In recent years the crucial role of CD4^(+)T cells in tumor immunomodulation has garnered increasing recognition.While conventional cancer immunotherapy research has predominantly focused on the cytotoxic function of ...In recent years the crucial role of CD4^(+)T cells in tumor immunomodulation has garnered increasing recognition.While conventional cancer immunotherapy research has predominantly focused on the cytotoxic function of CD8+T cells,emerging evidence has now shown that CD4^(+)T cells enhance antitumor immunity by delivering co-stimulatory signals,secreting cytokines,and promoting cytotoxic T lymphocyte(CTL)activation and display unique immunoregulatory capabilities through direct tumor cell killing or remodeling of the tumor microenvironment.The high heterogeneity and functional plasticity of CD4^(+)T cell subsets significantly influence clinical responses to immunotherapy with underlying mechanisms involving multi-level regulatory networks,including epigenetic modulation and metabolic reprogramming.Deciphering the functional heterogeneity of CD4^(+)T cells and the interactions with the tumor microenvironment will provide essential mechanistic insights for next-generation immunotherapies,such as immune checkpoint inhibitors and chimeric antigen receptor T(CAR-T)therapies,thereby advancing personalized treatment paradigms.展开更多
Background Overtraining Syndrome(OTS)is a condition resulting from excessive physical activity without adequate recovery,predominantly affecting elite athletes and military personnel.While overreaching can be a tempor...Background Overtraining Syndrome(OTS)is a condition resulting from excessive physical activity without adequate recovery,predominantly affecting elite athletes and military personnel.While overreaching can be a temporary state,non-functional overreaching may progress to chronic OTS.This review explores various hypotheses regarding the pathogenesis of OTS,including glycogen depletion,dysregulated cytokine response,oxidative stress,and alterations in the autonomic nervous system function.It also highlights the systemic impact of OTS on multiple organ systems,immune function,and overall health,linking the condition to chronic inflammation and an increased disease susceptibility.Additionally,it addresses the role of the gut microbiome in health modulation through physical activity.Methods This narrative review was conducted through a structured search of peer-reviewed journal articles in databases such as PubMed,Web of Science,and Google Scholar,focusing on studies involving human participants and published in English.Results OTS has systemic effects on multiple organ systems,immune function,and overall health,leading to chronic inflammation and increased disease susceptibility.Athletes with OTS exhibit higher morbidity rates,influenced by factors such as sleep deprivation and stress.The review also emphasizes the role of the gut microbiome as a significant modulator of health through physical activity.Conclusion Balanced training and recovery are crucial for preventing OTS and maintaining optimal health and quality of life in physically active individuals.Understanding the complex pathophysiology of OTS is essential for developing effective prevention and treatment strategies.展开更多
CD8^(+)T cell exhaustion,a critical challenge in the immune response to cancer,is characterized by a profound decline in the functionality of effector CD8^(+)T cells.This state of exhaustion is accompanied by the upre...CD8^(+)T cell exhaustion,a critical challenge in the immune response to cancer,is characterized by a profound decline in the functionality of effector CD8^(+)T cells.This state of exhaustion is accompanied by the upregulation of various inhibitory receptors and significant shifts in both transcriptional and epigenetic profiles,thus ultimately leading to inadequate tumor control.Therapeutic strategies aimed at reversing CD8^(+)T cell exhaustion have the potential to rejuvenate immune responses and enhance treatment efficacy.This review compiles current knowledge regarding the molecular mechanisms underlying CD8^(+)T cell exhaustion,including the roles of immune checkpoint molecules,the tumor microenvironment,metabolic reprogramming,transcription factors,and epigenetic modifications.Emerging therapeutic approaches designed to combat CD8^(+)T cell exhaustion are evaluated,with emphasis on the modulation of immune checkpoints;targeting of metabolic and transcriptional changes;and exploration of other innovative strategies,such as epigenetic editing and engineered CAR-T cells.Importantly,we expand the exhaustion concept to immune cells beyond CD8^(+)T cells,such as CD4^(+)T cells,natural killer cells,and myeloid populations,thereby highlighting the broader implications of systemic immunosuppression in the cancer context.Finally,we propose avenues for future research aimed at further elucidating the factors and molecular mechanisms associated with CD8^(+)T cell exhaustion,thereby underscoring the critical need for strategies aimed at reversing this state to improve outcomes in cancer immunotherapy.展开更多
Objectives:This study aimed to establish the concept of overcoming exhaustion,providing a reference basis for nursing management and conducting related nursing research.Methods:Liehr and Smith’s three-phase,nine-step...Objectives:This study aimed to establish the concept of overcoming exhaustion,providing a reference basis for nursing management and conducting related nursing research.Methods:Liehr and Smith’s three-phase,nine-step concept-building process was used to create the concept of overcoming exhaustion.The nine steps were as follows:1)write a practice story;2)name the emerging concept;3)select a theoretical lens;4)link concept to literature;5)gather a concept story;6)identify final core qualities;7)formulate concept definition;8)create a concept model;and 9)specify the concept building synthesis.Results:The concept of overcoming exhaustion was identified based on the elements of a practice story,the life experiences of nurses who struggle with the demands of caring for their patients,their families,and themselves.The theory of self-transcendence was then recognized as the theoretical lens from which to ground the concept.The core qualities,despair and moments of calmness,were derived from the literature and confirmed through a concept story.A definition of the concept integrating the core qualities was formed:overcoming exhaustion involves realizing moments of calmness amidst despair.A model was created to demonstrate the relationship between core qualities,despair,and moments of calmness.Conclusions:The concept of overcoming exhaustion was developed and,through the concept-building process,was defined as realizing moments of calmness amidst despair.By identifying the complexities of overcoming exhaustion,this work lays the foundation for a future research program to develop understanding and interventions that support nurse well-being in the context of ongoing personal and professional demands.展开更多
