Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

Design of pH-responsive antimicrobial peptide melittin analog-camptothecin conjugates for tumor therapy

Melittin,a classical antimicrobial peptide,is a highly potent antitumor agent.However,its significant toxicity seriously hampers its application in tumor therapy.In this study,we developed novel melittin analogs with pH-responsive,cell-penetrating and membranelytic activities by replacing arginine and lysine with histidine.After conjugation with camptothecin(CPT),CPT-AAM-1 and CPT-AAM-2 were capable of killing tumor cells by releasing CPT at low concentrations and disrupting cell membranes at high concentrations under acidic conditions.Notably,we found that the C-terminus of the melittin analogs was more suitable for drug conjugation than the N-terminus.CPT-AAM-1 significantly suppressed melanoma growth in vivo with relatively low toxicity.Collectively,the present study demonstrates that the development of antitumor drugs based on pH-responsive antimicrobial peptide-drug conjugates is a promising strategy.

A Stable Open-Shell Conjugated Diradical Polymer with Ultra-High Photothermal Conversion Efficiency for NIR-Ⅱ Photo-Immunotherapy of Metastatic Tumor

Massive efforts have been concentrated on the advance of eminent near-infrared(NIR) photothermal materials(PTMs) in the NIR-Ⅱ window(1000–1700 nm), especially organic PTMs because of their intrinsic biological safety compared with inorganic PTMs. However, so far, only a few NIR-Ⅱresponsive organic PTMs was explored, and their photothermal conversion efficiencies(PCEs) still remain relatively low. Herein, donor–acceptor conjugated diradical polymers with open-shell characteristics are explored for synergistically photothermal immunotherapy of metastatic tumors in the NIR-Ⅱ window. By employing side-chain regulation, the conjugated diradical polymer TTB-2 with obvious NIR-Ⅱ absorption was developed, and its nanoparticles realize a record-breaking PCE of 87.7% upon NIR-Ⅱ light illustration. In vitro and in vivo experiments demonstrate that TTB-2 nanoparticles show good tumor photoablation with navigation of photoacoustic imaging in the NIR-Ⅱ window, without any side-effect. Moreover, by combining with PD-1 antibody,the pulmonary metastasis of breast cancer is high-effectively prevented by the efficient photo-immunity effect. Thus, this study explores superior PTMs for cancer metastasis theranostics in the NIR-Ⅱ window, offering a new horizon in developing radical-characteristic NIR-Ⅱ photothermal materials.

Effect of electron-electron interaction on polarization process of exciton and biexciton in conjugated polymer

By using one-dimensional tight-binding model modified to include electron-electric field interaction and electron-electron interaction,we theoretically explore the polarization process of exciton and biexciton in cis-polyacetylene.The dynamical simulation is performed by adopting the non-adiabatic evolution approach.The results show that under the effect of moderate electric field,when the strength of electron-electron interaction is weak,the singlet exciton is stable but its polarization presents obvious oscillation.With the enhancement of interaction,it is dissociated into polaron pairs,the spin-flip of which can be observed through modulating the interaction strength.For the triplet exciton,the strong electron-electron interaction restrains its normal polarization,but it is still stable.In the case of biexciton,the strong electron-electron interaction not only dissociate it,but also flip its charge distribution.The yield of the possible states formed after the dissociation of exciton and biexciton is also calculated.

Optimization of the Process for Preparing Bivalent Polysaccharide Conjugates to Develop Multivalent Conjugate Vaccines against Streptococcus pneumoniae or Neisseria meningitidis and Comparison with the Corresponding Licensed Vaccines in Animal Models

