Revolutionizing tumor immunotherapy:unleashing the power of progenitor exhausted T cells

In exploring persistent infections and malignancies, a distinctive subgroup of CD8^(+) T cells, progenitor exhausted CD8^(+) T(Tpex) cells, has been identified. These Tpex cells are notable for their remarkable self-renewal and rapid proliferation abilities. Recent strides in immunotherapy have demonstrated that Tpex cells expand and differentiate into responsive exhausted CD8^(+) T cells, thus underscoring their critical role in the immunotherapeutic retort. Clinical examinations have further clarified a robust positive correlation between the proportional abundance of Tpex cells and enhanced clinical prognosis. Tpex cells have found noteworthy applications in the formulation of inventive immunotherapeutic approaches against tumors. This review describes the functions of Tpex cells in the tumor milieu, particularly their potential utility in tumor immunotherapy. Precisely directing Tpex cells may be essential to achieving successful outcomes in immunotherapy against tumors.

Contrasting Regional Responses of Indian Summer Monsoon Rainfall to Exhausted Spring and Concurrently Emerging Summer El Nino Events

The inverse relationship between the warm phase of the El Nino Southern Oscillation(ENSO)and the Indian Summer Monsoon Rainfall(ISMR)is well established.Yet,some El Nino events that occur in the early months of the year(boreal spring)transform into a neutral phase before the start of summer,whereas others begin in the boreal summer and persist in a positive phase throughout the summer monsoon season.This study investigates the distinct influences of an exhausted spring El Nino(springtime)and emerging summer El Nino(summertime)on the regional variability of ISMR.The two ENSO categories were formulated based on the time of occurrence of positive SST anomalies over the Nino-3.4 region in the Pacific.The ISMR’s dynamical and thermodynamical responses to such events were investigated using standard metrics such as the Walker and Hadley circulations,vertically integrated moisture flux convergence(VIMFC),wind shear,and upper atmospheric circulation.The monsoon circulation features are remarkably different in response to the exhausted spring El Nino and emerging summer El Nino phases,which distinctly dictate regional rainfall variability.The dynamic and thermodynamic responses reveal that exhausted spring El Nino events favor excess monsoon rainfall over eastern peninsular India and deficit rainfall over the core monsoon regions of central India.In contrast,emerging summer El Nino events negatively impact the seasonal rainfall over the country,except for a few regions along the west coast and northeast India.

Protection, Development and Utilization of Industrial Heritage Under the Background of Transformation of Exhausted Cities: A Case Study of Construction Planning of Anyuan National Mine Park

Firstly,the status quo of Pingxiang City as a resource-exhausted city was introduced firstly,and then the development situation of Anyuan Coal Mine,which is the representative of traditional coal industry in Pingxiang,was summarized.Moreover,the classification and value of mining heritage were analyzed,and it is proposed that the development of mine heritage tourism and urban transformation should be combined.The planning of Anyuan National Mine Park under the background of urban transformation was analyzed to provides an idea for the protection and utilization of industrial heritage.

Coordination of economic development and ecological environment in resource exhausted cities

This paper establishes the evaluation index system of ecological environment and economic development in resource exhausted cities, and calculates the level of economic development and ecological environment during the year 2005-2012 by using the entropy method. Furthermore, this study analyzes the coordination degree and coordinated development degree by using the coordination model. The results show that the coordination relationship of economic development and ecological environment continues to improve from 2005 to 2012 in most of these resource exhausted cities. By 2012, other resource depletion cities are in all kinds of hierarchical coordination except Yichun and Hegang. From the standpoint of coordination development degree, although most of these resource exhausted cities have been increased continuously but the level is also lower except in Tongling and Xinyu. Finally, this paper puts forward the corresponding countermeasures and suggestions according to the results of the analysis.

