Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia

Objective:In B-cell acute lymphoblastic leukemia(B-ALL),current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50%of cases,underscoring the urgent need for new therapeutic regimens for this patient population.The present study aimed to determine whether HZX-02-059,a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase(PIKfyve)and tubulin,is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients.Methods:Cell proliferation,vacuolization,apoptosis,cell cycle,and in-vivo tumor growth were evaluated.In addition,Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL.Results:HZX-02-059 was found to inhibit cell proliferation,induce vacuolization,promote apoptosis,block the cell cycle,and reduce in-vivo tumor growth.Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase(PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations.Conclusion:Overall,these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.

Dual-targeted treatment for inflammatory bowel disease:Whether fecal microbiota transplantation can be an important part of it

Inflammatory bowel disease(IBD)is a chronic gastrointestinal inflammatory disease.With the emergence of biologics and other therapeutic methods,two biologics or one biologic combined with a novel small-molecule drug has been proposed in recent years to treat IBD.Although treatment strategies for IBD are being optimized,their efficacy and risks still warrant further consideration.This editorial explores the current risks associated with dual-targeted treatment for IBD and the great potential that fecal microbiota transplantation(FMT)may have for use in combination therapy for IBD.We are focused on addressing refractory IBD or biologically resistant IBD based on currently available dual-targeted treatment by incorporating FMT as part of this dual-targeted treatment.In this new therapy regimen,FMT represents a promising combination therapy.

Comprehensive Online Management Based on Cloud Platform for Breast Cancer Patients Using Dual-Targeted Therapy with Macromolecular Monoclonal Antibodies

Objective: The purpose of the study was to explore the application effects of the cloud platform-based comprehensive online management for breast cancer patients using dual-targeted therapy with macromolecular monoclonal antibodies. Methods: 120 breast cancer patients treated by dual-targeted therapy with macromolecular monoclonal antibodies were managed by a cloud platform from March to November 2019. Comprehensive online management included consultation about drugs and side effects and frequently asked questions in the dual-targeted therapy with macromolecular monoclonal antibodies. Results: In the consultation about drugs and side effects, there were five patients with fever, neutrophil, cough, and fatigue;24 with diarrhea;25 with nausea;11 with oral mucosal inflammation;10 with rashes and dry skin;8 with insomnia;and 1 with palpitation. Moreover, 110 patients with anxiety about the missed or delayed treatment were properly handled. Conclusion: The comprehensive online management of dual-targeted therapy with macromolecular monoclonal antibodies based on the cloud platform is helpful to satisfy the at-home breast cancer patients’ needs, ensure the continuity of dual-targeted therapy with macromolecular monoclonal antibodies for breast cancer patients, prevent misinformation, alleviate patients’ negative psychological emotions, and reduce patients’ economic losses. The online cloud platform integrated management model is crucial for managing patients with breast cancer treated by dual-targeted therapy.

Engineered a dual-targeting HA-TPP/A nanoparticle for combination therapy against KRAS-TP53 co-mutation in gastrointestinal cancers

KRAS-TP53 co-mutation is strongly associated with poor prognosis and high malignancy in gastrointestinal cancers.Therefore,a novel approach to oncotherapy may lie in combination therapy targeting both KRAS and TP53.Herein,we present a novel self-assembled nanoparticle(HA-TPP/A)that are functionalized nano-carrier hyaluronic acid(HA)-TPP conjugate(HA-TPP)to degrade mutant p53 proteins(mutp53)and co-deliver AMG510 for treating KRAS-TP53 co-alteration of gastrointestinal cancers by inhibiting the mutant KRAS and mutp53 signaling pathways.The HA-TPP/A nanoparticles led to ubiquitination-dependent proteasomal degradation of mutp53 by targeting damage to mitochondria.Furthermore,these nanoparticles abrogated the gain-of-function(GOF)phenotypes of mutp53 and increased sensitivity to AMG510-induced cell killing,thereby reducing cell proliferation and migration in gastrointestinal cancer with KRAS-TP53 co-mutation.The co-loaded HA-TPP/A nanoparticles demonstrated remarkable therapeutic efficacy in a tumor-bearing mouse model,particularly in KRAS-TP53 double mutant expressing cancer cells,compared with single drug and combined free drug groups.Notably,HA-TPP/A is the first reported nanoparticle with an ability to co-target KRAS-TP53,providing a promising approach for therapy in highly malignant gastrointestinal tumors and potentially expanding clinical indications for AMG510 targeted therapies in gastrointestinal tumors.

