expression of c‐Myc and PD‐L1, which are key regulators of tumor glycolysis and immune evasion. Collectively, this study presents a novel strategy to enhance photoimmunotherapy of the pancreatic cancer by provoking T cells activation and overcoming adaptive immune resistance.

Molten-salt assisted solid-state synthesis is considered a promising method in obtaining layer-structured cathodes for lithium-ion batteries with homogeneous elemental distribution and controllable morphologies. However, drawbacks like resource wasting which have arisen from redundant salt removal after sintering greatly hinder the broader application of this technique. In this paper, a closed-loop utilization of molten salts is proposed for the first time with specific electrochemical properties of the products studied. Results confirm the feasibility of this strategy, and that with only replenishing LiOH, the recycled LiOH-LiCl molten salts can be successfully reused into another LiNi0.5Co0.2Mn0.3O2 synthesis, which exhibits almost equal electrochemical performance to the product using fresh molten salts. We believe this research can provide significant insight in guiding green and environmental-friendly preparation methods involving molten salts.

The high-capacity phosphorus- (P-) based anode materials for sodium-ion batteries (NIBs) often face poor performance retentions owing to the low conductivity and large volume expansion. It is thus essential to buffer these problems by appropriately alloying with other elements such as tin (Sn) and constructing well-designed microstructures. Herein, a series of P-/Sn-based composites have been synthesized by the facile and low-cost one-step ball milling. Pair distribution function (PDF) has been employed as a hardcore quantitative technique to elucidate their structures combined with other techniques, suggesting the formation and ratios of Sn4P3 and Sn crystalline domains embedded inside an amorphous P/carbon matrix. The composite with the largest amount of Sn4P3 in the P/C matrix can deliver the most balanced electrochemical performance, with a capacity of 422.3 mA-h g−1 for 300 cycles at a current density of 1000 mA g−1. The reaction mechanism has been elucidated by 23Na and 31P solid-state nuclear magnetic resonance (NMR) investigations. The study sheds light on the rational design and concrete identification of P-/Sn-based amorphous-dominant composite materials for NIBs.

Application of modern delivery techniques to natural bioactive products improves their permeability, bioavailability, and therapeutic efficacy. Many natural products have desirable biological properties applicable to wound healing but are limited by their inability to cross the stratum corneum to access the wound. Over the past two decades, modern systems such as microneedles, lipid-based vesicles, hydrogels, composite dressings, and responsive formulations have been applied to natural products such as curcumin or aloe vera to improve their delivery and efficacy. This article reviews which natural products and techniques have been formulated together in the past two decades and the success of these applications for wound healing. Many cultures prefer natural-product-based traditional therapies which are often cheaper and more available than their synthetic counterparts. Improving natural products’ effect can provide novel wound-healing therapies for those who trust traditional compounds over synthetic drugs to reduce medical inequalities.

Summary: Li2MnO3 endows Li-rich layered oxides with a superior energy density; however, its electron transfer mechanism is still unclear. Here, the electronic and thermodynamic behavior of LixMnO3 (x = 0.5–2) is determined using first-principles computations. The cationic redox, anionic redox, and local electron exchange in Mn-O polyhedron are revealed. An obvious electron donation inclination of manganese is demonstrated when the Li+ content is low. Through ab initio molecular dynamics, high valence Mn6+ and Mn7+ are generated in the form of MnO4 tetrahedrons with structural transformation toward a disordered structure, controlled by the Li+ content and dynamic energy barrier. Furthermore, a local redox reaction between Mn6+ or Mn7+ and their surrounding oxygen atoms is elucidated. Consequently, a comprehensive understanding regarding the electron transfer in LixMnO3 is provided. Our results bring insight regarding the electron transfer mechanism in Li-rich layered oxide cathode materials and encourage further reconsideration and investigation into its redox mechanism.