Adsorptive Removal of Heavy Metals from Aqueous Solution with Environmental Friendly Material—Exhausted Tea Leaves

In this study adsorptive removal of Pb(II) and Cu(II) from aqueous solution by using environmental friendly natural polymers present in exhausted tea leaves has been studied. The biosorbent was modified with dimethylamine to introduce N-functional groups on the surface of adsorbent. The modified adsorbent was characterized by elemental analysis, zeta potential analysis, SEM, DRFTIR, XRD and TG/DTA analysis to conform the modification. Adsorption capacity of the adsorbent was determined as the function of pH of the solution, initial concentration of the solution and contact time. The adsorption experiments were performed using batch experiments. The maximum adsorption capacities of the adsorbent were found to be 91.68 and 71.20 mg/g for Pb(II) and Cu(II), respectively. To minimize the process cost, regeneration of the biosorbent and recovery of metal ions was explored by desorption study. The results indicate that the adsorbent holds great potential for the sequestration of Pb(II) and Cu(II) from their aqueous solution. Hence the modified exhausted tea leaves (MTL) have been investigated as a new cost effective and efficient biosorbent for removal of Pb(II) and Cu(II) from their aqueous solution.

Exhausted T cells and epigenetic status

Exhausted T cells are a group of dysfunctional T cells,which are present in chronic infections or tumors.The most significant characteristics of exhausted T cells are attenuated effector cytotoxicity,reduced cytokine production,and upregulation of multiple inhibitory molecular receptors(e.g.,PD-1,TIM-3,and LAG-3).The intracellular metabolic changes,altered expression of transcription factors,and a unique epigenetic landscape constitute the exhaustion program.Recently,researchers have made progress in understanding exhausted T cells,with the definition and identification of exhausted T cells changing from phenotypebased to being classified at the transcriptional and epigenetic levels.Recent studies have revealed that exhausted T cells can be separated into two subgroups,namely TCF1^(+)PD-1^(+)progenitor-like precursor exhausted cells and TCF1-PD-1^(+)terminally differentiated exhausted T cells.Moreover,the progenitor-like precursor cell population may be a subset of T cells that can respond to immunotherapy.Studies have also found that TOX initiates and dominates the development of exhausted T cells at the transcriptional and epigenetic levels.TOX also maintains T cell survival and may affect decisions regarding treatment strategies.In this review,we discuss the latest developments in T cell exhaustion in regards to definitions,subpopulations,development mechanisms,differences in diverse diseases,and treatment prospects for exhausted T cells.Furthermore,we hypothesize that the epigenetic state regulated by TOX might be the key point,which can determine the reversibility of exhaustion and the efficacy of immunotherapy.

Total soy saponins improve the antioxidant capacity of the myocardium and exercise ability in exhausted rats

Purpose：The aim of the present study was to investigate the impact of total soy saponins（TS） on the myocardial antioxidant capacity in rats exercised to exhaustion.Methods：The one-time exhausted treadmill model was used.All rats were divided into 4 groups：the control group,the TS group,the exhausted group,and the TS exhausted group.The TS and TS exhausted groups were fed TS at a dosage of 20 mg/kg body weight,once a day,for 2 weeks.The exhausted group was given a placebo,and the control group was not given any treatment.The treadmill speed was set at 30 m/min,and the rats（exhausted and TS exhausted groups） were trained at this speed until exhausted.The rats were decapitated and anatomized immediately after exhausted.A 10% homogenate of the myocardial tissue was prepared.Results：TS significant y increased the exercise time by 20.62%（p〈0.05）.As compared with the control group,the enzyme activities for catalase（CAT）,glutathione peroxidase（GSH-Px）,and glutathione reductase（GR） were significant y enhanced in the TS group（p〈0.01）;GR and GSH-Px activity was significant y enhanced in the TS exhausted group（p〈0.01）;malondialdehyde（MDA） levels were significant y decreased in the TS exhausted group（p〈0.05）.As compared with the exhausted group,the GSH-Px activity was significant y enhanced in the TS exhausted group（p〈0.01）;CAT,GSH-Px,and GR activities were significant y enhanced in the TS group（p〈0.01）.As compared with the TS group,the CAT and GR activity in the TS exhausted group was significant y decreased（p〈0.01）.Conclusion：TS can improve the exercised rats＇ antioxidant activity in their cardiac muscle to varying degrees,decrease MDA and serum AST and LDH levels,increase the exercise time,and delay the occurrence of sports fatigue.

