Background:The level of premature deaths(deaths among those aged 30-69 years)caused by cancer is an important indicator of evaluating the level of cancer prevention and control.However,the current burden and temporal ...Background:The level of premature deaths(deaths among those aged 30-69 years)caused by cancer is an important indicator of evaluating the level of cancer prevention and control.However,the current burden and temporal trends in cancer-related premature deaths,and their impact on life expectancy at the global,regional,and national levels are not clear.Methods:Cancer mortality data for 185 countries were obtained from the GLOBOCAN 2022 database.High-quality cancer mortality data and national population statistics for 47 countries were extracted from the United Nations and national cancer registry databases,covering the period 2003-2022.Countries were classified based on the human development index(HDI).The death probability,the year of life lost(YLL),and the potential gain in life expectancy(PGLE)attributable to premature deaths from site-specific and all-cancers combined were calculated.Results:Globally,the probability of premature cancer deaths was 6.49%(95%UI 6.49-6.50).The YLLs caused by cancer-related premature death were 163.86 million(95%UI 163.70-164.03),constituting 65.58%of the total cancer-related YLLs.The PGLEs were 1.16 years(95%UI 1.16-1.16).The premature death probability increased with higher HDI levels in men,but decreased in women.Cancer-related premature deaths as a proportion of total cancer deaths varied from 18.31%(95%UI 18.20-18.43)in Japan to 84.44%(95%UI 76.10-91.16)in São Toméand Príncipe.Lung cancer was the leading cause of cancer-related premature deaths in men,and breast cancer ranked first in women.By eradicating premature deaths attributable to lung,liver,colorectal,and stomach cancer in men,and to breast,cervical,and lung cancer in women,0.55 years(95%UI 0.55-0.55)and 0.49 years(95%UI 0.49-0.49)of PGLEs could be achieved,accounting for 48.67%and 42.24%of the total PGLEs,respectively.Cancer-related premature deaths decreased significantly in 38 countries during 2003-2022(P<0.05).The probability of premature cancer-related deaths decreased by more than 15.50%from 2015 to 2022 in 16 countries.Conclusions:Cancer-related premature deaths declined in many countries,with 16 of them having achieved the expected reduction by 2022.The current burden of cancer-related premature deaths is profound but varies around the world.Eliminating premature deaths from major cancer types could substantially increase life expectancy,underscoring the importance of prevention and treatment efforts for these cancers.展开更多
Objective:This integrative review aims to synthesize observational evidence on the prevalence,predictors,and psychosocial correlates of death anxiety in patients with hear t failure(HF).Methods:A comprehensive literat...Objective:This integrative review aims to synthesize observational evidence on the prevalence,predictors,and psychosocial correlates of death anxiety in patients with hear t failure(HF).Methods:A comprehensive literature search was conducted using 5 major databases:Scopus,Pub Med,Science Direct,Embase,and Pro Quest.Inclusion criteria were primary research studies published in English between January 2014 and March 2025 that quantitatively assessed death anxiety among patients with HF and explored its associations with demographic,clinical,or psychosocial variables.Results:A total of 12 eligible studies were identified and systematically reviewed,revealing that death anxiety is moderate to high among most samples.Key predictors of this anxiety included older age,feelings of loneliness,low socioeconomic status,and longer duration of HF.Additionally,several studies highlighted protective factors such as spiritual orientation,religious coping,and resilience.Interventions,including cognitive-behavioral therapy(CBT)and illness perception training,showed significant reductions in death anxiety.Conclusions:Death anxiety is a prevalent and impactful concern among Patients with HF,influenced by both individual and contextual factors.Routine assessment and integration of psychosocial and spiritual care—alongside evidence-based psychological interventions—are essential to address this critical aspect of HF management.展开更多
