Advances in Polysaccharide-Based Microneedle Systems for the Treatment of Ocular Diseases

The eye,a complex organ isolated from the systemic circulation,presents significant drug delivery challenges owing to its protective mechanisms,such as the blood-retinal barrier and corneal impermeability.Conventional drug administration methods often fail to sustain therapeutic levels and may compromise patient safety and compliance.Polysaccharidebased microneedles(PSMNs)have emerged as a transformative solution for ophthalmic drug delivery.However,a comprehensive review of PSMNs in ophthalmology has not been published to date.In this review,we critically examine the synergy between polysaccharide chemistry and microneedle technology for enhancing ocular drug delivery.We provide a thorough analysis of PSMNs,summarizing the design principles,fabrication processes,and challenges addressed during fabrication,including improving patient comfort and compliance.We also describe recent advances and the performance of various PSMNs in both research and clinical scenarios.Finally,we review the current regulatory frameworks and market barriers that are relevant to the clinical and commercial advancement of PSMNs and provide a final perspective on this research area.

Ⅱ型胸神经联合胸横肌平面阻滞在乳腺癌根治Ⅰ期假体乳房重建术后镇痛的应用

目的:评估超声引导下Ⅱ型胸神经阻滞(pectoral nerves blockⅡ,PECSⅡ)联合胸横肌平面(transverse thoracic muscle plane,TTMP)阻滞对乳腺癌根治Ⅰ期假体乳房重建术后的镇痛效果。方法:选择2022年3月至2023年1月于天津医科大学肿瘤医院行择期单侧乳腺癌根治Ⅰ期假体乳房重建术患者60例,随机分为全身麻醉复合PECSⅡ联合TTMP组(P组)30例和全身麻醉组(C组)30例,C组给与常规麻醉诱导,P组在麻醉诱导后行超声引导下PECSⅡ联合TTMP。采用视觉模拟评分(visual analog scale,VAS)评估术后1、6、12、24 h患者静息和咳嗽运动时疼痛强度,记录围术期阿片类药物总消耗量和不良反应。分别于麻醉诱导前、手术结束时、术后12 h和24 h采血测定白细胞介素(interleukin,IL)-1β、IL-6、及肿瘤坏死因子(tumor necrosis factor,TNF)-α水平。于术后24 h行15项恢复质量(15-item quality of recovery,QoR-15)评分。结果:与C组相比,P组在术后1、6、12 h静息和咳嗽运动时VAS评分均未超过3分,显著降低(P<0.001)。术后24 h静息时VAS评分两组无显著性差异(P=0.198),而咳嗽运动时P组的VAS评分显著低于C组(P<0.05)。术后24 h的P组芬太尼总消耗量为(240.97±18.76)μg,明显低于C组的(318.37±22.63)μg(P<0.001)。P组患者在手术结束时、术后12 h和24 h血清中的IL-1β、IL-6和TNF-α水平均显著低于C组(P<0.001)。P组术后24 h的QoR-15评分为(136.63±4.41)分,高于C组的(130.13±3.52)分(P<0.001)。结论:与单纯全身麻醉相比,超声引导下全身麻醉复合PECSⅡ联合TTMP可明显降低乳腺癌根治Ⅰ期假体乳房重建术后24 h疼痛强度和炎性因子水平,减少围术期阿片类药物用量,提高早期的恢复质量。

转移性癌性骨痛的分子机制及临床治疗研究进展

晚期癌症患者肿瘤骨转移诱发的骨痛是癌痛的最常见症状。癌性骨痛可显著影响患者的生存质量并使预后恶化。癌性骨痛包括背景痛及爆发性疼痛等多种形式,其发病机制复杂,包括炎性疼痛及神经病理性疼痛等,并随肿瘤的进展而变化。目前临床治疗主要包括外周及中枢镇痛药物、破骨细胞抑制剂等药物治疗,及放疗、神经损毁及神经调节等非药物治疗。阐明癌性骨痛的分子机制对优化治疗具有指导意义,本文将对转移性癌性骨痛的发病机制及临床治疗的进展进行综述。