Higher PD-1 expression concurrent with exhausted CD8+ T cells in patients with de novo acute myeloid leukemia

Objective： To investigate the association between the T cell inhibitory receptor programmed death 1（PD-1）and T cell exhaustion status in T cells from patients with de novo acute myeloid leukemia（AML） and AML in complete remission（CR）.Methods：Surface expression of PD-1 and the exhaustion and immunosenescence markers CD244 and CD57 on CD3＋,CD4＋ and CD8＋ T cells from peripheral blood samples from 20 newly diagnosed,untreated AML patients and 10 cases with AML in CR was analyzed by flow cytometry.Twenty-three healthy individuals served as control.Results：A significantly higher percentage of PD-1＋ cells were found for CD3＋ T cells in the de novo AML group compared with healthy controls.In addition,an increased level of PD-1＋ CD8＋ T cells,but not PD-1＋ CD4＋,was found for CD3＋ T cells in the de novo AML and AML-CR samples.A higher percentage of CD244＋ CD4＋,CD244＋ CD8＋,CD57＋ CD4＋ and CD57＋ CD8＋ T cells was found in CD3＋ T cells in samples from those with de novo AML compared with those from healthy controls.Strong increased PD-1＋ CD244＋ and PD-1＋ CD57＋ coexpression was found for CD4＋ and CD8＋ T cells in the de novo AML group compared with healthy controls.Conclusions：We characterized the major T cell defects,including co-expression of PD-1 and CD244,CD57-exhausted T cells in patients with de novo AML,and found a particular influence on CD8＋ T cells,suggesting a poor anti-leukemia immune response in these patients.

Tempering of exhausted T cells to comprehend their adaptive response for suitable clinical translation

Although cancer immunotherapy has taken center stage,exhaustion of T cells is undeniably one of the major problems preventing it from being fully successful[1].Certainly,reversal of T-cell exhaustion or dysfunction is of great importance for developing new strategies and restoring immune function.Nevertheless,counterarguments about the adverse effect of reversing T-cell exhaustion(leading to overactivation of T cells and cytotoxicity)and even their irreversible properties have been quite common in scientific debates.With more to be discovered about the reasons for T-cell failure,a better understanding of the molecular factors/determinants[2,3]that shape/remodel“heterogeneous”dysfunctional T cells in cancer makes clear sense.Indeed,two recent publications in Nature immunology have described the intriguing perspective of T-cell exhaustion[4,5].Of interest,Vignali et al.focused on the hypoxia-driven CD39-dependent suppressor function of exhausted T cells,whereas Saadey et al.emphasized restoring the epigenetic balance of TGFβ1/BMP signaling in exhausted T cells to unlock responsiveness to immune checkpoint blockade therapy.

面向未来低碳道路养护的超薄罩面功能性研究综述

Highway maintenance mileage reached 5.25 million kilometers in China by 2021.Ultra-thin overlay is one of the most commonly used maintenance technologies,which can significantly enhance the economic and environmental benefits of pavements.To promote the low-carbon development of ultrathin overlays,this paper mainly studied the mechanism and influencing factors of several ultra-thin overlay functions.Firstly,the skid resistance,noise reduction,rutting resistance,and crack resistance of ultrathin overlays were evaluated.The results indicated that the high-quality aggregates improved the skid and rutting resistance of ultra-thin overlay by 5%-20%.The optimized gradations and modified binders reduced noise of ultra-thin overlay by 0.4-6.0 dB.The high viscosity modified binders improved the rutting resistance of ultra-thin overlay by about 10%-130%.Basalt fiber improved the cracking resistance of ultra-thin overlay by more than 20%.Due to the thinner thickness and better road performance,the performance-based engineering cost of ultra-thin overlay was reduced by about 30%-40%compared with conventional overlays.Secondly,several environmentally friendly functions of ultra-thin overlay were investigated,including snow melting and deicing,exhaust gas purification and pavement cooling.The lower thickness of ultra-thin overlay was conducive to the diffusion of chloride-based materials to the pavement surface.Therefore,the snow melting effect of self-ice-melting was better.In addition,the ultra-thin overlay mixture containing photocatalytic materials could decompose 20%-50%of the exhaust gas.The colored ultra-thin overlay was able to reduce the temperature of the pavement by up to 8.1℃.The temperature difference between the upper and lower surfaces of the ultra-thin overlay containing thermal resistance materials could reach up to 12.8℃.In addition,numerous typical global engineering applications of functional ultra-thin overlay were summarized.This review can help better understand the functionality of ultra-thin overlays and promote the realization of future multi-functional and low-carbon road maintenance.