Objectives:Emotional exhaustion among healthcare professionals,particularly pharmacists,significantly impacts their well-being and efficacy in patient care.Understanding the psychological mechanisms contributing to em...Objectives:Emotional exhaustion among healthcare professionals,particularly pharmacists,significantly impacts their well-being and efficacy in patient care.Understanding the psychological mechanisms contributing to emotional exhaustion is essential for developing effective interventions.The present research sought to investigate the potential mediating roles of rumination and coping strategies(adaptive and maladaptive)in the relationship between perceived stress and emotional exhaustion among pharmacists.Methods:A cross-sectional survey was carried out between September 2023 and January 2024 involving 576 pharmacists working in public hospitals in Punjab who met the inclusion criteria and actively participated in the study.We employed the Perceived Stress Scale,the Ruminative Response Scale,the Brief Coping Orientation to Problems Experienced Inventory(COPE),and the Oldenburg Burnout Inventory(OLBI)to assess the hypothesized study model.Path analysis was employed to test the hypothesized mediation model,incorporating simple and chain mediation processes.Results:The findings provided empirical evidence supporting a positive association between perceived stress and emotional exhaustion.Rumination significantlymediated this relationship.Further,both adaptive andmaladaptive coping strategieswere found tomediate this relationship,withmaladaptive coping demonstrating amore substantial impact.Conclusion:The chainmediation model demonstrated that rumination and coping strategies(both maladaptive and adaptive)significantly mediate the relationship between perceived stress and emotional exhaustion among pharmacists.Specifically,rumination was found to be a key mediator,with maladaptive coping strategies having a more substantial impact.These findings provide a deeper understanding of the psychological mechanisms contributing to emotional exhaustion in the pharmacy profession.展开更多
This study investigated the relationship between AI anxiety and deviant behavior,as well as the roles of emotional exhaustion and leader support in this context.The sample comprised 381 Chinese e-commerce employees(72...This study investigated the relationship between AI anxiety and deviant behavior,as well as the roles of emotional exhaustion and leader support in this context.The sample comprised 381 Chinese e-commerce employees(72.7%female,age range 21–36 years).The results of the Process model analysis indicate that AI anxiety significantly is associated with higher deviant behaviour.Emotional exhaustion partially mediates this relationship between AI anxiety and employee deviant behavior exacerbating deviant behaviour.Leader support moderates the AI anxiety effect on emotional exhaustion such that when leader support is low.AI anxiety is associated with higher emotional exhaustion among employees.By implication,high levels of leader support can alleviate AI anxiety of employees.Employer organizations should provide appropriate guidance when introducing AI technology to prevent AI anxiety and associated emotional exhaustion and deviant behavior.展开更多
Exhausted T cell(Tex)is a specific state of T cell dysfunction,in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation.The enrichment of exhausted CD...Exhausted T cell(Tex)is a specific state of T cell dysfunction,in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation.The enrichment of exhausted CD8^(+)T cell(CD8^(+)Tex)in the tumor microenvironment is one of the important reasons leading to the poor efficacy of immunotherapy.Recent studies have reported many reasons leading to the CD8^(+)T cell exhaustion.In addition to cancer cells,myeloid cells can also contribute to T cell exhaustion via many ways.In this review,we discuss the history of the concept of exhaustion,CD8^(+)T cell dysfunction states,the heterogeneity,origin,and characteristics of CD8^(+)Tex.We then focus on the effects of myeloid cells on CD8^(+)Tex,including tumor-associated macrophages(TAMs),dendritic cells(DCs)and neutrophils.Finally,we systematically summarize current strategies and recent advancements in therapies reversing and CD8^(+)T cell exhaustion.展开更多
Objective:The aim of this study was to explore the burden of care for patients undergoing hemodialysis from the experiences of family caregivers.Methods:In this qualitative study,a content analysis approach was used f...Objective:The aim of this study was to explore the burden of care for patients undergoing hemodialysis from the experiences of family caregivers.Methods:In this qualitative study,a content analysis approach was used for data collection and analysis.Participants were 16 family caregivers selected through purposive sampling from four medical education centers affiliated with Ahvaz Jundishapur University of Medical Sciences,Iran.Semi-structured interviews were held to collect data.Results:Four categories were developed as follows:‘care challenges’,‘psychological vulnerabilities’,‘the chronic nature of care’and“care in the shade”.The categories led to the development of the main theme of‘progressive exhaustion’experienced by the family caregivers during the provision of care to patients undergoing hemodialysis.Conclusion:Family caregivers have a significant role in the process of patient care,and this role leads them to progressive exhaustion;therefore,the overall health of the caregivers should be taken into account and more attention should be paid to their quality of life,social welfare,and satisfaction level.展开更多
There are a plethora of empirical pieces about employees’pro-environmental behaviors.However,the extant literature has either ignored or not fully examined various factors(e.g.,negative or positive non-green workplac...There are a plethora of empirical pieces about employees’pro-environmental behaviors.However,the extant literature has either ignored or not fully examined various factors(e.g.,negative or positive non-green workplace factors)that might affect employees’pro-environmental behaviors.Realizing these voids,the present paper proposes and tests a serial mediation model that examines the interrelationships of job insecurity,emotional exhaustion,met expectations,and proactive pro-environmental behavior.We used data gathered from hotel customer-contact employees with a time lag of one week and their direct supervisors in China.After presenting support for the psychometric properties of the measures via confirmatory analysis in LISREL 8.30,the abovementioned linkages were gauged using the PROCESS plug-in for statistical package for social sciences.The findings delineated support for the hypothesized associations.Specifically,emotional exhaustion and met expectations partly mediated the effect of job insecurity on proactive pro-environmental behavior.More importantly,emotional exhaustion and met expectations serially mediated the influence of job insecurity on proactive pro-environmental behavior.These findings have important theoretical implications as well as significant implications for diminishing job insecurity,managing emotional exhaustion,increasing met expectations,and enhancing ecofriendly behaviors.展开更多