Objective:This study aimed to describe,optimize and evaluate a method for preparing multivalent conjugate vaccines by simultaneous conjugation of two different bacterial capsular polysaccharides(CPs)with tetanus toxoid(TT)as bivalent conjugates.Methods:Different molecular weights(MWs)of polysaccharides,activating agents and capsular polysaccharide/protein(CP/Pro)ratio that may influence conjugation and immunogenicity were investigated and optimized to prepare the bivalent conjugate bulk.Using the described method and optimized parameters,a 20-valent pneumococcal conjugate vaccine and a bivalent meningococcal vaccine were developed and their effectiveness was compared to that of corresponding licensed vaccines in rabbit or mouse models.Results:The immunogenicity test revealed that polysaccharides with lower MWs were better for Pn1-TT-Pn3 and MenA-TT-MenC,while higher MWs were superior for Pn4-TT-Pn14,Pn6A-TT-Pn6B,Pn7F-TT-Pn23F and Pn8-TT-Pn11A.For activating polysaccharides,1-cyano-4-dimethylaminopyridinium tetrafluoroborate(CDAP)was superior to cyanogen bromide(CNBr),but for Pn1,Pn3 and MenC,N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride(EDAC)was the most suitable option.For Pn6A-TT-Pn6B and Pn8-TT-Pn11A,rabbits immunized with bivalent conjugates with lower CP/Pro ratios showed significantly stronger CP-specific antibody responses,while for Pn4-TT-Pn14,higher CP/Pro ratio was better.Instead of interfering with the respective immunological activity,our bivalent conjugates usually induced higher IgG titers than their monovalent counterparts.Conclusion:The result indicated that the described conjugation technique was feasible and efficacious to prepare glycoconjugate vaccines,laying a solid foundation for developing extended-valent multivalent or combined conjugate vaccines without potentially decreased immune function.

Three-Dimensional Conjugate Tooth Surface Design and Contact Analysis of Harmonic Drive with Double-Circular-Arc Tooth Profle

A three-dimensional conjugate tooth surface design method for Harmonic Drive with a double-circular-arc tooth profle is proposed. The radial deformation function of the fexspline (FS), obtained through Finite Element (FE) analysis, is incorporated into the kinematics model. By analyzing the FS tooth enveloping process, the optimization of the overlapping conjugate tooth profle is achieved. By utilizing the hobbing process, the three-dimensional machinable tooth surface of FS can be acquired. Utilizing the coning deformation of the FS, simulations are conducted to analyze the multi-section assembly and meshing motion of the machinable tooth surface. The FE method is utilized to analyze and compare the loaded contact characteristics. Results demonstrate that the proposed design method can achieve an internal gear pair consisting of a circular spline with a spur gear tooth surface and the FS with a machinable tooth surface. With the rated torque, approximately 24% of the FS teeth are engaged in meshing, and more than 4/5 of the tooth surface in the axial direction carries the load. The contact patterns, maximum contact pressure, and transmission error of the machinable tooth surface are 227.2%, 40.67%, and 71.24% of those on the spur gear tooth surface, respectively. It clearly demonstrates exceptional transmission performance.

Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy

Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted therapy.However,metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and heterogeneity.Herein,choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types,and a choline-modified strategy for small molecule-drug conjugates(SMDCs)design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy,instead of directly inhibiting choline metabolism.As a proof-of-concept,choline-modified SMDCs were designed,screened,and investigated for their druggability in vitro and in vivo.This strategy improved tumor targeting,preserved tumor inhibition and reduced toxicity of paclitaxel,through targeted drug delivery to tumor by highly expressed choline transporters,and site-specific release by carboxylesterase.This study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.

High Level of Ubiquitin Conjugate Enzyme E2O Indicates Poor Prognosis of Patients with Hepatocellular Carcinoma

Objective Ubiquitin conjugate enzyme E2O(UBE2O)is a ubiquitin-conjugating enzyme that has been reported to be involved in tumorigenesis.This study investigated the role of UBE2O in hepatocellular carcinoma(HCC).Methods The expression of UBE2O was detected using qRT-PCR,Western blotting,and immunohistochemical staining.Cell proliferation and Transwell assays were used to detect proliferation,migration,and invasion of HCC cells,respectively.Bioinformatic analysis was performed to analyze the relationship between UBE2O and the clinical features,prognosis,and immune cell infiltration of HCC.Results UBE2O was significantly over-expressed in HCC tissues.High expression of UBE2O was associated with poor tumor grade and poor prognosis.Functional experiments showed that down-regulation of UBE2O inhibited HCC cell proliferation,migration,and invasion.Co-expression gene analysis and gene set enrichment analysis showed that UBE2O was associated with protein hydrolysis,cell cycle,and cancer-related pathways in HCC.The results of immune analysis revealed that the expression of UBE2O was positively correlated with the immune infiltration and expression of immune-related chemokines of HCC.Conclusions UBE2O is significantly correlated with the prognosis of HCC and may be a valuable prognostic biomarker for HCC.