A COUPLING MODEL OF WATER FLOWS AND GAS FLOWS IN EXHAUSTED GAS BUBBLE ON MISSILE LAUNCHED UNDERWATER

The gas and water flows during an underwater missile launch are numerically studied. For the gas flow, the explicit difference scheme of Non-oscillation and Non-free-parameter Dissipation (NND) is utilized to solve the Euler equations for compressible fluids in the body-fitted coordinates. For the water flow, the Hess-Smith method is employed to solve the Laplace equation for the velocity potential of irrotational water flows based on the potential theory and the boundary element method. The hybrid Eulerian-Lagrangian formulation for the free boundary conditions is used to compute the changes of the free surface of the exhausted gas bubble in time stepping. On the free surface of the exhausted gas bubble, the matched conditions of both the normal velocities and pressures are satisfied. From the numerical simulation, it is found that the exhausted gas bubble grows more rapidly in the axial direction than in the radial direction and the bubble will shrink at its "neck" finally. Numerical results of the movement of the shock wave and the distribution of the Mach number and the gas pressure within the bubble were presented, which reveals that at some time, the gas flow in the Laval nozzle is subsonic and the gas pressure in the nozzle is very high. Influences of various initial missile velocities and chamber total pressures and water depths on both the time interval when the gas flow in the nozzle is subsonic and the peak of the gas pressure at the nozzle end were discussed. It was suggested that a reasonable adjustment of the chamber total pressure can improve the performance of the engine during the underwater launch of missiles.

New perspective on the treatment of rheumatic arthritis based on“strengthening body resistance(Fú Zhèng)”in the theory of co-inhibitory receptor-regulated T-cell immunity

Co-inhibitory receptors serve as crucial regulators of T-cell function,playing a pivotal role in modulating the delicate balance between immune tolerance and autoimmunity.Initially identified in autoimmune disease models,co-inhibitory receptors,including CTLA-4,PD-1,TIM-3,and TIGIT,were found to be integral to immune regulation.Their blockade or absence in these models resulted in the induction or exacerbation of autoimmune diseases.Additionally,scholars have observed that co-inhibitory receptors on lymphocytes hold the potential to influence the prognosis in the context of chronic inflammation.Consequently,the blocking of co-suppressor receptors has emerged as a novel therapeutic approach for inhibiting refractory inflammatory diseases,particularly rheumatoid arthritis.From the standpoint of traditional Chinese medicine(TCM),the treatment of rheumatoid arthritis based on the“strengthening body resistance(FúZhèng)”theory can be construed as the regulation of co-suppressor receptors to modulate the body’s immune function in combating chronic inflammation.This article provides a succinct overview of the role of co-suppressor receptors in anti-inflammatory processes and explores the research prospects of co-suppressor receptor intervention in the treatment of rheumatoid arthritis.The exploration integrates the“strengthening body resistance(FúZhèng)”theory with relevant Chinese medicine formulations.