In the tumor immune microenvironment, CD8<sup>+</sup> T cells differentiate towards functional failure. The exhaustion of CD8<sup>+</sup> T cells (Tex) showed varying degrees of effect dysfunct...In the tumor immune microenvironment, CD8<sup>+</sup> T cells differentiate towards functional failure. The exhaustion of CD8<sup>+</sup> 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<sup>+</sup> 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.展开更多
Fengjiu Yi(Model FJY - 1) is a patent medical and health instrument newly developed by the authors. It incorporates the drug action and physiotherapy into an integral whole, exerting comprehensive regulation and it is...Fengjiu Yi(Model FJY - 1) is a patent medical and health instrument newly developed by the authors. It incorporates the drug action and physiotherapy into an integral whole, exerting comprehensive regulation and it is an effective therapeutic method. In the present paper, 300 cases of exhaustion syndrome were all cured by the instrument after 7 - 17 sessions of treatment.展开更多
In this study,stress relaxation compression tests were performed to investigate the strain rate sensitivity,activation volume and mobile dislocations in carbon nanotubes/aluminum(CNTs/Al)composites.The results reveal ...In this study,stress relaxation compression tests were performed to investigate the strain rate sensitivity,activation volume and mobile dislocations in carbon nanotubes/aluminum(CNTs/Al)composites.The results reveal that,with the addition of CNTs,the strain rate sensitivity of CNTs/Al increased.Meanwhile,a smaller V*of CNTs/Al compared with pure Al was attributed mainly to the CNT-Al interfaces and partly to the increased forest dislocations cutting activities in grain interior,which was related to the tendency of short ranges order formation during plastic deformation.The incorporation of CNTs also improved the dislocation storage capability and reduced the dislocation velocity,leading to a lower mobile dislocation exhaustion rate.展开更多
Although work factors have been associated with both presenteeism and exhaustion among hospital physicians, we lack knowledge on the dynamic relationship between demands in the work context and presenteeism and how th...Although work factors have been associated with both presenteeism and exhaustion among hospital physicians, we lack knowledge on the dynamic relationship between demands in the work context and presenteeism and how this can be mediated by symptoms of exhaustion when controlling for job resources. The objective of this study is to examine a health impairment process of presenteeism among university hospital physicians. A cross-sectional survey of 545 university hospital physicians in Norway was conducted. Variables included in the model were presenteeism, exhaustion, work-family conflict, role conflict, social support and control over work pace. Findings from structural equation modeling indicated that exhaustion mediates the relationship between job demands and presenteeism. Job resources had no direct effect on presenteeism in the hypothesized model. The variables in the study explained 17% of the variance in presenteeism. The study is one of the first to demonstrate that the relationship between job demands and presenteeism is mediated by exhaustion when controlling for job resources. The results highlight the importance of considering the link between health symptoms and job demands to reduce the negative effects of presenteeism.展开更多
CD8+ cytotoxic T lymphocyte (CTL) exhaustion is one of the major obstacles for the effectiveness of virus control in chronic infectious diseases. We previously generated novel ovalbumin (OVA)-specific 41BBL-expressing...CD8+ cytotoxic T lymphocyte (CTL) exhaustion is one of the major obstacles for the effectiveness of virus control in chronic infectious diseases. We previously generated novel ovalbumin (OVA)-specific 41BBL-expressing OVA-TEXO and human immunodeficiency virus (HIV-1) Gag-specific Gag-TEXO vaccines, inducing therapeutic immunity in wild-type C57BL/6 (B6) mice, and converting CTL exhaustion in recombinant OVA-specific adenovirus AdVOVA-infected B6 (AdVOVA-B6) mice with chronic infection. IL-21 cytokine plays an important role in controlling chronic infections. Therefore, in this study, we constructed recombinant transgene IL-21-expressing AdVIL-21, and generated IL-21-expressing OVA-TEXO/IL-21 and Gag-TEXO/IL21 vaccines, or control vaccines (OVA-TEXO/Null and Gag-TEXO/Null) by infecting OVA-TEXO and Gag-TEXO cells with AdVIL-21 or the control AdVNull, lacking transgene, and assessed their effects in B6 or AdVOVA-B6 mice. We demonstrate that both OVA-TEXO/IL-21 and control OVA-TEXO/Null vaccines are capable of converting CTL exhaustion in chronic infection. However, the OVA-TEXO/IL-21 vaccine more efficiently rescues exhausted CTLs by increasing stronger CTL proliferation and effector cytokine IFN-γ expression than the control OVA-TEXO/Null vaccine in AdVOVA-B6 mice with chronic infection, though both vaccines stimulated comparable OVA-specific CTL responses and protective immunity against OVA-expressing BL6-10OVA melanoma lung metastasis in wild-type B6 mice. In vivo, the OVA-TEXO/IL-21-stimulated CTLs more efficiently up-regulate phosphorylation of mTORC1-controlled EIF4E and expression of mTORC1- regulated T-bet molecule than the control OVA-TEXO/Null-stimulated ones. Importantly, the Gag-TEXO/IL21 vaccine induces stronger Gag-specific therapeutic immunity against established Gag-expressing BL6-10Gag melanoma lung metastases than the control Gag-TEXO/Null vaccine in chronic infection. Therefore, this study should have a strong impact on developing new therapeutic vaccines for patients with chronic infections.展开更多