Highly potent chemotherapy provides rapid therapeutic efficacy in melanoma, but is often limited by drug resistance, off-target toxicity, and systemic toxicity. Combination therapy with chemotherapy and immunotherapy ...Highly potent chemotherapy provides rapid therapeutic efficacy in melanoma, but is often limited by drug resistance, off-target toxicity, and systemic toxicity. Combination therapy with chemotherapy and immunotherapy has attracted much attention but still faces challenges such as inconsistent immune responses and systemic toxicity. To address these limitations, we developed cathepsin B-activatable doxorubicin(DOX) prodrug nanoparticles(Cat B-NPs) for inducing tumor-specific immunogenic cell death(ICD), while minimizing off-target toxicity in normal tissues with low cathepsin B expression. The cathepsin Bactivatable DOX prodrug was synthesized by conjugating the cathepsin B-cleavable peptide(FRRL) to DOX, yielding FRRL-DOX. The amphiphilic FRRL-DOX formed stable nanoparticles(163.6 ± 13.5 nm) through intermolecular hydrophobic interaction and π-π stacking. In melanoma cells overexpressing cathepsin B, Cat B-NPs effectively induced cancer cellspecific ICD, while sparing normal cells and immune cells. When Cat B-NPs-treated B16F10cells were co-cultured with immune cells, Cat B-NPs enhanced the phagocytic activity of macrophages and induced the maturation of dendritic cells(DCs). In melanoma models,Cat B-NPs passively accumulated at tumor tissues through the enhanced permeability and retention effect and were selectively activated by intratumoral cathepsin B, enabling highdose treatment that induced robust ICD. Importantly, combination therapy with Cat B-NPs and anti-PD-L1 antibody enhanced ICD, DC maturation and T-cell activation, resulting in complete tumor regression in 50% of treated mice by converting the immunosuppressive tumor environment into an immune-responsive state. In a lung metastasis model, highdose Cat B-NPs with anti-PD-L1 also suppressed metastatic burden without systemic toxicity, supporting their potential as a safe and effective chemo-immunotherapy for melanoma.展开更多
The development of highly efficient and multifunctional nanozymes holds promise for addressing the challenges posed by drugresistant bacteria.Here,copper single-atom-loaded MoS_(2) nanozymes(CuSAs/MoS_(2))were develop...The development of highly efficient and multifunctional nanozymes holds promise for addressing the challenges posed by drugresistant bacteria.Here,copper single-atom-loaded MoS_(2) nanozymes(CuSAs/MoS_(2))were developed to effectively combat drug-resistant bacteria by synergistically integrating the triple strategies of oxidative damage,cuproptosis-like death and disruption of cell wall synthesis.Density functional theory revealed that each Cu center coordinated with three sulfur ligands,enhancing the adsorption of H_(2)O_(2),which reduced the activation energy of the key step by 17%,thereby improving peroxidase-like(PODlike)activity.The generation of reactive oxygen species in combination with CuSAs/MoS_(2) glutathione peroxidase-like(GSH-Px-like)for glutathione scavenging resulted in an imbalance in redox homeostasis within bacteria.CuSAs/MoS_(2),which act as nanopioneers,drive oxidative stress to initiate the process of cuproptosis-like death,leading to abnormal aggregation of lipoylated proteins and inactivation of iron-sulfur cluster proteins.Moreover,CuSAs/MoS_(2) inhibited the biosynthesis of the peptidoglycan synthesis precursors D-glutamate and m-diaminopimelic acid and disrupted the peptidoglycan cross-linking process mediated by penicillin-binding proteins,effectively blocking the compensatory cell wall remodeling pathway ofβ-lactam-resistant bacteria.Overall,CuSAs/MoS_(2) with multiple functions can not only efficiently kill bacteria but also decelerate the development of bacterial resistance to combat drug-resistant bacterial infections.展开更多