Dual-targeting nanovesicles enhance specificity to dynamic tumor cells in vitro and in vivo via manipulation of αvβ3-ligand binding

The dynamic or flowing tumor cells just as leukemia cells and circulating tumor cells face a microenvironment difference from the solid tumors,and the related targeting nanomedicines are rarely reported.The existence of fluidic shear stress in blood circulation seems not favorable for the binding of ligand modified nanodrugs with their target receptor.Namely,the binding feature is very essential in this case.Herein,we utilized HSPC,PEG-DSPE,cholesterol and two avb3 ligands(RGDm7 and DT4)with different binding rates to build dual-targeting nanovesicles,in an effort to achieve a"fast-binding/slow-unbinding"function.It was demonstrated that the dual-targeting nanovesicles actualized effi-cient cellular uptake and antitumor effect in vitro both for static and dynamic tumor cells.Besides,the potency of the dual-targeting vesicles for flowing tumor cells was better than that for static tumor cells.Then,a tumor metastasis mice model and a leukemia mice model were established to detect the killing ability of the drug-loaded dual-targeting vesicles to dynamic tumor cells in vivo.The therapy efficacy of the dual-targeting system was higher than other controls including single-targeting ones.Generally,it seems possible to strengthen drug-targeting to dynamic tumor cells via the control of ligandereceptor interaction.

Membrane dual-targeting probes:A promising strategy for fluorescence-guided prostate cancer surgery and lymph node metastases detection

Fluorescence-guided surgery(FGS)with tumor-targeted imaging agents,particularly those using the near-infrared wavelength,has emerged as a real-time technique to highlight the tumor location and margins during a surgical procedure.For accurate visualization of prostate cancer(PCa)boundary and lymphatic metastasis,we developed a new approach involving an efficient self-quenched near-infrared fluorescence probe,Cy-KUE-OA,with dual PCa-membrane affinity.Cy-KUE-OA specifically targeted the prostate-specific membrane antigen(PSMA),anchored into the phospholipids of the cell membrane of PCa cells and consequently showed a strong Cy7-de-quenching effect.This dual–membrane-targeting probe allowed us to detect PSMA-expressing PCa cells both in vitro and in vivo and enabled clear visualization of the tumor boundary during fluorescence-guided laparoscopic surgery in PCa mouse models.Furthermore,the high PCa preference of Cy-KUE-OA was confirmed on surgically resected patient specimens of healthy tissues,PCa,and lymph node metastases.Taken together,our results serve as a bridge between preclinical and clinical research in FGS of PCa and lay a solid foundation for further clinical research.

Tumor and dendritic cell dual-targeting nanocarriers maximize the therapeutic potential of IDO1 inhibitor in vivo

Researches on indoleamine-2,3-dioxygenase-1(IDO1),a neoplastic pathogenesis-related protein,have provided a new angle of view to regulate malignancy-related immunosuppression.However,the therapeutic efficacy of IDO1 inhibitors is subject to key limitations as both cancer and dendritic cells tend to be trapped in the IDO1-mediated immune dysfunction,which poses challenges to the inhibitory potency of drug regimens in multiple targets.Here,we report on the fabrication technique of a biomimetic nanocarrier that is endowed with the whole array of cancer cell membrane proteins for encapsulating the most used IDO1 probe indoximod(IND).By fully utilizing the homologous adhesion proteins and antigenic motifs on cytomembrane,these nanoparticulate particles are capable of infiltrating tumors and actively accumulating in cancer and dendritic cells,as well as hitching a ride on dendritic cells to tumor-draining lymph nodes.Ultimately,by increasing the distribution of drugs in both tumor cells and dendritic cells in tumor-draining lymph nodes,these formulations greatly enhance the efficacy of IND without the aid of chemotherapeutic drugs,achieving substantial control of tumor growth.Overall,this leverage of bionanotechnology maximizes the therapeutic potential of IND and can provide a theoretical reference for the clinical application of IDO1 inhibitors.