The aim of this study was to evaluate a Nature Based Rehabilitation (NBR) for a group of patients with Exhaustion Disorder (ED) in the southwest Sweden. A multidisciplinary team consisting of an occupational therapist...The aim of this study was to evaluate a Nature Based Rehabilitation (NBR) for a group of patients with Exhaustion Disorder (ED) in the southwest Sweden. A multidisciplinary team consisting of an occupational therapist, a physiotherapist, a medical doctor practising symbolic drama and a nurse with gardening experience provided NBR in an agricultural environment. Patients were offered 14 weeks of rehabilitation in a group of eight persons, three mornings per week. Seventeen patients participated in the study and 15 completed the study. A semi-structured interview was conducted at the beginning of the rehabilitation and at the end and a follow-up interview by telephone was done one year after completion of the rehabilitation. The interviews were recorded and transcribed. Assessment scales used included: Stress and Crisis Inventory (SCI-93), Coping Resources Inventory (CRI) and Visual Analogue Scale (VAS). Weekly notes from the staff members were reviewed and compared with the patient’s own experience. The interviews and the staff notes were analysed with semantic thematic analysis. Result showed that this kind of NBR with a multidisciplinary team promotes improved health and improved quality of life for patients with ED and may thus constitute a good alternative to treatment, provided the ED has not become chronic.展开更多
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 ...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.展开更多
Uniformity of air flow in extraction openings in exhaust air channels for manure gas exhaustion is determined by the distribution of pressure. The areas required in extraction vents and in extraction ducts are determi...Uniformity of air flow in extraction openings in exhaust air channels for manure gas exhaustion is determined by the distribution of pressure. The areas required in extraction vents and in extraction ducts are determined by the uniformity of air flow desired along the duct and by the loss of pressure that can be accepted. The area ratio between the vents and the cross section of the exhaust air duct will have a strong influence on both uniformity of flow and loss of pressure. The following ventilation properties were studied： Uniformity of air flow; Variations in static pressure along a duct; Air velocity at different distances from the vents. The area ratio should be about 1 for uniform exhaustion. The studies showed that the relative variation in air velocity is independent of the level of the ventilation rate. The uniformity of the exhaust distance is influenced in about the same way by the area ratio as the air velocity in the exhaust vents. Thus, it is important that the area ratio is not too high if a good exhaust function should be guaranteed. The studies also demonstrated that the uniformity of the exhaust distance is independent of the ventilation flow rate. The exhaust ventilation range is, maximally 0.3 m from the vents. The static friction coefficient was on average 0.80.展开更多
T cell exhaustion is a prevalent phenomenon in chronic infections and tumor microenvironments,severely compromising the effectiveness of antitumor and antiviral immunity.In recent years,there has been significant prog...T cell exhaustion is a prevalent phenomenon in chronic infections and tumor microenvironments,severely compromising the effectiveness of antitumor and antiviral immunity.In recent years,there has been significant progress in understanding the underlying mechanisms of T cell exhaustion,including external factors and intrinsic cellular changes that drive this dysfunctional state.Key external factors such as persistent antigen exposure,immune checkpoint signaling,and the cytokine milieu,as well as intrinsic changes such as altered metabolic processes,epigenetic modifications,and transcriptional reprogramming,contribute to T cell dysfunction.Emerging therapies targeting T cell exhaustion aim to restore immune function and enhance antitumor and antiviral immunity.These therapeutic strategies include immune checkpoint inhibition,cytokine therapies,metabolic reprogramming,and cell-based therapies.Despite these advancements,reversing T cell exhaustion presents several challenges,such as individual variability,resistance,and potential side effects.Furthermore,accurately assessing markers of T cell functional recovery and the long-term impacts of these therapeutic approaches remain challenging research areas.This review provides an overview of the history and milestones in T cell exhaustion research;summarizes the mechanisms of T cell exhaustion and its implications in cancer,chronic infections,and autoimmune diseases;discusses advancements and challenges in emerging therapies;and explores future research directions aimed at improving T cell function and enhancing immune responses.展开更多
T cells are central components of the adaptive immune system and play key roles in antitumor and antiviral responses.The diverse cell fates of T cells enable them to respond to different durations and strengths of ant...T cells are central components of the adaptive immune system and play key roles in antitumor and antiviral responses.The diverse cell fates of T cells enable them to respond to different durations and strengths of antigen stimulation and various cytokine milieus in a context-dependent manner.During acute infection or vaccination,T cells differentiate into effector cells and later develop into memory cells after antigen clearance,which mediate immune protection against the same antigen.In contrast,during cancer and chronic infection,T cells fail to enter the canonical effector or memory cell differentiation path.Instead,antigen-specific T cells enter a dysfunctional,partially responsive state called exhaustion.Exhausted T cells are heterogeneous.A subset of exhausted T cells exhibits stem cell-like properties.These stem-like T cells sustain immunity through self-renewal and repopulation of terminally differentiated progenies.Stem-like properties are critical for T cell immunity induced by immunotherapy.This review summarizes recent advances in understanding the molecular mechanisms controlling the exhaustion and stemness of T cells and explores the potential of rewiring these circuits to increase the efficiency of T-cell-based immunotherapy.展开更多
基金supported by The National Key Research and Development Program of China(Grant No.2021YFA0910100)Healthy Zhejiang One Million People Cohort(Grant No.K-20230085)+6 种基金supported by National Natural Science Foundation of China(Grant Nos.82304946 and 82573745)Post-doctoral Innovative Talent Support Program(Grant No.BX2023375)567 Foundation of Zhejiang Province(Grant No.LMS25H160006)supported by the National Natural Science Foundation of China(Grant No.82473489)the Medical Science and Technology Project of Zhejiang Province(Grant No.WKJ-ZJ-2202)the Natural Science Foundation of Zhejiang Province(Grant No.LBD24H290001)supported by the National Natural Science Foundation of China(Grant No.82403546).
