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.

Promise of spatially resolved omics for tumor research

Tumors are spatially heterogeneous tissues that comprise numerous cell types with intricate structures.By interacting with the microenvironment,tumor cells undergo dynamic changes in gene expression and metabolism,resulting in spatiotemporal variations in their capacity for proliferation and metastasis.In recent years,the rapid development of histological techniques has enabled efficient and high-throughput biomolecule analysis.By preserving location information while obtaining a large number of gene and molecular data,spatially resolved metabolomics(SRM)and spatially resolved transcriptomics(SRT)approaches can offer new ideas and reliable tools for the in-depth study of tumors.This review provides a comprehensive introduction and summary of the fundamental principles and research methods used for SRM and SRT techniques,as well as a review of their applications in cancer-related fields.

CDK6 inhibits lymphoid cell infiltration and represents a prognostic marker in HPV+ squamous cell carcinoma of head and neck

Objective:We investigated the correlations between cyclin-dependent kinase 4/6(CDK4/6)levels and human papillomavirus(HPV)infection state in head and neck squamous cell cancer(HNSCC).The aim was to explore the potential value of CDK4/6 inhibitors in the treatment of HNSCC.Methods:Multiomic sequencing data for HNSCC were obtained from The Cancer Genome Atlas(TCGA),and the mRNA levels and copy number variations(CNVs)of CDK4 and CDK6 were strictly analyzed.Overall survival(OS)curves were produced using the Kaplan-Meier method,and survival differences between groups were assessed by the log-rank test.Next,gene set enrichment analysis(GSEA)was applied to interrogate CDK4/6-associated molecular pathways in HPV-positive(HPV+)and HPV-negative(HPV-)HNSCC.Last,lymphoid cell infiltrates in each type of HNSCC were explored,and the correlations between CDK4/6 expression and lymphoid infiltrates were explored by Tumor Immune Estimation Resource(TIMER)analysis.Results:Overexpression of either CDK6 or CDK4 was not a relevant factor for OS in HPV-HNSCC(CDK6:top 40%vs.bottom 40%,P=0.885;CDK4:top 40%vs.bottom 40%,P=0.267).In HPV+HNSCC,CDK6 but not CDK4 was a relevant factor for OS(CDK6:top 40%vs.bottom 40%,P=0.002;CDK4:top 40%vs.bottom 40%,P=0.452).GSEA found that overexpressed CDK6 in HPV+HNSCC inhibited pathways involved in the tumor immune response,suggesting its roles in antitumor immunity.TIMER analysis results revealed that CDK6 but not CDK4 accumulation was negatively correlated with the number of tumor-infiltrating lymphocytes specific for HPV+HNSCC,which led to tumor response suppression.Conclusions:CDK6,but not CDK4,is a poor prognostic marker specific in HPV+HNSCC patients.Overexpressed CDK6 might stimulate tumor progression by suppressing lymphocytes infiltration independent of its kinase activity.Only abrogating its kinase activity using current CDK4/6 inhibitors was not enough to block its tumor promotion function.

Correlation study of relative parameters of intracranial pressure and prognosis of patient with craniocerebral injury

Objective:To analyze the correlation of the relative parameters of intracranial pressure to the prognosis in patients with craniocerebral injury.Methods:The clinical data of 80 patients with closed craniocerebral injury were retrospectively analyzed,and all of these patients underwent conventional examinations of arterial blood pressure and intracranial pressure.Neumatic DCR system was used to monitor relative parameters of intracranial pressure from patients.According to the score of Glasgow outcome scale(GOS)upon discharge,they were divided into favorable prognosis group(GOSⅢ-Ⅴ,n=46)and unfavorable prognosis group(GOSⅠ-Ⅱ,n=34).The relative parameters of intracranial pressure of two groups were compared so as to analyze the correlation of the prognosis in patients to ICP-related parameters.Results:Pressure reactivity index(PRx)and intracranial pressure(ICP)of favorable prognosis group were significantly higher than those of unfavorable prognosis group(t=12.27,t=5.22,p<0.05).Meanwhile,cerebral perfusion pressure(CPP)and ICP-ABP wave amplitude correlation(IAAC)of favorable prognosis group were significantly lower than those of unfavorable prognosis group(t=14.54,t=14.78,p<0.05).The average age,gender,duration of admission to neurosurgical intensive care unit(NICU)and GCS(Glasgow coma scale)score on admission of the two groups were not statistically significant.Conclusions:The prognosis and ICP-related parameters(such as PRx,ICP,CPP,etc.)in patients with craniocerebral injury are risk factors for the prognosis effect.Therefore,to monitor the above-mentioned indicators has an important clinical value for assessing the prognosis of craniocerebral injury.

Experimentation of acute injured spinal cord by transplanting the bone marrow stromal cells