双碳目标下徐州农村住宅节能潜力及改造策略研究

本研究针对徐州农村住宅在双碳目标背景下的节能现状与改造策略进行深入分析。研究发现,徐州农村住宅普遍存在保温性能不足、门窗气密性差、遮阳系统不完善及能源使用单一等问题,节能潜力巨大。为充分开发徐州农村住宅的节能潜力,本研究提出了一系列节能改造措施,包括改善围护结构、提升门窗气密性、优化遮阳系统及提高能源使用效率等。同时,强调了提升居民节能意识和技术支持的重要性。本研究旨在为农村住宅节能改造提供实践指导,促进可持续发展。

A dual-targeted multifunctional nanoformulation for potential prevention and therapy of Alzheimer’s disease

Antioxidation and adjustable treatment strategies are critical for the effective treatment of Alzheimer’s disease(AD).Here,we design a dual-targeted Prussian blue nanoformulation(PTCN)that can cross the blood-brain barrier and target amyloid beta aggregates further exert antioxidant effects.An adjustable gradient dosing strategy with PTCN is used for the first time to design the preventive and therapeutic trials based on the severity of oxidative stress at different AD stages.The results show that PTCN could effectively ameliorate AD-related pathological processes,improve the cognitive decline,and rescue hippocampal atrophy of APP/PS1 mice in both preventive and therapeutic trials.Altogether,PTCN provided here is a successful combination of three traditional biomaterials with good biosafety,which has broad prospects for the early prevention,mild remission,and late treatment of AD,and is expected to be developed into personalized therapeutic drugs and healthcare products for clinical AD in the future.

考虑多能耦合的虚拟电厂优化运行模型与策略研究

针对可再生能源大规模接入电网背景下引发的能源供需失衡、运营效率低下等问题,提出了一种考虑园区多能耦合特性的虚拟电厂(VPP)运行优化模型。基于提出的面向多能耦合园区虚拟电厂的基础概念,建立了考虑多能耦合特性的虚拟电厂各类能源系统的功率平衡模型,可兼顾园区多能源经济运行与新能源消纳的需求;基于功率平衡模型建立多能耦合虚拟电厂的优化运行模型,并采用混合整数线性规划进行求解;基于引入了多能耦合设备的VPP进行仿真分析,验证了上述模型在提高园区异质能源综合利用率、降低运营成本、提升率等方面具有显著优势。

双模态成像仿生纳米粒对甲状腺髓样癌的声动力治疗

背景:声动力疗法作为一种新型抗肿瘤治疗手段具有非侵入性和时空可控性的特点,在甲状腺髓样癌无创性治疗中具有广阔的应用前景。目的:制备具有双模态成像能力的仿生癌细胞膜涂层脂质纳米粒,检测纳米粒的理化性质、靶向能力、成像效果、细胞毒性和抗迁移能力。方法:以二棕榈酰磷脂酰胆碱、二棕榈酰磷脂酰甘油、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000、胆固醇、血卟啉单甲醚、全氟己烷为原料,通过薄膜水合-超声振荡法制备脂质纳米粒HP@LNP,其中血卟啉单甲醚装载于脂质纳米结构的疏水层,全氟己烷装载于脂质纳米结构的亲水核心层内;将甲状腺髓样癌细胞膜包覆于脂质纳米粒HP@LNP表面,构建具有主动靶向甲状腺髓样癌细胞能力的仿生脂质纳米粒MHP@LNP。表征纳米粒MHP@LNP的理化性质、靶向能力、免疫逃逸能力、成像效果、细胞毒性和抗迁移能力。结果与结论:①脂质纳米粒MHP@LNP呈现典型的核壳结构,粒径为131.06 nm,平均电位为-30.59 mV,凝胶电泳结果显示脂质纳米粒MHP@LNP与癌细胞膜蛋白图谱相符合,荧光共定位结果显示脂质纳米粒MHP@LNP与癌细胞膜的荧光信号显著重合。脂质纳米粒MHP@LNP纳米粒内血卟啉单甲醚的包封率为87.8%,载药率为14.6%。在低强度聚焦超声刺激下,脂质纳米粒MHP@LNP可发生相变产生微泡,在4 min时超声信号强度达到最大值。在激光照射下,脂质纳米粒MHP@LNP的光声信号强度与其质量浓度呈现线性相关。脂质纳米粒MHP@LNP具有同源细胞靶向能力和免疫逃逸能力。未经低强度聚焦超声照射前的脂质纳米粒MHP@LNP具有良好的生物相容性,而经低强度聚焦超声照射后产生具有细胞毒性的活性氧,有效杀伤甲状腺髓样癌细胞,并抑制甲状腺髓样癌细胞的迁移能力。②结果表明,脂质纳米粒MHP@LNP能够在超声和光声双模态成像引导下实现声动力治疗,用于治疗甲状腺髓样癌。