文摘In recent years the crucial role of CD4^(+)T cells in tumor immunomodulation has garnered increasing recognition.While conventional cancer immunotherapy research has predominantly focused on the cytotoxic function of CD8+T cells,emerging evidence has now shown that CD4^(+)T cells enhance antitumor immunity by delivering co-stimulatory signals,secreting cytokines,and promoting cytotoxic T lymphocyte(CTL)activation and display unique immunoregulatory capabilities through direct tumor cell killing or remodeling of the tumor microenvironment.The high heterogeneity and functional plasticity of CD4^(+)T cell subsets significantly influence clinical responses to immunotherapy with underlying mechanisms involving multi-level regulatory networks,including epigenetic modulation and metabolic reprogramming.Deciphering the functional heterogeneity of CD4^(+)T cells and the interactions with the tumor microenvironment will provide essential mechanistic insights for next-generation immunotherapies,such as immune checkpoint inhibitors and chimeric antigen receptor T(CAR-T)therapies,thereby advancing personalized treatment paradigms.
基金supported by the project SVV-2023-260656 and the Cooperatio Program,research area HEAS.
文摘Background Overtraining Syndrome(OTS)is a condition resulting from excessive physical activity without adequate recovery,predominantly affecting elite athletes and military personnel.While overreaching can be a temporary state,non-functional overreaching may progress to chronic OTS.This review explores various hypotheses regarding the pathogenesis of OTS,including glycogen depletion,dysregulated cytokine response,oxidative stress,and alterations in the autonomic nervous system function.It also highlights the systemic impact of OTS on multiple organ systems,immune function,and overall health,linking the condition to chronic inflammation and an increased disease susceptibility.Additionally,it addresses the role of the gut microbiome in health modulation through physical activity.Methods This narrative review was conducted through a structured search of peer-reviewed journal articles in databases such as PubMed,Web of Science,and Google Scholar,focusing on studies involving human participants and published in English.Results OTS has systemic effects on multiple organ systems,immune function,and overall health,leading to chronic inflammation and increased disease susceptibility.Athletes with OTS exhibit higher morbidity rates,influenced by factors such as sleep deprivation and stress.The review also emphasizes the role of the gut microbiome as a significant modulator of health through physical activity.Conclusion Balanced training and recovery are crucial for preventing OTS and maintaining optimal health and quality of life in physically active individuals.Understanding the complex pathophysiology of OTS is essential for developing effective prevention and treatment strategies.
基金supported by grants from the National Natural Science Foundation of China(Grant No.82171810)the Program of Shandong Provincial Scientific and Technological Development of Traditional Chinese Medicine(Grant No.M-2023210)。
文摘CD8^(+)T cell exhaustion,a critical challenge in the immune response to cancer,is characterized by a profound decline in the functionality of effector CD8^(+)T cells.This state of exhaustion is accompanied by the upregulation of various inhibitory receptors and significant shifts in both transcriptional and epigenetic profiles,thus ultimately leading to inadequate tumor control.Therapeutic strategies aimed at reversing CD8^(+)T cell exhaustion have the potential to rejuvenate immune responses and enhance treatment efficacy.This review compiles current knowledge regarding the molecular mechanisms underlying CD8^(+)T cell exhaustion,including the roles of immune checkpoint molecules,the tumor microenvironment,metabolic reprogramming,transcription factors,and epigenetic modifications.Emerging therapeutic approaches designed to combat CD8^(+)T cell exhaustion are evaluated,with emphasis on the modulation of immune checkpoints;targeting of metabolic and transcriptional changes;and exploration of other innovative strategies,such as epigenetic editing and engineered CAR-T cells.Importantly,we expand the exhaustion concept to immune cells beyond CD8^(+)T cells,such as CD4^(+)T cells,natural killer cells,and myeloid populations,thereby highlighting the broader implications of systemic immunosuppression in the cancer context.Finally,we propose avenues for future research aimed at further elucidating the factors and molecular mechanisms associated with CD8^(+)T cell exhaustion,thereby underscoring the critical need for strategies aimed at reversing this state to improve outcomes in cancer immunotherapy.