Study of the Influence of the Distance between Smoke Outlets and Fire Source on Smoke Flow Characteristics in Tunnel Fires

This paper explores the smoke flow characteristics in tunnel fires,giving a particular emphasis on the effects of different distances between the smoke outlets and the fire source.It examines the smoke behavior under different conditions,including variations in heat release rates,exhaust volumetric flow rates,spacing between smoke outlets,and the longitudinal fire source positions.Results indicate that altering the fire source positions and the smoke outlets in the tunnel leads to variations in the properties of smoke flow both the fire source upstream and downstream;the distance between fire source and smoke outlet increases gradually,airflow rate decreases initially and eventually reaches a stable state.Similarly,smoke mass flow rate exhibits an increasing trend that eventually reaches a stable state.Moreover,the heat exchange between the tunnel walls and hot smoke increases as the smoke outlet moves further away from the fire source.This interaction leads to a reduction in the heat exhaust coefficient and a decrease in the distance the smoke spreads.This study investigates the impact of altering the relative longitudinal fire source positions and smoke outlet on smoke flow characteristics by numerical simulation.A theoretical analytical method is used to give a predictive model for the heat exhaust coefficient and the smoke spreading distance.This research can support the theory and technical process of tunnel smoke exhaust prevention and control.

Heat Recovery from Automotive Exhaust Using Heat Pipes with Limited Fluid Charge

Experiments were conducted in this study to examine the thermal performance of a thermosyphon,made from Inconel alloy 625,could recover waste heat from automobile exhaust using a limited amount of fluid.The thermosyphon has an outer diameter of 27 mm,a thickness of 2.6 mm,and an overall length of 483 mm.The study involved directing exhaust gas onto the evaporator.This length includes a 180-mm evaporator,a 70-mm adiabatic section,a 223-mm condenser,and a 97-mm finned exchanger.The study examined the thermal performance of the thermosyphon under exhaust flow rates ranging from 0–10 g/sec and temperatures varying from 300℃–900℃.The influence of three parameters—inclination angle(5°–45°),water mass(2–5.3 g),and the quantity of non-condensable gas Argon(0–0.6 g)—was investigated to assess their impacts on the thermosyphon’s thermal efficiency.The experimental findings revealed that with 3 g of water and 0.0564 g of argon in the thermosyphon,the condenser reached its highest temperature at around 200℃.The ideal fuel loading rate for the thermosyphon falls between 0.2 and 0.7 g/s.Moreover,as inclination angles rise,outer wall temperatures of the thermosyphon increase.This is attributed to the explicit expansion of the effective heating area within the evaporation section,coupled with an amplified gravitational component of the water flux.Additionally,an upsurge in the quantity of non-condensable gas(NCG)can mitigate temperature gradients on the outer wall,resulting in a decline in the thermosyphon’s performance.The insulation applied to the adiabatic section demonstrated efficacy in augmenting temperature gradients on the outer wall,thereby improving the overall performance of the thermosyphon.As the water charge within the thermosyphon increases,there is a corresponding rise in heat transfer rates both from the exhaust to the thermosyphon and from the thermosyphon to the fuel.

Study on the Influence of Setting Parameters of Tunnel Centralized Smoke Extraction System on Fire Smoke Flow and Temperature Decay

The centralized smoke exhaust system of shield tunnel is an important determinant for tunnel fire safety,and the use of different design parameters of the tunnel smoke exhaust system will affect the smoke exhaust effect in the tunnel,and the influence of different design parameters on the smoke exhaust effect and temperature attenuation of the tunnel can help engineers in designing a more effective centralized smoke exhaust system for the tunnel.In this paper,the Fire Dynamic Simulator(FDS)is utilized to examine smoke exhaust vent settings for a centralized exhaust system in shield tunnel with both flat and sloped conditions,including slopes of+4.5%and−4.5%,under a 30MWfire power with a 150m^(3)/s smoke exhaust rate.The results suggest that maintaining a vent spacing of 60m and a vent size of 4.0 m×1.5 m is a reasonable configuration for centralized smoke exhaust systems in both flat and slope shield tunnels.This choice helpsminimize construction costs and prevent excessive smoke accumulation.It also promotes favorable conditions for maintaining temperature distribution at 2-m height,visibility,smoke spread distance,and temperature below the ceiling,all below the threshold values,while ensuring high smoke extraction efficiency.However,in the slope section,the chimney effect can disrupt exhaust efficiency,visibility,ceiling temperature,and temperature distribution at a height of 2 m.Employing different opening methods,such as having 2 vents up and 4 vents down in a+4.5%slope and 4 vents up and 2 vents down in a−4.5%slope,can help mitigate these effects.Furthermore,the temperature decay formula for shield tunnels follows a bi-exponential decay pattern,and different design parameters of centralized smoke exhaust systems have minimal effects on temperature decay in shield tunnels.