When insulating polymers meet conjugated polymers:the noncovalent bonding does matter

Insulating polymers are characterized by a predominantlyσ-covalent structure,which localize electrons in the atoms and exhibit dielectricity.Insulating polymers typically adopt a more linear and extended conformation,as the repeating units are connected by single covalent bonds,resulting in a relatively straight and extended chain structure.For most insulating polymers,the contour length(L_(c))is significantly larger than their persistence length(Lp)due to the rotation of C−C single bonds(Fig.1(a)).Consequently,this leads to a flexible,random-coil chain conformation.This structural feature contributes to the great mechanical durability and resistance to crack initiation during stretching or bending processes.In contrast,conjugated polymers possess aπ-conjugated molecular structure,allowing electron mobility along the main chain,called delocalization,which imparts semiconducting properties[1,2].The presence of rigid,alternating single and multiple bonds results in comparable Lc and Lp,thereby yielding a stiff or semi-flexible conformation(Fig.1(b))[3,4].As a consequence,most conjugated polymers are prone to fracture under low strain levels(<10%)[5−7].

Gas‐phase fluorination of conjugated microporous polymer microspheres for effective interfacial stabilization in lithium metal anodes

Lithium(Li)metal anodes have attracted extensive attention due to their ultrahigh theoretical capacity and low potential.However,the uneven deposition of Li near the unstable electrode/electrolyte interfaces leads to the growth of Li dendrites and the degradation of active electrodes.Herein,we directly fluorinate alkyne-containing conjugated microporous polymers(ACMPs)microspheres with fluorine gas(F_(2))to introduce a novel fluorinated interlayer as an interfacial stabilizer in lithium metal batteries.Using density functional theory methods,it is found that as-prepared fluorinated ACMP(FACMP)has abundant partially ionic C–F bonds.The C–F bonds with electrochemical lability yield remarkable lithiophilicity during cycling.The in situ reactions between the active C–F bonds and Li ions enable transfer of lithium fluoride microcrystals to the solid electrolyte interphase(SEI)layers,guaranteeing effective ionic distribution and smooth Li deposition.Consequently,Li metal electrodes with the fluorinated interlayers demonstrate excellent cycling performances in both half-batteries and full cells with a lithium bis(trifluoromethanesulfonyl)imide electrolyte as well as a nonfluorinated lithium bis(oxalate)borate electrolyte system.This strategy is highly significant in customizable SEI layers to stabilize electrode interfaces and ensure high utilization of Li metal anodes,especially in a nonfluorinated electrolyte.

Activating coordinative conjugated polymer via interfacial electron transfer for efficient CO_(2) electroreduction

With tunable local electronic environment,high mass density of MN4sites,and ease of preparation,metal-organic conjugated coordinative polymer(CCP) with inherent electronic conductivity provides a promising alternative to the well-known M-N-C electrocatalysts.Herein,the coordination reaction between Cu^(2+)and 1,2,4,5-tetraaminobenzene(TAB) was conducted on the surface of metallic Cu nanowires,forming a thin layer of CuN4-based CCP(Cu-TAB) on the Cu nanowire.More importantly,interfacial transfer of electrons from Cu core to the CuN4-based CCP nanoshell was observed within the resulting CuTAB@Cu,which was found to enrich the local electronic density of the CuN4sites.As such,the CuTAB@Cu demonstrates much improved affinity to the*COOH intermediate formed from the rate determining step;the energy barrier for C-C coupling,which is critical to convert CO_(2)into C2products,is also decreased.Accordingly,it delivers a current density of-9.1 mA cm^(-2)at a potential as high as 0.558 V(vs.RHE) in H-type cell and a Faraday efficiency of 46.4% for ethanol.This work emphasizes the profound role of interfacial interaction in tuning the local electronic structure and activating the CuN4-based CCPs for efficient electroreduction of CO_(2).

Cobalt phthalocyanine-based conjugated polymer as efficient and exclusive electrocatalyst for CO_(2) reduction to ethanol

Electrocatalytic conversion of carbon dioxide to high value-added chemicals is a promising method for solving the energy crisis and global warming.Electrochemical active metal-containing conjugated polymers have been widely studied for heterogeneous carbon dioxide reduction.In the present contribution,we designed and synthesized a stable cobalt phthalocyanine-based conjugated polymer,named CoPPc-TFPPy-CP,and also explored its electro-catalytic application in carbon dioxide reduction to liquid products in an aqueous solution.In the catalyst,cobalt phthalocyanine acts as building blocks connected with 1,3,6,8-tetrakis(4-formyl phenyl)pyrenes via imine-linkages,leading to mesoporous formation polymers with the pore size centered at 4.1nm.And the central co-balt atoms shifted to a higher oxidation state after condensation.With these chemical and structural natures,the catalyst displayed a remarkable electrocatalytic CO_(2) reduction performance with an ethanol Faradaic efficiency of 43.25%at-1.0V vs RHE.While at the same time,the electrochemical reduction process catalyzed by cobalt phthalocyanine produced only carbon monoxide and hydrogen.To the best of our knowledge,CoPPc-TFPPy-CP is the first example among organic polymers and metal-organic frameworks that produces ethanol from CO_(2) with a remarkable selectivity.