腹横肌平面阻滞用于腹部肿瘤微创手术术中及术后镇痛的临床观察

目的:观察超声引导下腹横肌平面(transversus abdominis plane,TAP)阻滞对微创腹部肿瘤手术镇痛和术中血流动力学的影响。方法:选取2016年2月至2016年8月于天津医科大学肿瘤医院行腹部肿瘤微创手术的60例患者,随机分为全麻组(G组)和全麻联合TAP阻滞组(G+T组)。G+T组在麻醉诱导后行双侧TAP阻滞。记录两组患者基本信息、手术时间、苏醒时间、定向力恢复时间、术中瑞芬太尼用量。记录切皮前、后5 min,手术开始后30 min、手术结束时的平均动脉压(mean arterial pressure,MAP)、心率(heart rate,HR)。采用视觉模拟评分法(visual analogue scale,VAS),评估定向力恢复即刻、术后2、6、12、24 h患者的疼痛程度。当VAS评分>4时,自控静脉镇痛(patient controlled intravenous analgesia,PCIA)给药,记录使用次数及不良反应情况。结果:与G组相比,G+T组的术中瑞芬太尼用量、苏醒时间、定向力恢复时间均明显降低(P<0.05)。G组中,和切皮前基础值相比,切皮后5min及手术开始后30min的MAP和HR均明显增高(P<0.05);而G+T组,术中MAP和HR均未见显著性改变(P>0.05)。同时,G+T组在切皮后5 min和手术开始后30 min的MAP和HR均低于G组(P<0.05)。与G组相比,术后2、6、12 h,G+T组VAS评分显著性降低(P<0.05)。结论:全麻联合TAP阻滞能降低微创腹部肿瘤手术术中阿片类药物用量,达到更好的镇痛效果和血流动力学稳定状态,降低术后不良反应的发生。

无管化麻醉在胸科手术中的应用研究进展

电视胸腔镜手术(video-assisted thoracoscopic surgery,VATS)是目前治疗肺癌最常用的微创外科方式,但在提高患者舒适度和促进快速康复方面仍有待改进。一种新的无管化电视胸腔镜手术(tubeless VATS)正在逐渐发展,可以避免给患者使用气管插管、中心静脉导管、硬膜外导管、胸腔引流管和导尿管。Tubeless VATS结合当前最先进、创伤最小的麻醉、视频辅助外科和围术期护理方法,可确保手术的安全性和可行性,并且能够使患者在术后实现早期进食、下床和出院,使胸科日间手术成为可能。Tubeless VATS在肺癌手术乃至胸外科手术中的应用,见证了胸腔镜手术从微创到超微创的发展,使患者从快速康复外科治疗中最大获益。

围手术期麻醉对肿瘤患者预后影响的研究进展

超过80%恶性肿瘤患者在肿瘤诊断和治疗过程中需要麻醉,且超过半数患者需要行手术治疗。因此,明确围手术期麻醉对肿瘤的作用及其机制,对临床上麻醉方式和麻醉镇痛药物的选择具有重要意义。现阶段基础研究证实麻醉相关药物可从肿瘤微环境(tumor microenvironment,TME)、上皮-间质转化(epithelial-mesenchymal transition,EMT)以及肿瘤干细胞(cancer stem cell,CSC)等方面发挥其抑制或促进肿瘤复发转移的作用。基于上述研究结果,本文汇总了围手术期麻醉对肿瘤患者预后影响的相关临床研究结果和进展,比较了围手术期不同麻醉方式及麻醉镇痛药物对肿瘤患者预后的影响,为临床中肿瘤患者围手术期麻醉的管理提供理论基础。

Oxidation-strengthened disulfide-bridged prodrug nanoplatforms with cascade facilitated drug release for synergetic photochemotherapy