Objective:In this study,bone marrow stromal cells(BMSCs)were transplanted in situ after spinal cord injury(SCI)in rats.It was proved that the implanted BMSCs could differentiate into neuron-like cells in the injured spinal cord,and the long-term motor ability test was carried out to investigate the recovery of neurological dysfunction after transplantation.Methods:(1)An improved Alien’s SCI rat model(weight 10 g,height 30 mm)was made by Alien weight drop method.Methyl eosin(Haematoxyli-n/eosin,HE)was used to identify with SCI.(2)The BMSCs were identified by the method of bone marrow adherent culture in vitro.The morphology of the cells was observed by cell staining,and CD44 was detected by BMSCs.After three cultures,the cells were transfected with lentiviral vectors carrying Green Fluorescent Protein(GFP)gene.(3)Cell survival after passage and transplantation:the GFP labeled BMSCs in situ(injury zone)were implanted into the injury model.The spinal cord sections were sacrificed after 2 weeks(2w),4 weeks(4w)and 6 weeks(6w)respectively,and the cells expressing GFP were observed under immunofluorescence microscope.(4)The modified Rivlin oblique plate test and spinal motor function blood brain barrir(BBB)score method were used to compare the changes of exercise ability in the simple injury group,2w after transplantation group,4w after transplantation group and 6w after transplantation group.Results:(1)The Alien’s SCI rat model was made by using Alien’s heavy drop method,and the effect was reliable and stable.(2)The proliferation of BMSCs after 3 passages has stabilized.After culture and amplification in vitro,the cell morphology changed to be conical,protruding interwoven into a network.Therefore,it could be used as a source of cell transplantation after SCI.The morphology of the cells was observed by staining,and the positive CD44 was detected.(3)BMSCs were transfected into the SCI model by lentiviral vector carrying GFP gene,and the expression of GFP in 6w was observed.(4)The results of modified inclined plane test and Rivlin locomotor BBB score of rats in simple injury group were significantly worse than those in transplantation control group(p<.05).2w,4w and 6w after transplantation groups could improve long-term motor function.The recovery of neurological dysfunction after 6w was the best,and the difference was statistically significant(p<.05).Conclusions:BMSCs transplantation could promote the recovery of neurological dysfunction after SCI,and the mechanism may be related to the differentiation of BMSCs into neurons and glial cells,and the BMSCs induced by transplantation could interact with peripheral nerve cells and produce some cytokines.

Electrical control of excitonic oscillator strength and spatial distribution in a monolayer semiconductor

Electrical modulation of luminescence is significant to modern light-emitting devices.Monolayer transition metal dichalcogenides are emerging direct-bandgap luminescent materials with unique excitonic properties,and the multiple exciton complexes provide new opportunities to modulate the property of luminescence in atomically thin semiconductors.Here,we report an electrical control of exciton emission in the oscillator strength and spatial distribution of excitons in a monolayer WS2.Effective modulation of excitonic emission intensity with a degree of modulation of~92%has been demonstrated by an electric field at room temperature.The spatial carrier redistribution tuned by a lateral electric field results in distinct excitonic emission patterns by design.The modulation approach to exciton oscillator strength and distribution provides an efficient way to investigate the exciton diffusion dynamics and to construct electrically tunable optoelectronic devices.

Scalable rolling-structured triboelectric nanogenerator with high power density for water wave energy harvesting toward marine environmental monitoring

In the context of advocating a green and low-carbon era,ocean energy,as a renewable strategic resource,is an important part of planning and building a new energy system.Triboelectric nanogenerator(TENG)arrays provide feasible and efficient routes for large-scale harvesting of ocean energy.In previous work,a spherical rolling-structured TENG with three-dimensional(3D)electrodes based on rolling motion of dielectric pellets was designed and fabricated for effectively harvesting low-frequency water wave energy.In this work,the external shape of the scalable rolling-structured TENG(SR-TENG)and internal filling amount of pellets were mainly optimized,achieving an average power density of 10.08 W∙m^(−3)under regular triggering.In actual water waves,the SR-TENG can deliver a maximum peak power density of 80.29 W∙m^(−3)and an average power density of 6.02 W∙m^(−3),which are much greater than those of most water wave-driven TENGs.Finally,through a power management,an SR-TENG array with eight units was demonstrated to successfully power portable electronic devices for monitoring the marine environment.The SR-TENGs could promote the development and utilization of ocean blue energy,providing a new paradigm for realizing the carbon neutrality goal.

Industrial Heritage Valorisation and Creative Industry Proliferation in Shanghai's Urban Regeneration

While industrial manufacturing is giving way to the creative economy in the 21^(st) century,Shanghai-similar to many major cities around the world-is keen to bolster a stronger economy and increase its competitive­ness by encouraging the development of cultural and creative industries.Over the past decade,the Shanghai munic­ipal government has made a concerted effort to exploit the heritage assets of the city’s industrial past to reform its economic structure.There has been a deliberate attempt to establish a stronger correlation between industrial herit­age conservation and creative industry cluster development.The aim of this research is to investigate the process of converting former industrial sites into loci of creativity.In doing so,we can determine the main actors,how different stakeholder groups came into play and the evolution of the subtle interplay between the designation of heritage architecture and that of creative industry cluster.Drawing on qualitative research methods,this paper presents a detailed analysis of three case studies in Shanghai:M50 Creative Park,1933 Shanghai and the Cool Docks.The results reveal the changing positions of three major stakeholder groups.Whereas the private sector and the general public have developed increasing interests in the embedded economic and cultural values of the former industrial struc­tures,local government has consciously reduced its presence and influence in valorising industrial heritage.Thus,the growing public awareness of cultural heritage protection and the increasing interest in the economic contribu­tion of cultural and creative industries are intrinsic to Shanghai’s reindustrialisation in the 21^(st) century.

Design method of supercritical hydrocarbon fuel injection for a scramjet

Both the fuel transfer control scheme and the knowledge of fuel temperature and pressure values before injection are important to a scramjet engine.A measurement method of the fluid temperature suitable for small channel is presented,and a fluid transfer control scheme of the area of injecting holes is designed using the balance equations of fluid mass,energy and entropy.A convective heat transfer experiment is conducted to evaluate the temperature measurement and the fluid transfer control design method of the heat absorbing supercritical hydrocarbon fuel.The results show that during the heating process the injecting pressure meets the requirement,and the fluid transfer control system works well.Such results suggest that the design method in the present work would be useful in the design of regenerative cooling for scramjet engines.