Combination treatment of inflammatory bowel disease:Present status and future perspectives

The treatment of patients with inflammatory bowel disease(IBD),especially those with severe or refractory disease,represents an important challenge for the clinical gastroenterologist.It seems to be no exaggeration to say that in these patients,not only the scientific background of the gastroenterologist is tested,but also the abundance of“gifts”that he should possess(insight,intuition,determ-ination,ability to take initiative,etc.)for the successful outcome of the treatment.In daily clinical practice,depending on the severity of the attack,IBD is treated with one or a combination of two or more pharmaceutical agents.These combin-ations include not only the first-line drugs(e.g.,mesalazine,corticosteroids,antibiotics,etc)but also second-and third-line drugs(immunosuppressants and biologic agents).It is a fact that despite the significant therapeutic advances there is still a significant percentage of patients who do not satisfactorily respond to the treatment applied.Therefore,a part of these patients are going to surgery.In recent years,several small-size clinical studies,reviews,and case reports have been published combining not only biological agents with other drugs(e.g.,immunosuppressants or corticosteroids)but also the combination of two biologi-cal agents simultaneously,especially in severe cases.In our opinion,it is at least a strange(and largely unexplained)fact that we often use combinations of drugs in a given patient although studies comparing the simultaneous administration of two or more drugs with monotherapy are very few.As mentioned above,there is a timid tendency in the literature to combine two biological agents in severe cases unresponsive to the applied treatment or patients with severe extraintestinal manifestations.The appropriate dosage,the duration of the administration,the suitable timing for checking the clinical and laboratory outcome,as well as the treatment side-effects,should be the subject of intense clinical research shortly.In this editorial,we attempt to summarize the existing data regarding the already applied combination therapies and to humbly formulate thoughts and suggestions for the future application of the combination treatment of biological agents in a well-defined category of patients.We suggest that the application of biomarkers and artificial intelligence could help in establishing new forms of treatment using the available modern drugs in patients with IBD resistant to treatment.

数字金融对城市碳排放的非线性影响研究

数字金融在经济社会全面绿色转型中发挥政策集成和导向作用,是降碳减排的重要工具。本文基于金融领域的数字化变革现实,以2011—2021年中国284个地级市面板数据为基础,运用固定效应模型、中介效应模型和调节效应模型探究数字金融对碳排放的非线性影响及潜在机制。研究发现:数字金融对碳排放存在先增后减的倒“U”型影响,这一趋势通过一系列稳健性检验得以证实。异质性分析表明,这种倒“U”型影响主要发生在外围城市和资源型城市,在非资源型城市表现为负向线性关系。中介效应分析凸显了技术创新和创业活动作为数字金融影响碳排放的关键途径。调节效应分析强调了地方政府经济增长目标将削弱数字金融对碳排放的倒“U”型影响,环境治理目标则强化两者的倒“U”型关系。地方政府应从数字金融的发展方向、作用方向和配置方向着手,释放碳减排红利。

我国海运碳排放市场机制构建的进路统筹

海运碳减排需要统筹运用包括市场机制在内的多种措施。欧盟推进单边海运碳排放交易机制虽然对市场机制在海运领域的运用具有正向推进价值,但基于其制度对共同但有区别责任原则的忽视等原因,与我国的航运利益并不相符。我国应当联合其他非欧盟国家反对欧盟的单边措施,并积极推进国际海事组织(IMO)层面多边海运碳排放市场机制的构建,推动海运碳排放真正实现公正公平的过渡。同时,在国内层面,基于国际国内统筹推进的整体要求,我国需要厘定基于国内立法的海运碳排放市场措施及其实施路径,构建相应的制度保障。

“双碳”视阈下绿色金融发展影响碳排放的内在机制研究

加快绿色金融发展是我国新发展阶段促进发展方式绿色转型和实现“双碳”目标的战略要求。基于空间Durbin模型和GMM动态分析方法,利用我国2006—2021年30个省(区、市)的面板数据,对绿色金融发展与省际碳排放效果之间的内在关系进行实证研究。研究发现:绿色金融发展能够显著减少区域碳排放,相关结论经过稳健性检验后依然成立;低碳技术创新和融资约束作为中介变量,共同构成了绿色金融发展影响碳排放的传导路径。进一步分析表明,绿色金融发展对碳排放有明显的空间溢出效应,并在我国不同经济发展水平的地区存在区域异质性。研究结论可为新时代我国构建绿色金融发展体系、制定促进“双碳”战略目标实现的相关政策提供支撑。