One of the major barriers in utilizing prodrug nanocarriers for cancer therapy is the slow release of parent drug in tumors.Tumor cells generally display the higher oxidative level than normal cells,and also displayed the heterogeneity in terms of redox homeostasis level.We previously found that the disulfide bond-linkage demonstrates surprising oxidationsensitivity to form the hydrophilic sulfoxide and sulphone groups.Herein,we develop oxidation-strengthened prodrug nanosystem loaded with pyropheophorbide a(PPa)to achieve light-activatable cascade drug release and enhance therapeutic efficacy.The disulfide bond-driven prodrug nanosystems not only respond to the redox-heterogeneity in tumor,but also respond to the exogenous oxidant(singlet oxygen)elicited by photosensitizers.Once the prodrug nanoparticles(NPs)are activated under irradiation,they would undergo an oxidative self-strengthened process,resulting in a facilitated drug cascade release.The IC50 value of the PPa@PTX-S-S NPs without irradiation was 2-fold higher than those of NPs plus irradiation.In vivo,the PPa@PTX prodrug NPs display prolonged systemic circulation and increased accumulation in tumor site.The PPa@PTXS-S NPs showed much higher efficiency than free PTX or the PPa@PTX-C-C NPs to suppress the growth of 4 T1 tumors.Therefore,this novel oxidation-strengthened disulfide-bridged prodrug-nanosystem has a great potential in the enhanced efficacy of cancer synergetic photochemotherapy.

Morphine-3-glucuronide upregulates PD-L1 expression via TLR4 and promotes the immune escape of non-small cell lung cancer

Objective:Patients with cancer pain are highly dependent on morphine analgesia,but studies have shown a negative correlation between morphine demand and patient outcomes.The long-term use of morphine may result in abnormally elevated serum morphine-3-glucuronide(M3G)levels.Hence,the effects of M3G on tumor progression are worth studying.Methods:The effects of M3G on PD-L1 expressions in human non-small cell lung cancer(NSCLC)cell lines were first evaluated.Activation of TLR4 downstream pathways after M3G treatment was then determined by Western blot.The effects of M3G on human cytotoxic T lymphocytes(CTL)cytotoxicity and INF-γrelease was also detected.Finally,the LLC murine lung adenocarcinoma cell line were used to establish a murine lung cancer model,and the effects of M3G on tumor growth and metastasis were determined.Results:M3G promoted the expressions of PD-L1 in the A549 and H1299 cell lines in a TLR4-dependent manner(P<0.05).M3G activated the PI3 K and the NFκB signaling pathways,and this effect was antagonized by a TLR4 pathway inhibitor.A PI3 K pathway inhibitor reversed the M3G-mediated PD-L1 upregulation.M3G inhibited the cytotoxicity of CTL on A549 cells and decreased the level of INF-γ.Repeated M3G intraperitoneal injections promoted LLC tumor growth and lung metastasis through the upregulation of tumor expressed PD-L1 and the reduction of CTL in the tumor microenvironment.Conclusions:M3G specifically activated TLR4 in NSCLC cells and upregulated PD-L1 expression through the PI3 K signaling pathway,thereby inhibiting CTL cytotoxicity and finally promoting tumor immune escape.

Application of Bio-organic Fertilizer Containing High-efficient Nitrogen-fixing Bacillus amyloliquefaciens on Strawberry

With strawberry as a test material,the effects of the bio-organic fertilizer containing high-efficiency nitrogen-fixing Bacillus amyloliquefaciens on nutrient contents in strawberry-planted soil,wilt occurrence and strawberry yield and quality were studied by a plot experiment,so as to provide reference for scientific use of the bio-organic fertilizer and green production of strawberry.The results showed that after hole-applying the bio-organic fertilizer at a rate of 22.5 t/hm^2,the contents of NH^+_4-N,available P,available K and organic matter did not change much with time;and when replacing 50%of chemical fertilizers with the bio-organic fertilizer at a rate of 11.25 t/hm^2(K_3),the contents of NH^+_4-N and available P in the soil did not change much with time,and the contents of available K and organic matter decreased slightly with time,but were both higher than the CK(the unfertilized treatment).Meanwhile,the disease index values of strawberry wilt disease in treatments K_2 and K_3were significantly lower than those of the CK and the conventional fertilization treatment(K_1),and the vitamin C contents of strawberry fruit in the two treatments were significantly higher than that of the CK.The yield determination showed that the cumulative yields of treatments K_2 and K_3 increased by 9.8% and 3.3%,respectively,and the increase rates of the early yields(before the Spring Festival)were 30.6% and 21.9%,respectively.Therefore,the application of the bio-organic fertilizer can replace chemical fertilizers,and can achieve the effects of reducing the occurrence of wilt,improving the early yield of fruit commodity and improving fruit quality.