Ectopic Tcf1 expression instills a stem-like program in exhausted CD8^(+) T cells to enhance viral and tumor immunity

Exhausted CD8^(+)T(Tex)cells are dysfunctional due to persistent antigen exposure in chronic viral infection and tumor contexts.A stem cell-like Tex(Tex-stem)subset can self-renew and differentiate into terminally exhausted(Tex-term)cells.Here,we show that ectopic Tcf1 expression potently promoted the generation of Tex-stem cells in both a chronic viral infection and preclinical tumor models.Tcf1 overexpression diminished coinhibitory receptor expression and enhanced polycytokine-producing capacity while retaining a heightened responses to checkpoint blockade,leading to enhanced viral and tumor control.Mechanistically,ectopically expressed Tcf1 exploited existing and novel chromatin accessible sites as transcriptional enhancers or repressors and modulated the transcriptome by enforcing pre-existing expression patterns in Tex-stem cells,such as enhanced suppression of Blimp1 and Bim and acquisition of new downstream genes,including Mx1,Tox2,and Runx3.These findings reveal a pronounced impact of ectopic Tcf1 expression on Tex functional restoration and highlight the therapeutic potential of harnessing Tcf1-enforced transcriptional programs.

Difference in the anti-fatigue effect of moxibustion at different acupoints in one-off exhausted rats

Objective:To explore the difference in the anti-fatigue effect of moxibustion at different acupoints through observing the impacts of moxibustion at"Shènshù(肾俞BL23)","Zúsānlǐ(足三里ST36)","Guānyuán(关元CV4)"and"Shénquè(神阙CV8)"on energy metabolic indexes in the one-off exhausted rats.Methods:A total of 56 SPF male rats were randomized into 7 groups,named a blank group,a model group,a non-acupoint group,a"BL23"group,a"ST36"group,a"CV4"group and a"CV8"group,8 rats in each group.The one-off exhaustion model was established by weight-bearing swimming experiment.Right after the exhaustive swimming of rats in each intervention group,the mild moxibustion was applied at the corresponding acupoints for 15 min immediately.4 h after the exhaustive swimming,the blood was collected from the femoral artery and the quadriceps femoris of the left hindlimb was stripped.The levels of blood lactate(BLD),lactate dehydrogenase(LDH),creatine kinase(CK)and blood urea nitrogen(BUN),the expressions of adenosine triphosphatease(ATP),fructose-6-phosphofructokinase(PFK)and malomdialdehyde(MDA)in the quadriceps femoris and the activity of superoxide dismutase(SOD)and catalase(CAT)were detected.Results:Compared with the model group and the non-acupoint group,the levels of serum BLD,LDH,CK and BUN were all lower those in the"BL23"group,the"ST36"group,the"CV4"group and the"CV8"group,indicating a statistical significance(all P<0.05).Compared with the model group and the nonacupoint group,PFK was higher in the"BL23"group,indicating a statistical significance(both P<0.05).Compared with the model group and the non-acupoint group,PFK was higher in the"ST36"group and the"CV4"group,indicating a statistical significance(all P<0.05).Conclusion:It was found in the research that moxibustion at"BL23""ST36""CV4"and"CV8"regulated the energy metabolism in the one-off exhausted rats so as to bring the anti-fatigue effect into play and the effect was different among the acupoints.Moxibustion at"CV8"may work on the prevention of the protein decomposition in the skeletal muscle and moxibustion at"BL23"may be against the oxidation in the skeletal muscle.