文摘Objectives:This study aimed to establish the concept of overcoming exhaustion,providing a reference basis for nursing management and conducting related nursing research.Methods:Liehr and Smith’s three-phase,nine-step concept-building process was used to create the concept of overcoming exhaustion.The nine steps were as follows:1)write a practice story;2)name the emerging concept;3)select a theoretical lens;4)link concept to literature;5)gather a concept story;6)identify final core qualities;7)formulate concept definition;8)create a concept model;and 9)specify the concept building synthesis.Results:The concept of overcoming exhaustion was identified based on the elements of a practice story,the life experiences of nurses who struggle with the demands of caring for their patients,their families,and themselves.The theory of self-transcendence was then recognized as the theoretical lens from which to ground the concept.The core qualities,despair and moments of calmness,were derived from the literature and confirmed through a concept story.A definition of the concept integrating the core qualities was formed:overcoming exhaustion involves realizing moments of calmness amidst despair.A model was created to demonstrate the relationship between core qualities,despair,and moments of calmness.Conclusions:The concept of overcoming exhaustion was developed and,through the concept-building process,was defined as realizing moments of calmness amidst despair.By identifying the complexities of overcoming exhaustion,this work lays the foundation for a future research program to develop understanding and interventions that support nurse well-being in the context of ongoing personal and professional demands.
基金supported by Social Policy Grant through Nazarbayev University,Kazakhstan.
文摘Objectives:Emotional exhaustion among healthcare professionals,particularly pharmacists,significantly impacts their well-being and efficacy in patient care.Understanding the psychological mechanisms contributing to emotional exhaustion is essential for developing effective interventions.The present research sought to investigate the potential mediating roles of rumination and coping strategies(adaptive and maladaptive)in the relationship between perceived stress and emotional exhaustion among pharmacists.Methods:A cross-sectional survey was carried out between September 2023 and January 2024 involving 576 pharmacists working in public hospitals in Punjab who met the inclusion criteria and actively participated in the study.We employed the Perceived Stress Scale,the Ruminative Response Scale,the Brief Coping Orientation to Problems Experienced Inventory(COPE),and the Oldenburg Burnout Inventory(OLBI)to assess the hypothesized study model.Path analysis was employed to test the hypothesized mediation model,incorporating simple and chain mediation processes.Results:The findings provided empirical evidence supporting a positive association between perceived stress and emotional exhaustion.Rumination significantlymediated this relationship.Further,both adaptive andmaladaptive coping strategieswere found tomediate this relationship,withmaladaptive coping demonstrating amore substantial impact.Conclusion:The chainmediation model demonstrated that rumination and coping strategies(both maladaptive and adaptive)significantly mediate the relationship between perceived stress and emotional exhaustion among pharmacists.Specifically,rumination was found to be a key mediator,with maladaptive coping strategies having a more substantial impact.These findings provide a deeper understanding of the psychological mechanisms contributing to emotional exhaustion in the pharmacy profession.
基金funded by Guangxi Eco-Engineering Vocational&Technical College Talent Introduction Research Project and 2024 Guangxi Vocational Education Teaching Reform Research Project grant number[GXSTKYZX20240603]and[GXGZJG2024B125]and the APC was funded by GEVT College.
文摘This study investigated the relationship between AI anxiety and deviant behavior,as well as the roles of emotional exhaustion and leader support in this context.The sample comprised 381 Chinese e-commerce employees(72.7%female,age range 21–36 years).The results of the Process model analysis indicate that AI anxiety significantly is associated with higher deviant behaviour.Emotional exhaustion partially mediates this relationship between AI anxiety and employee deviant behavior exacerbating deviant behaviour.Leader support moderates the AI anxiety effect on emotional exhaustion such that when leader support is low.AI anxiety is associated with higher emotional exhaustion among employees.By implication,high levels of leader support can alleviate AI anxiety of employees.Employer organizations should provide appropriate guidance when introducing AI technology to prevent AI anxiety and associated emotional exhaustion and deviant behavior.
基金supported by grants from the National Key Research and Development Program of China(No.2022YFA1304504)National Natural Science Foundation of China(No.82293633 and 82270180)。
文摘Exhausted T cell(Tex)is a specific state of T cell dysfunction,in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation.The enrichment of exhausted CD8^(+)T cell(CD8^(+)Tex)in the tumor microenvironment is one of the important reasons leading to the poor efficacy of immunotherapy.Recent studies have reported many reasons leading to the CD8^(+)T cell exhaustion.In addition to cancer cells,myeloid cells can also contribute to T cell exhaustion via many ways.In this review,we discuss the history of the concept of exhaustion,CD8^(+)T cell dysfunction states,the heterogeneity,origin,and characteristics of CD8^(+)Tex.We then focus on the effects of myeloid cells on CD8^(+)Tex,including tumor-associated macrophages(TAMs),dendritic cells(DCs)and neutrophils.Finally,we systematically summarize current strategies and recent advancements in therapies reversing and CD8^(+)T cell exhaustion.
文摘Objective:The aim of this study was to explore the burden of care for patients undergoing hemodialysis from the experiences of family caregivers.Methods:In this qualitative study,a content analysis approach was used for data collection and analysis.Participants were 16 family caregivers selected through purposive sampling from four medical education centers affiliated with Ahvaz Jundishapur University of Medical Sciences,Iran.Semi-structured interviews were held to collect data.Results:Four categories were developed as follows:‘care challenges’,‘psychological vulnerabilities’,‘the chronic nature of care’and“care in the shade”.The categories led to the development of the main theme of‘progressive exhaustion’experienced by the family caregivers during the provision of care to patients undergoing hemodialysis.Conclusion:Family caregivers have a significant role in the process of patient care,and this role leads them to progressive exhaustion;therefore,the overall health of the caregivers should be taken into account and more attention should be paid to their quality of life,social welfare,and satisfaction level.