LAL test and RPT for endotoxin detection of CPT-11/DSPE-mPEG_(2000) nanoformulation: What if traditional methods are not applicable?

Endotoxin detection is an important step in drug characterization. Herein we found that a chemotherapeutic drug nanoformulation composed of irinotecan hydrochloride(CPT-11) and an amphiphilic molecule DSPE-mPEG_(2000) can interfere with the limulus amebocyte lysate assay(LAL). Furthermore, the rabbit pyrogen test(RPT) results indicated that at a relatively high dosage, the drug irinotecan hydrochloride can induce a hypothermia effect which may render the RPT results ambiguous in determination of the safety of the drug formulation.Our findings demonstrate limitations of endotoxin detection in micellar drugs,and call for the necessity of developing reliable endotoxin detection methods that can overcome the interference of nanomaterials in order to better ensure the drug safety of patients in future pharmaceutical drug development.

Single nanozyme-based colorimetric biosensor for dopamine with enhanced selectivity via reactivity of oxidation intermediates

Reliable and selective sensing of dopamine(DA)is essential for early diagnosis of mental diseases.Among the various potential methods,nanozyme-based sensing systems have demonstrated promising sensitivity and reliability.However,owing to the lack of substrate specificity,it is challenging to selectively detect DA using nanozymes.Herein,based on the reactivity of the DA oxidation intermediates,we report a cascade colorimetric sensing system for the selective detection of DA using only a single nanozyme.It was disclosed that the oxidation product of DA catalyzed by Co-N-doped carbon sheets(Co-N-C,a common oxidase-like nanozyme),dopamine quinone(DAQ),showed significant biocatalytic electron-donating activity in the reduction of O_(2)to generate O_(2)·-.Further using O_(2)·-to oxidize3,3,5,5-tetramethylbenzidine(TMB),a colorimetric sensing platform for DA was constructed with a linear detection range of 50 nmol/L to 50μmol/L and a low limit of detection of 4 nmol/L.Thanks to the reactivity of the oxidation product,without any biometric units(such as nucleic acids,enzymes,and antibodies/antigens),the reaction selectivity of DA against other interferences(e.g.,ascorbic acid,adrenaline,5-hydroxytryptamine,and glutathione)was enhanced up to 71-fold.Beyond complicated cascade systems requiring at least two nanozymes,sophisticated artificial recognition via multiple interactions was simplified by exploiting the oxidative properties of product intermediates;thus,only a single common oxidase-like nanozyme was needed.This work offers a new strategy to enhance the selectivity of nanozymes for bioanalytical applications.

Crosstalk Between Peripheral Innervation and Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma(PDAC)is a highly aggressive lethal malignancy,characterized by late diagnosis,aggressive growth,and therapy resistance,leading to a poor overall prognosis.Emerging evidence shows that the peripheral nerve is an important non-tumor component in the tumor microenvironment that regulates tumor growth and immune escape.The crosstalk between the neuronal system and PDAC has become a hot research topic that may provide novel mechanisms underlying tumor progression and further uncover promising therapeutic targets.In this review,we highlight the mechanisms of perineural invasion and the role of various types of tumor innervation in the progression of PDAC,summarize the potential signaling pathways modulating the neuronal-cancer interaction,and discuss the current and future therapeutic possibilities for this condition.