基于联邦学习的分布式电采暖互动模式设计与展望

随着“双碳”目标的提出,以及“以电代煤”政策的贯彻落实,大量电采暖设备取代传统燃煤取暖投入运行并接入电网将成为必然趋势。大量电采暖设备可以作为需求侧可调资源进行新能源消纳,但是分布式电采暖所处地理区域较为分散,传统集中式管理的方式又存在隐私泄露、数据孤岛等问题。联邦学习作为一种分布式技术可在保护隐私的前提下支撑电采暖负荷互动,在分布式电采暖互动领域具有较强的适用性。分析了基于联邦学习的分布式电采暖互动需求,以及边缘缓存、隐私防护、通信传输优化和异构资源融合等技术在基于联邦学习的电采暖互动场景中的应用方式,并展望了未来基于联邦学习的分布式电采暖互动前景。

能耗双控转向碳排放双控的理论逻辑与实践路径

能耗双控向碳排放双控转变是推进碳达峰碳中和的制度保障,系统分析能耗双控转向碳排放双控的理论逻辑及实践路径,对促进企业适应国内国际市场、降低碳排放,保障中国“双碳”目标的实现有重要现实意义。能耗双控通过需求效应、技术效应和要素替代效应影响节能降碳,碳排放双控主要通过技术创新效应、技术溢出效应和产业结构升级效应的综合作用促进节能降碳,碳排放双控节能降碳的作用机制更加完善,更加注重碳排放控制,更能够精准控碳。能耗双控转向碳排放双控有利于企业能源转型、绿电消费的增加,对于“双碳”目标的实现、国际竞争力的提高具有深远的影响。能耗双控转向碳排放双控背景下,中国面临能耗双控转向碳排放双控的识别阶段、分阶段、落实阶段难题,碳市场建设不足,碳排放监管和执法体系不完善的挑战;为顺利推动能耗双控转向碳排放双控,本文提出统筹推进分阶段、差异化考核工作,通过加大碳市场覆盖范围、完善碳交易机制、优化用能权交易市场等加强碳市场建设,加强碳排放监管和法治体系建设等关键举措和推动路径。中国实现绿色低碳发展须注重能耗双控向碳排放双控转变,准确把握能耗双控转向碳排放双控,促进“双碳”目标实现。

ESG表现对商业银行盈利能力的影响

基于2012—2021年我国37家上市商业银行的季度数据,使用因子分析法构建了商业银行盈利能力指标,利用基本回归模型实证检验了ESG表现对商业银行盈利能力的影响,并通过构建中介效应模型探索了ESG表现影响商业银行盈利能力的路径。结果表明:良好的ESG表现可以通过降低商业银行的风险来提高其盈利能力。又通过异质性分析发现,良好的ESG表现能明显通过降低城市商业银行风险来提高盈利能力。

双碳目标下农业机械发展趋势探究

随着我国绿色农业经济的发展,人们对绿色农业机械的发展更加关注。目前绿色农业机械技术仍处于起步阶段,但是农业机械低碳化、智能化依然是未来的发展趋势。该文重点分析了中国农业机械低碳化发展的关键环节,并从中国农机发展历程、农机低碳化发展现状、农机低碳化核心技术创新及农机低碳化应用推广等方面阐述其阶段性特征和发展方向,对未来低碳化农业机械技术发展及市场推广应用提出几点建议。文章指出通过创新驱动、市场驱动、政策驱动促进低碳农业机械快速、高质量发展,推动农业产业结构优化升级,加快落后产能装备快速淘汰,构建绿色农业经济体制,助推中国农业经济绿色转型及国家“双碳”指标顺利达成。

联合疗法在炎症性肠病中的应用进展

炎症性肠病(inflammatory bowel disease,IBD)是一种难治性肠道炎症性疾病,药代动力学的失效及药效学逃逸导致目前以单一靶向治疗为主的方案受到限制,而对于重症及肠外表现的治疗不尽如人意,加速了人们研究联合疗法的进度,既往比较成熟的联合治疗案例进一步推动双靶向治疗方案的研究,该文就IBD联合疗法作一概述。