The ABC of ADCs (Antibody-Drug Conjugates): A Comprehensive Review of Technical, Regulatory, and Clinical Challenges

Over the past several decades, there has been a significant surge in the development of Antibody-Drug Conjugates (ADCs). Designing an ideal ADC presents a multifaceted challenge, requiring the precise orchestration of various elements such as antigens, antibodies, linkers, and payloads. While ADCs aim to target tumor cells specifically, several antigens can also be found in regular tissues, potentially compromising the specificity of ADCs in therapeutic applications. The complexity extends to antibody selection, necessitating effective targeting of the desired antigen and ensuring compatibility with linkers for effective payload delivery. Additionally, the linker and payload combination are critical for the ADC’s therapeutic efficiency, balancing stability in circulation and timely payload release upon target binding. ADC doses must be safe for normal tissues while ensuring the released payloads are effective. The success of ADCs is attributed to their unmatched efficacy compared to traditional chemotherapy agents. The current research article aims to provide a technical review of Antibody-Drug Conjugates (ADCs) for cancer therapies. A brief discussion on the basics of ADCs, regulatory approach, overview, and technical complexities for quantification is presented. This review also summarizes recently approved ADCs and introduces the concepts of antibodies, linkers, and payloads. The article also outlines cancer-specific ADCs currently in late-stage clinical trials for cancer treatment.

Antibody-Drug Conjugates (ADCs): Navigating Four Pillars of Safety, Development, Supply Chain and Manufacturing Excellence

Antibody-drug conjugates (ADCs) are pioneering biologics that merge antibodies’ specificity with small molecules’ potency. With a handful of FDA-approved ADCs in the market and many under development, ADCs are poised to revolutionize therapeutics. This paper examines the complexities of ADC production, emphasizing the importance of process characterization and the pivotal role of supply chain characteristics, safety requirements, and Contract Manufacturing Organizations (CMOs) with proficiency. The swift transition of antibody-drug conjugate (ADC) programs from early to advanced clinical stages underscores the urgency for quick and efficient commercial launch preparation. This article delves into strategies to hasten commercial readiness, supply chain strategy, the significance of partnering with adept contract development and manufacturing organizations (CDMOs), and the challenges of ADC production.

Classification of Hallux Valgus Using Conjugated Deformity

Hallux valgus is a complex deformity of the forefoot. It is the result of multiple effects of endogenous and exogenous etiological factors with different degrees of influence. The degree of hallux valgus deformity was assessed by radiological values of hallux valgus (HVA) and intermetatarsal (IMA) angle. Thus, each hallux valgus deformity corresponds to a pair (HVA, IMA) of hallux valgus angle (HVA) and intermetatarsal angle (IMA) values in the plane of the deformity. The intensity of the point position vector S (HVA, IMA) in the deformation plane determined by the relation represents the absolute (conjugate) value of the power deformities. The goal of the article is to explain the advantage of the definition of the degree of hallux valgus deformity using its absolute (conjugate) value, and then to show that the degree of deformity defined in this way enables a better classification of deformities for all values of the HVA and IMA angles. Furthermore, in this article, applying the definition of conjugate deformity, analytical expressions were constructed for the assessment of the average value of deformity correction after operative treatment, as well as the error assessment of deformity correction after operative treatment. All obtained results were checked on a sample of 396 operatively treated feet.