High recoverable energy storage density of Na_(0.5)Bi_(0.5)TiO_(3) lead-free ceramics modified by Bi(Mg_(0.5)Hf_(0.5))O_(3)

Enhancing the availability and reliability of dielectric ceramic energy storage devices is of great importance.In this work,(1-x)Na_(0.5)Bi_(0.5)TiO_(3)-xBi(Mg_(0.5)Hf_(0.5))O_(3)(NBT-xBMH)lead-free ceramics were created utilizing a solid-state reaction technique.All NBT-xBMH ceramics have a single perovskite structure.With increasing BMH doping,the grain size shrinks drastically,which greatly enhances the breakdown electric field(310 kV/cm at x=0.25).Additionally,the relaxation behaviors of NBT-xBMH ceramics with high BMH content are more remarkable.Among all designed components,the NBT-0.25BMH ceramic exhibits the best energy storage performance with a high Wrec of 4.63 J/cm^(3) and anηof 75.1%at 310 kV/cm.The NBT-0.25BMH ceramic has exceptional resistance to fluctuations in both frequency(5-500 Hz)and temperature(30-100°C).Charge-discharge test shows that the NBT-0.25BMH ceramic has a quick discharge rate(t0.9<110 ns).With these properties,the NBT-0.25BMH ceramic may have applications in microdevices as well as in ultra-high power electronic systems.

BRSK2 in pancreatic β cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes

Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion andβ-cell biology.However,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been determined.Here,we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population.BRSK2 protein levels are significantly elevated inβcells from T2DM patients and high-fat diet(HFD)-fed mice due to enhanced protein stability.Mice with inducibleβ-cell-specific Brsk2 knockout(βKO)exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions.Moreover,βKO mice are protected from HFD-induced hyperinsulinemia,obesity,insulin resistance,and glucose intolerance.Conversely,gain-of-function BRSK2 in matureβcells reversibly triggers hyperglycemia due toβ-cell hypersecretion-coupled insulin resistance.Mechanistically,BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner.The enhanced basal insulin secretion drives insulin resistance andβ-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 inβcells.These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay betweenβcells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.

外泌体递药系统及其在肿瘤治疗中的应用

癌症是世界上第二大死亡原因,其每年的发病率都很高。尽管现有的治疗方法在过去十年中取得了重大进展。但是由于现有多数抗肿瘤药物具有非特异性细胞毒性、生物相容性差和生物利用度低等缺点,导致化疗等方法的治疗效果较差。外泌体是由多种细胞分泌的囊泡,具有磷脂双层结构和纳米颗粒大小。它具有良好的生物相容性、高稳定性和良好的靶向性。在癌症治疗中,外泌体作为一种潜在有效的药物递送系统已经引起越来越多的关注。本文综述了外泌体作为靶向肿瘤药物载体的设计策略,并试图为基于外泌体的纳米载体在各种肿瘤治疗中的应用提供新的见解。

Optical meta-waveguides for integrated photonics and beyond

The growing maturity of nanofabrication has ushered massive sophisticated optical structures available on a photonic chip.The integration of subwavelength-structured metasurfaces and metamaterials on the canonical building block of optical waveguides is gradually reshaping the landscape of photonic integrated circuits,giving rise to numerous metawaveguides with unprecedented strength in controlling guided electromagnetic waves.Here,we review recent advances in meta-structured waveguides that synergize various functional subwavelength photonic architectures with diverse waveguide platforms,such as dielectric or plasmonic waveguides and optical fibers.Foundational results and representative applications are comprehensively summarized.Brief physical models with explicit design tutorials,either physical intuition-based design methods or computer algorithms-based inverse designs,are cataloged as well.We highlight how meta-optics can infuse new degrees of freedom to waveguide-based devices and systems,by enhancing light-matter interaction strength to drastically boost device performance,or offering a versatile designer media for manipulating light in nanoscale to enable novel functionalities.We further discuss current challenges and outline emerging opportunities of this vibrant field for various applications in photonic integrated circuits,biomedical sensing,artificial intelligence and beyond.

Inverse design of digital nanophotonic devices using the adjoint method

A high-efficiency inverse design of"digital"subwavelength nanophotonic devices using the adjoint method is proposed.We design a single-mode 3dB power divider and a dual-mode demultiplexer to demonstrate the efficiency of the proposed inverse design approach,called the digitized adjoint method,for single-and dual-object optimization,respectively.The optimization comprises three stages:1)continuous variation for an"analog"pattern;2)forced permittivity biasing for a"quasi-digital"pattern;and 3)a multilevel digital pattern.Compared with the conventional brute-force method,the proposed method can improve design efficiency by about five times,and the performance optimization can reach approximately the same level.The method takes advantages of adjoint sensitivity analysis and digital subwavelength structure and creates a new way for the efficient and high-performance design of compact digital subwavelength nanophotonic devices,which could overcome the efficiency bottleneck of the brute-force method,which is restricted by the number of pixels of a digital pattern,and improve the device performance by extending a conventional binary pattern to a multilevel one.