Optimization of different intensities of exercise preconditioning in protecting exhausted exercise induced heart injury in rats

This study was to optimize the exercise preconditioning(EP)intensity in protecting from exhaustive exercise-induced cardiac injury(EECI).A total of 98 male Sprague-Dawley rats were divided into 7 groups(n=14):the control group(C),the exhaustive exercise group(EE)and the EP+EE groups,which include the V10(53.0%VO_(2max)),V15(58.4%VO_(2max)),V20(67.0%VO_(2max)),V26(74.0%VO_(2max))and V30(80.0%VO_(2max))groups.Except the C group,the other groups were subjected to treadmill running.The serum contents of N terminal pro B type natriuretic peptide(NT-proBNP)and cardiac troponin I(cTn-I)were detected by the enzyme-linked immunosorbent assay method,ECG was recorded,heart function was detected by pressure volume catheter and the activities of mitochondrial electron transfer pathway(ET pathway)complexesⅠ,ⅡandⅣwere measured by high-resolution respiration instrument.Compared to the EE group,the EP groups have shown decrease of NT-proBNP and cTn-I,improvement of mitochondrial respiratory function and car-diac function.Compared to other EP groups,the V26 group has shown significant decrease of myocardial enzymes and improvement of mitochondrial function.The correlation analysis showed the EP effect was proportional to EP intensity in the range of 53.0%VO_(2max)-74.0%VO_(2max).High intensity and long duration of exhaustive exercise caused cardiac injury and EP could decrease serum level of NT-proBNP and cTn-I,improve electrical derangement and the left ventricular function,and raise the activities of ET pathway complexesⅠ,ⅡandⅣ.The protection of EP on EECI was improved as the EP intensity was increased from 53.0%VO_(2max)to 74.0%VO_(2max)and when EP intensity was 74.0%VO_(2max),the effect was the most obvious among all the setting EP groups.

The Mechanisms of CD8+ T Cells Exhaustion in the Tumor Microenvironment and Immune Therapy

In the tumor immune microenvironment, CD8+ T cells differentiate towards functional failure. The exhaustion of CD8+ T cells (Tex) showed varying degrees of effect dysfunction, loss of proliferation ability, and sustained high expression of a variety of inhibitory receptors, with metabolic and epigenetic changes. Tex cells are heterogeneous, including several subsets with different characteristics at different stages of differentiation. Immune checkpoint inhibitors (ICIs) can restore the effect or function of Tex cells, indicating that this T cell subset plays a key role in tumor immunotherapy. The understanding of the mechanism of CD8+ T cell exhaustion will be helpful to the implementation of tumor immunotherapy. This article reviews the production, differentiation and functional characteristics of Tex cells and their relationship with tumor immunotherapy.

System analysis based on the T cell exhaustion‑related genes identifies CD38 as a novel therapy target for ovarian cancer

Ovarian cancer(OV)is highly heterogeneous tumor with a very poor prognosis.Studies increasingly show that T cell exhaustion is prognostically relevant in OV.The aim of this study was to dissect the heterogeneity of T cell subclusters in OV through single cell transcriptomic analysis.The single RNA-sequencing(scRNA-seq)data of five OV patients were analyzed,and six major cell clusters were identified after threshold screening.Further clustering of T cell-associated clusters revealed four subtypes.Pathways related to oxidative phosphorylation,G2M checkpoint,JAK-STAT and MAPK signaling were significantly activated,while the p53 pathway was inhibited in the CD8+exhausted T cells.The standard marker genes of CD8+T cell exhaustion were screened to develop a T-cell related gene score(TRS)based on random forest plots in TCGA cohort.The patients with low TRS have better prognosis compared to the patients with high TRS in both TCGA and GEO.In addition,most genes included in the TRS showed significant differences in expression levels between the high-and low-risk groups.Immune cell infiltration was analyzed using the MCPcounter and xCell algorithms,which revealed significant differences between the two risk groups,indicating that the different prognoses may stem from the respective immune landscapes.In addition,CD38 knockdown in OV cell lines increased apoptosis and inhibited invasion in vitro.Finally,we performed a drug sensitivity analysis and identified six potential drug candidates for OV.To summarize,we identified the heterogeneity and clinical significance of T cell exhaustion in OV and built a superior prognostic model based on T cell exhaustion genes,which can contribute to the development of more precise and effective therapies.