共轭亚油酸对高脂饮食肥胖小鼠肠道微生物菌群的影响

目的探讨共轭亚油酸(CLA)对肥胖小鼠肠道菌群的影响。方法24只LDLR^(-/-)雄鼠随机分成3组,每组8只:选择普通饲料喂养正常组小鼠,喂养生理盐水;选择高脂饲料喂养高脂组小鼠,应用生理盐水灌胃;选择高脂饲料喂养干预组小鼠,应用CLA灌胃。所有小鼠均正常喂养16周,每2周记录小鼠体重,第15周进行口服葡萄糖耐量试验(OGTT)。取小鼠眼球血进行血清中脂质和胰岛素指标检测;采用RT-PCR分析回肠中炎症因子和肠道闭锁小带蛋白-1(ZO-1)、闭锁蛋白(Ocln)在mRNA水平的相对表达量;采用16S rDNA高通量测序法分析小鼠肠道菌群的变化。结果相对于正常组,高脂组小鼠的体重明显增加、糖脂代谢紊乱、回肠炎症水平增加和肠道微生物菌群紊乱。CLA干预后,干预组小鼠体重下降(P=0.025),糖脂代谢紊乱改善,回肠炎症因子Toll样受体4(TLR4)和肿瘤坏死因子-α(TNF-α)相对表达量明显下降(P<0.001),肠道紧密连接蛋白ZO-1(P=0.006)和Ocln(P=0.004)相对表达量增加,厚壁菌门和双歧杆菌丰度增加。结论CLA可能通过改善高脂饮食诱导的肥胖小鼠的肠道菌群结构与功能,提高肠道双歧杆菌和厚壁菌门的丰度,减轻高脂组小鼠的体重、平衡紊乱的糖脂代谢、降低肠内炎症因子的表达及恢复受损的肠黏膜屏障。

一种腰部为椭圆线的罗茨真空泵转子型线设计与分析

转子作为罗茨泵的关键零部件之一,对产品的整机性能具有重要影响,而转子设计的核心是转子型线的设计。本文以腰部椭圆线为基础开展转子型线设计,转子位于节圆内的型线由椭圆线构成,位于节圆外的型线由椭圆线的共轭曲线组成。设计中首先确定位于腰部的椭圆线及其啮合角,然后应用两个转子间的啮合关系,分析求解型线位于节圆外的共轭曲线,从而获得整个转子型线。最后,设计了抽速为70 L/s的罗茨泵转子,并分析了转子容积利用率与独立可变参数的关系。该型线与顶部为椭圆线的转子型线相比,容积利用率可大于50%,优势明显。

共轭回转式电火花精密加工工艺及其展望

回顾了电火花精密加工工艺的提出及其实现四类技术条件和回转式电火花加工的发展演变过程,着重介绍了共轭回转式电火花精密加工工艺的基本原理及其工艺特点,展示了应用回转式电火花精密加工的典型零件,并对回转式电火花精密加工进行技术展望。

基于区域构造应力场探讨2014年鲁甸地震余震活动发生在共轭断裂上的原因

2014年8月3日云南省昭通市鲁甸县发生MS6.5地震。该事件的特殊之处在于余震活动表现在共轭的昭通-鲁甸断裂和包谷垴-小河断裂上。为了从应力角度探究地震活动发生在2条断裂上的原因及确定主震发生在哪条断裂上,文中首先搜集了鲁甸地震周围的震源机制数据,求解了区域构造应力场,然后采用新发展的模糊聚类断层面拟合法获得了地震2条断层的产状参数:NNW-SSE向分支的走向和倾角分别为336.67°和88.41°,近EW向分支的走向和倾角分别为266.10°和86.42°。之后,将应力场投影到2条断层面上,发现包谷垴-小河断裂和昭通-鲁甸断裂的相对剪应力都很大,说明2条断层均可能发生地震活动。相比之下,包谷垴-小河断裂处的相对剪应力更大,可能预示着包谷垴-小河断裂的地震活动比昭通-鲁甸断裂更强烈。上述分析得到了2条断层上地震活动的M-T图和总体地震矩的支持。

贝叶斯统计中共轭先验分布的教学研究

先验分布在贝叶斯统计中扮演着关键角色,而共轭先验则是其中最为重要的一种。学生对共轭先验分布的理解和掌握程度直接影响他们对贝叶斯统计方法的学习效果。目前的大多数教材通常是先介绍一些常见分布的共轭先验,然后再证明其共轭性质。然而,这种教学方法缺乏深度和灵活性。为了解决这个问题,本文提出在更广泛的指数族分布下,给出参数共轭先验的一般表达形式。接着,针对一些常见分布,通过从指数分布族结构推导出其待估参数的共轭先验,使得学生不仅能深刻理解共轭先验的本质,还能学到一种更为灵活的共轭先验选择策略。这种从一般到具体的教学方法有助于提高学生对贝叶斯统计的理解深度,并培养学生灵活运用共轭先验的能力。