Abstract Immunotherapy aiming to harness the exquisite power of the immune system has emerged as a crucial part of clinical cancer management. However, only a subset of cancer patients responds to current immunotherapy because of low immunogenicity of the tumor cells and immunosuppressive tumor microenvironment. Herein, host–guest prodrug nanovectors are reported for active tumor targeting and combating immune tolerance in tumors. The prodrug nanovectors are designed by integrating hyaluronic acid (HA) and reduction‐labile heterodimer of Pheophorbide A (PPa) and NLG919 into the supramolecular nanocomplexes, where PPa and NLG919 act as a photosensitizer and potent inhibitor of indoleamine 2,3‐dioxygenase 1 (IDO‐1), respectively. Meanwhile, HA is employed to achieve active tumor targeting by recognizing CD44 overexpressed on the surface of tumor cell membranes. Near infrared (NIR) laser irradiation triggers the release of reactive oxygen species to provoke antitumor immunogenicity and intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Meanwhile, the immunosuppressive tumor microenvironment (ITM) is reversed by NLG919‐mediated IDO‐1 inhibition. Combination of photodynamic immunotherapy and IDO‐1 blockade efficiently eradicates CT26 colorectal tumors in the immunocompetent mice. The host–guest nanoplatform capable of eliciting effective antitumor immunity by inactivating inhibitory immune response can be applied to other immune modulators for improved cancer immunotherapy.

The Mann-Kendall (MK) statistical test has been widely applied in the trend detection of the hydrometeorological time series. Previous studies have mainly focused on the null hypothesis of “no trend” or the “Type I Error.” However, few studies address the capability of the MK test to successfully recognize the trends. In some cases, especially when the trend test is jointly applied with hydropower station design, flood risk assessment, and water quality evaluation, the “Type II error” is equally important and should not be neglected. To cope with this problem, we carry out Monte Carlo simulations and the results indicate that in addition to the significance level and the sample length, the MK test power has a close relationship with the sample variance and the magnitude of the trend. For a given time series with fixed length, the power of the MK test increases as the slope increases and declines with increasing sample variance. A deterministic relationship between the slope and the standard deviation of the white noise that can be used for evaluating the power of the MK test has also been detected. Furthermore, we find that a positive autocorrelation contained in the time series will increase both the Type I and the Type II errors due to the enlargement of the variance in the MK statistics. Finally, we recommend that researchers slightly increase the significance level and lengthen the time series sample to improve the power of the MK test in future studies.

Cancer vaccines represent a promising personalized therapeutic approach to treating cancer. Here, the authors report the efficacy in a metastatic model of a cancer vaccine-mediated postoperative immunotherapy, based on the coencapsulation of the JQ1 and a photosensitizer ICG together with inactivated tumor cells into a hydrogel matrix.

Abstract Background We previously reported that clioquinol acts as a zinc ionophore and inhibits the NF-κB signalling pathway. Other research has demonstrated that zinc deficiency plays a vital role in the occurrence and development of some solid tumours, and intracellular zinc supplementation may reverse this process and enhance the tumour sensitivity to anticancer treatment. Thus, we investigated the radiosensitization effects of clioquinol combined with zinc on HeLa and MCF-7 cells in vitro. Methods The dose effect of growth inhibition of clioquinol combined with zinc on cell viability was determined by a cell counting kit 8 (CCK-8) assay. The radiosensitization effect of clioquinol combined with zinc and/or MG132 in HeLa and MCF-7 cells was detected by the clonogenic assay. The cell cycle distribution and apoptosis of clioquinol combined with zinc on HeLa cells were analyzed by flow cytometry. A luciferase reporter construct was used to study the effect of clioquinol combined with zinc on NF-κB activity in HeLa cells. DNA double-strand breaks were detected by immunofluorescence. The mRNA and protein levels of ATM were analyzed by quantitative real-time PCR and Western blotting, respectively. Results Our research showed that clioquinol combined with zinc markedly increased the radiosensitivity of HeLa and MCF-7 cells in low toxic concentrations and resulted in a post-irradiation decrease in G2 phase arrest and an increase in apoptosis. Clioquinol combined with zinc also inhibited NF-κB activation, decreased ATM expression and increased DNA double-strand breaks (DSBs) induced by ionizing radiation. Conclusions These findings indicated that clioquinol combined with zinc enhanced the radiosensitivity of HeLa and MCF-7 cells by the down-regulation of ATM through the NF-κB signalling pathway.

Fluid flow and dust transportation in a realistic urban residential community under dust storm weather conditions are investigated using computational fluid dynamics (CFD) with a grid resolution of several meters. The dust transportation and concentration distribution are obtained through the Lagrangian-formulated discrete particle model by integrating the particle velocity between certain time intervals. The fluid flow is solved by the realizable $ k - \varepsilon $ model. It is found that the dust transportation and distribution are very closely related to the flow field. The flow field in a real residential community is very complicated. When the building axes are perpendicular to the wind direction, the flows resemble the classic street canyon flow. Places with a low wind speed and high vorticity usually have a high dust concentration. As the wind direction changes, the fluid flow and dust distribution differ from case to case, but the general features are kept. In addition, the building shape and particle-wall interaction conditions have additional effects on the dust distribution, which need further study in the future.