文摘There are a plethora of empirical pieces about employees’pro-environmental behaviors.However,the extant literature has either ignored or not fully examined various factors(e.g.,negative or positive non-green workplace factors)that might affect employees’pro-environmental behaviors.Realizing these voids,the present paper proposes and tests a serial mediation model that examines the interrelationships of job insecurity,emotional exhaustion,met expectations,and proactive pro-environmental behavior.We used data gathered from hotel customer-contact employees with a time lag of one week and their direct supervisors in China.After presenting support for the psychometric properties of the measures via confirmatory analysis in LISREL 8.30,the abovementioned linkages were gauged using the PROCESS plug-in for statistical package for social sciences.The findings delineated support for the hypothesized associations.Specifically,emotional exhaustion and met expectations partly mediated the effect of job insecurity on proactive pro-environmental behavior.More importantly,emotional exhaustion and met expectations serially mediated the influence of job insecurity on proactive pro-environmental behavior.These findings have important theoretical implications as well as significant implications for diminishing job insecurity,managing emotional exhaustion,increasing met expectations,and enhancing ecofriendly behaviors.
文摘In the tumor immune microenvironment, CD8<sup>+</sup> T cells differentiate towards functional failure. The exhaustion of CD8<sup>+</sup> 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<sup>+</sup> 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.
文摘Fengjiu Yi(Model FJY - 1) is a patent medical and health instrument newly developed by the authors. It incorporates the drug action and physiotherapy into an integral whole, exerting comprehensive regulation and it is an effective therapeutic method. In the present paper, 300 cases of exhaustion syndrome were all cured by the instrument after 7 - 17 sessions of treatment.
文摘In this study,stress relaxation compression tests were performed to investigate the strain rate sensitivity,activation volume and mobile dislocations in carbon nanotubes/aluminum(CNTs/Al)composites.The results reveal that,with the addition of CNTs,the strain rate sensitivity of CNTs/Al increased.Meanwhile,a smaller V*of CNTs/Al compared with pure Al was attributed mainly to the CNT-Al interfaces and partly to the increased forest dislocations cutting activities in grain interior,which was related to the tendency of short ranges order formation during plastic deformation.The incorporation of CNTs also improved the dislocation storage capability and reduced the dislocation velocity,leading to a lower mobile dislocation exhaustion rate.
文摘Although work factors have been associated with both presenteeism and exhaustion among hospital physicians, we lack knowledge on the dynamic relationship between demands in the work context and presenteeism and how this can be mediated by symptoms of exhaustion when controlling for job resources. The objective of this study is to examine a health impairment process of presenteeism among university hospital physicians. A cross-sectional survey of 545 university hospital physicians in Norway was conducted. Variables included in the model were presenteeism, exhaustion, work-family conflict, role conflict, social support and control over work pace. Findings from structural equation modeling indicated that exhaustion mediates the relationship between job demands and presenteeism. Job resources had no direct effect on presenteeism in the hypothesized model. The variables in the study explained 17% of the variance in presenteeism. The study is one of the first to demonstrate that the relationship between job demands and presenteeism is mediated by exhaustion when controlling for job resources. The results highlight the importance of considering the link between health symptoms and job demands to reduce the negative effects of presenteeism.
文摘CD8+ cytotoxic T lymphocyte (CTL) exhaustion is one of the major obstacles for the effectiveness of virus control in chronic infectious diseases. We previously generated novel ovalbumin (OVA)-specific 41BBL-expressing OVA-TEXO and human immunodeficiency virus (HIV-1) Gag-specific Gag-TEXO vaccines, inducing therapeutic immunity in wild-type C57BL/6 (B6) mice, and converting CTL exhaustion in recombinant OVA-specific adenovirus AdVOVA-infected B6 (AdVOVA-B6) mice with chronic infection. IL-21 cytokine plays an important role in controlling chronic infections. Therefore, in this study, we constructed recombinant transgene IL-21-expressing AdVIL-21, and generated IL-21-expressing OVA-TEXO/IL-21 and Gag-TEXO/IL21 vaccines, or control vaccines (OVA-TEXO/Null and Gag-TEXO/Null) by infecting OVA-TEXO and Gag-TEXO cells with AdVIL-21 or the control AdVNull, lacking transgene, and assessed their effects in B6 or AdVOVA-B6 mice. We demonstrate that both OVA-TEXO/IL-21 and control OVA-TEXO/Null vaccines are capable of converting CTL exhaustion in chronic infection. However, the OVA-TEXO/IL-21 vaccine more efficiently rescues exhausted CTLs by increasing stronger CTL proliferation and effector cytokine IFN-γ expression than the control OVA-TEXO/Null vaccine in AdVOVA-B6 mice with chronic infection, though both vaccines stimulated comparable OVA-specific CTL responses and protective immunity against OVA-expressing BL6-10OVA melanoma lung metastasis in wild-type B6 mice. In vivo, the OVA-TEXO/IL-21-stimulated CTLs more efficiently up-regulate phosphorylation of mTORC1-controlled EIF4E and expression of mTORC1- regulated T-bet molecule than the control OVA-TEXO/Null-stimulated ones. Importantly, the Gag-TEXO/IL21 vaccine induces stronger Gag-specific therapeutic immunity against established Gag-expressing BL6-10Gag melanoma lung metastases than the control Gag-TEXO/Null vaccine in chronic infection. Therefore, this study should have a strong impact on developing new therapeutic vaccines for patients with chronic infections.