Erythrocyte membrane-camouflaged carrier-free nanoassembly of FRET photosensitizer pairs with high therapeutic efficiency and high security for programmed cancer synergistic phototherapy

Phototherapy has been intensively investigated as a non-invasive cancer treatment option.However,its clinical translation is still impeded by unsatisfactory therapeutic efficacy and severe phototoxicity.To achieve high therapeutic efficiency and high security,a nanoassembly of Forster Resonance Energy Transfer(FRET)photosensitizer pairs is developed on basis of dual-mode photosensitizer co-loading and photocaging strategy.For proof-of-concept,an erythrocyte-camouflaged FRET pair co-assembly of chlorine e6(Ce6,FRET donor)and 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide(DiR,FRET acceptor)is investigated for breast cancer treatment.Notably,Ce6 in the nanoassemby is quenched by DiR and could be unlocked for photodynamic therapy(PDT)only when DiR is photobleached by 808-nm laser.As a result,Ce6-caused phototoxicity could be well controlled.Under cascaded laser irradiation(808-660 nm),tumor-localizing temperature rise following laser irradiation on DiR not only induces tumor cell apoptosis but also facilitates the tumor penetration of NPs,relieves tumor hypoxia,and promotes the PDT efficacy of Ce6.Such FRET pair-based nanoassembly provides a new strategy for developing multimodal phototherapy nanomedicines with high efficiency and good security.

Evaluation of thermophoretic effects on graphite dust coagulation in high-temperature gas-cooled reactors

In high-temperature gas-cooled reactors,graphite dust particles within the reactor core and the heat transfer equipment experience large temperature gradients.Under such conditions,thermophoresis may play an important role in determining aerosol evolution.This study presents a theoretical and numerical analysis of the thermophoretic effects on aerosol coagulation within these reactors.The coagulation rates for Brownian versus thermophoretic coagulation are calculated and compared for various temperature gradients.Our results show that thermophoretic coagulation dominates over Brownian coagulation for large temperature gradients.We defined an enhancement factor to evaluate the role of thermophoretic coagulation under various reactor conditions.The enhancement factor increased dramatically with increasing temperature gradient,decreasing pressure and increasing particle diameter,but was not very sensitive to temperature change.The time evolution of the particle size distribution related to combined Brownian and thermophoretic coagulation was simulated using a log-skew-normal method of moments.The simulation results indicate that aerosol evolution can be strongly accelerated by thermophoretic coagulation under large temperature gradients.

Cdx1b protects intestinal cell fate by repressing signaling networks for liver specification

In mammals,the expression of the homeobox family member Cdx2/CDX2 is restricted within the intestine.Conditional ablation of the mouse Cdx2 in the endodermal cells causes a homeotic transformation of the intestine towards the esophagus or gastric fate.In this report,we show that null mutants of zebrafish cdx1b,encoding the counterpart of mammalian CDX2,could survive more than 10 days post fertilization,a stage when the zebrafish digestive system has been well developed.Through RNA sequencing(RNA-seq)and single-cell sequencing(sc RNA-seq)of the dissected intestine from the mutant embryos,we demonstrate that the loss-of-function of the zebrafish cdx1b yields hepatocyte-like intestinal cells,a phenotype never observed in the mouse model.Further RNA-seq data analysis,and genetic double mutants and signaling inhibitor studies reveal that Cdx1b functions to guard the intestinal fate by repressing,directly or indirectly,a range of transcriptional factors and signaling pathways for liver specification.Finally,we demonstrate that heat shock-induced overexpression of cdx1b in a transgenic fish abolishes the liver formation.Therefore,we demonstrate that Cdx1b is a key repressor of hepatic fate during the intestine specification in zebrafish.