In this paper, a fluorescence resonance energy transfer (FRET)-based sensor for ultra-sensitive detection of H2O2 was developed by utilizing the unique enzymatic properties of peroxiredoxin (Prx) to H2O2. Cyan and yellow fluorescent protein (CFP and YFP) were fused to Prx and mutant thioredoxin (mTrx), respectively. In the presence of H2O2, Prx was oxidized into covalent homodimer through disulfide bonds, which were further reduced by mTrx to form a stable mixed disulfide bond intermediate between CFP-Prx and mTrx-YFP, inducing FRET. A linear quantification range of 10–320 nM was obtained according to the applied protein concentrations and the detection limit (LOD) was determined to be as low as 4 nM. By the assistance of glucose oxidase to transform glucose into H2O2, the CFP-Prx/mTrx-YFP system (CPmTY) was further exploited for the detection of glucose in real sample with good performance, suggesting this CPmTY protein sensor is highly practical.

Hydrodynamic models were commonly used for flood risk management in urban area. This paper presents initial efforts in developing an urban flood inundation model by coupling a one-dimensional (1D) model with a two-dimensional (2D) model to overcome the drawbacks of each individual modelling approach, and an additional module is used to simulate the rainfall-runoff process in study areas. For the 1D model, the finite difference method is used to discretize the Saint-Venant equations. An implicit dual time-stepping method (DTS) is then applied to a 2D finite volume model for an inundation simulation to improve computational efficiency. A total of four test cases are applied to validate the proposed model; its performance is demonstrated by a comparison with an explicit scheme and previously published results (an extensive physical experiment benchmark case, a vertical linking example, and two real drainage cases with actual topography). Results demonstrate that the proposed model is accurate and efficient in simulating urban floods for practical applications.

Terrestrial net primary productivity (NPP) plays an essential role in the global carbon cycle as well as for climate change. However, in the past three decades, terrestrial ecosystems across mainland China suffered from frequent drought and, to date, the adverse impacts on NPP remain uncertain. This study explored the spatiotemporal features of NPP and discussed the influences of drought on NPP across mainland China from 1982 to 2015 using the Carnegie Ames Stanford Application (CASA) model and the standardized precipitation evapotranspiration index (SPEI). The obtained results indicate that: (1) The total annual NPP across mainland China showed an non-significantly increasing trend from 1982 to 2015, with annual increase of 0.025 Pg C; the spring NPP exhibited a significant increasing trend (0.031 Pg C year−1, p < 0.05) while the summer NPP showed a higher decreasing trend (0.019 Pg C year−1). (2) Most areas of mainland China were spatially dominated by a positive correlation between annual NPP and SPEI and a significant positive correlation was mainly observed for Northern China; specific to the nine sub-regions, annual NPP and SPEI shared similar temporal patterns with a significant positive relation in Northeastern China, Huang-Huai-Hai, Inner Mongolia, and the Gan-Xin Region. (3) During the five typical drought events, more than 23% areas of mainland China experienced drought ravage; the drought events generally caused about 30% of the NPP reduction in most of the sub-regions while the NPP in the Qinghai-Tibet Plateau Region generally decreased by about 10%.

For H2 separation by Pd-based composite membranes, the pore mouth size distribution of the porous support immediately affects the quality of the deposited layer, including continuity and defect/pinhole formation. However, there is a lack of convenient and effective methods for characterization of pore mouth size of porous supports as well as of defect distribution of dense Pd-based composite membranes. Here we introduce a novel method by modifying conventional liquid–liquid displacement porometry. When the pore tunnels are filled with Liquid B and the outer surface is occupied by Liquid A, the reopening of the pore mouth depends on the pressure of Liquid B and the interfacial tension at the position of the pore mouth, from which the pore mouth size can be determined according to the Young–Laplace equation. Our experimental tests using this method with model samples show promising results, which are well supported by those obtained using FESEM (fild emission scanning electron microscope), AFM (atomic force microscope), and conventional liquid–liquid displacement porometry. This novel method can provide useful information for not only surface coatings on porous substrates but also for modification of dense membrane defects; thus, broad utilizations of this technique can be expected in future study.