文摘The aim of this study was to evaluate a Nature Based Rehabilitation (NBR) for a group of patients with Exhaustion Disorder (ED) in the southwest Sweden. A multidisciplinary team consisting of an occupational therapist, a physiotherapist, a medical doctor practising symbolic drama and a nurse with gardening experience provided NBR in an agricultural environment. Patients were offered 14 weeks of rehabilitation in a group of eight persons, three mornings per week. Seventeen patients participated in the study and 15 completed the study. A semi-structured interview was conducted at the beginning of the rehabilitation and at the end and a follow-up interview by telephone was done one year after completion of the rehabilitation. The interviews were recorded and transcribed. Assessment scales used included: Stress and Crisis Inventory (SCI-93), Coping Resources Inventory (CRI) and Visual Analogue Scale (VAS). Weekly notes from the staff members were reviewed and compared with the patient’s own experience. The interviews and the staff notes were analysed with semantic thematic analysis. Result showed that this kind of NBR with a multidisciplinary team promotes improved health and improved quality of life for patients with ED and may thus constitute a good alternative to treatment, provided the ED has not become chronic.
基金This experiment was supported by the following funds:The Shanghai Municipal Key Clinical Specialty(No.shslczdzk06302)National Natural Science Foundation of China(No.82103029)+1 种基金The Project of The Science and Technology Commission of Shanghai Municipality(No.21ZR1469500)The Shanghai Jiao Tong University Medicine-Engineering Fund(No.YG2021QN137).
文摘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.
文摘Uniformity of air flow in extraction openings in exhaust air channels for manure gas exhaustion is determined by the distribution of pressure. The areas required in extraction vents and in extraction ducts are determined by the uniformity of air flow desired along the duct and by the loss of pressure that can be accepted. The area ratio between the vents and the cross section of the exhaust air duct will have a strong influence on both uniformity of flow and loss of pressure. The following ventilation properties were studied： Uniformity of air flow; Variations in static pressure along a duct; Air velocity at different distances from the vents. The area ratio should be about 1 for uniform exhaustion. The studies showed that the relative variation in air velocity is independent of the level of the ventilation rate. The uniformity of the exhaust distance is influenced in about the same way by the area ratio as the air velocity in the exhaust vents. Thus, it is important that the area ratio is not too high if a good exhaust function should be guaranteed. The studies also demonstrated that the uniformity of the exhaust distance is independent of the ventilation flow rate. The exhaust ventilation range is, maximally 0.3 m from the vents. The static friction coefficient was on average 0.80.
基金supported by Chinese National Natural Science Funds(32125016,32525002,U24A20371,and W2411011)a special program from the Ministry of Science and Technology of China(2021YFA1101000,2022YFA1105200,2022YFF0608400,and 2023YFA1800200,2024YFC2707400)+6 种基金a Key R&D Program of Zhejiang Province(2023C03044 and 2024C03142)the Suzhou Innovation and Entrepreneurship Leading Talent Program(ZXL2022505,ZXL2022442)the Suzhou Medical College Basic Frontier Innovation Cross Project(YXY2303027,YXY2302017)the Joint Proiect of Pinnacle Disciplinary Group,the Second Affiliated Hospital of Chongqing Medical,Bo Xi Clinical Research Project of the First Affiliated Hospital of Soochow University(BXLC007)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)the Zhejiang Provincial Natural Science Foundation of China(LMS25H050002)the National Traditional Chinese Medicine Comprehensive Reform Demonstration Zone Science and Technology Construction Project(GZY-KJS-ZJ-2025-092).
文摘T cell exhaustion is a prevalent phenomenon in chronic infections and tumor microenvironments,severely compromising the effectiveness of antitumor and antiviral immunity.In recent years,there has been significant progress in understanding the underlying mechanisms of T cell exhaustion,including external factors and intrinsic cellular changes that drive this dysfunctional state.Key external factors such as persistent antigen exposure,immune checkpoint signaling,and the cytokine milieu,as well as intrinsic changes such as altered metabolic processes,epigenetic modifications,and transcriptional reprogramming,contribute to T cell dysfunction.Emerging therapies targeting T cell exhaustion aim to restore immune function and enhance antitumor and antiviral immunity.These therapeutic strategies include immune checkpoint inhibition,cytokine therapies,metabolic reprogramming,and cell-based therapies.Despite these advancements,reversing T cell exhaustion presents several challenges,such as individual variability,resistance,and potential side effects.Furthermore,accurately assessing markers of T cell functional recovery and the long-term impacts of these therapeutic approaches remain challenging research areas.This review provides an overview of the history and milestones in T cell exhaustion research;summarizes the mechanisms of T cell exhaustion and its implications in cancer,chronic infections,and autoimmune diseases;discusses advancements and challenges in emerging therapies;and explores future research directions aimed at improving T cell function and enhancing immune responses.
文摘T cells are central components of the adaptive immune system and play key roles in antitumor and antiviral responses.The diverse cell fates of T cells enable them to respond to different durations and strengths of antigen stimulation and various cytokine milieus in a context-dependent manner.During acute infection or vaccination,T cells differentiate into effector cells and later develop into memory cells after antigen clearance,which mediate immune protection against the same antigen.In contrast,during cancer and chronic infection,T cells fail to enter the canonical effector or memory cell differentiation path.Instead,antigen-specific T cells enter a dysfunctional,partially responsive state called exhaustion.Exhausted T cells are heterogeneous.A subset of exhausted T cells exhibits stem cell-like properties.These stem-like T cells sustain immunity through self-renewal and repopulation of terminally differentiated progenies.Stem-like properties are critical for T cell immunity induced by immunotherapy.This review summarizes recent advances in understanding the molecular mechanisms controlling the exhaustion and stemness of T cells and explores the potential of rewiring these circuits to increase the efficiency of T-cell-based immunotherapy.