Doxorubicin(DOX)is known to elicit potent antitumor immune responses through the induction of immunogenic cell death(ICD).However,its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell ...Doxorubicin(DOX)is known to elicit potent antitumor immune responses through the induction of immunogenic cell death(ICD).However,its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell death ligand 1(PD-L1),which hijacked the antitumor immunity.In this study,we developed a reactive oxygen species(ROS)-responsive dihydroartemisinin(DHA)prodrug to facilitate the delivery of DOX via hydrophobic and electrostatic interactions.Upon internalization by tumor cells,the nanoparticles(NPs)preferentially accumulated in endoplasmic reticulum(ER),exacerbating ER stress and amplifying ICD to enhance tumor immunogenicity.Simultaneously,the oxidative intracellular environment trigged the degradation of NPs,releasing DHA,which downregulated PD-L1 by disrupting signal transducer and activator of transcription 3(STAT3)phosphorylation and inactivating the nuclear factor kappa-B(NF-κB)pathway.Consequently,the effective PD-L1 blockade and robust ICD response,synergistically inhibited breast cancer progression,significantly enhancing the chemo-immunotherapy efficacy of doxorubicin.展开更多
Objective:To investigate the correlation between the occurrences of unexplained sudden death in Yunnan Province and the pathogen spectrum by using real-time fluorescent quantitative reverse transcription PCR,metagenom...Objective:To investigate the correlation between the occurrences of unexplained sudden death in Yunnan Province and the pathogen spectrum by using real-time fluorescent quantitative reverse transcription PCR,metagenomic next-generation sequencing(mNGS),and virus isolation techniques to test autopsy samples from cases of unexplained sudden death and fecal specimens from populations in affected areas.Methods:Real-time fluorescent quantitative reverse transcription PCR and Sanger sequencing were performed on 101 fecal samples collected from populations in affected areas.Virus isolation was conducted on fecal and gastric content samples from individuals who died suddenly.Additionally,metavirome sequencing and pathogen spectrum abundance detection were performed on 50 autopsy organ samples.Results:No specific fragments of enteroviruses were detected in 101 fecal samples from the population in the affected wards,and no viruses were isolated from fecal and gastric content samples of sudden death victims.Among the 50 autopsy organ samples,29 were successfully sequenced.High-throughput sequencing revealed low-abundance enterovirus reads in 11 samples(relative abundance≤0.91%in all cases);Enterovirus A114 was detected in 6 samples(with relative abundances of 0.211%,0.571%,0.910%,0.013%,0.002%,and 0.0000263%,respectively);Coxsackievirus A2 in 9 samples(with relative abundances of 0.111%,0.192%,0.051%,0.291%,0.007%,0.00019%,0.00342%,0.000551%,and 0.0000368%,respectively);and Coxsackievirus B3 in 9 samples(with relative abundances of 0.312%,0.486%,0.120%,0.765%,0.001%,0.001%,0.001%,0.0000999%,and 0.00000848%,respectively).Coexistence of 2-3 types of enteroviruses was observed in some samples.Genomic annotation results indicated that high-abundance bacteria were primarily Paeniclostridium sordellii and Escherichia coli,while viral species could not be successfully assembled due to their low abundance.Conclusion:Enterovirus infection may be one of the causes of some unexplained sudden deaths in Yunnan,and the possibility of varying degrees of enterovirus infection cannot be ruled out in some populations in the affected areas.The detection of bacteria may be attributed to the normal intestinal flora of the human body or contamination during the autopsy sampling process.展开更多
The field of nanomedicine has been revolutionized by the concept of immunogenic cell death(ICD)-enhanced cancer therapy,which holds immense promise for the efficient treatment of cancer.However,precise delivery of ICD...The field of nanomedicine has been revolutionized by the concept of immunogenic cell death(ICD)-enhanced cancer therapy,which holds immense promise for the efficient treatment of cancer.However,precise delivery of ICD inducer is severely hindered by complex biological barriers.How to design and build intelligent nanoplatform for adaptive and dynamic cancer therapy remains a big challenge.Herein,this article presents the design and preparation of CD44-targeting and ZIF-8 gated gold nanocage(Au@ZH) for programmed delivery of the 1,2-diaminocyclohexane-Pt(Ⅱ)(DACHPt) as ICD inducer.After actively targeting the CD44 on the surface of 4T1 tumor cell,this Pt-Au@ZH can be effectively endocytosed by the 4T1 cell and release the DACHPt in tumor acidic environment,resulting in ICD effect and superior antitumor efficacy both in vitro and in vivo in the presence of mild 808 nm laser irradiation.By integration of internal and external stimuli intelligently,this programmed nanoplatform is poised to become a cornerstone in the pursuit of effective and targeted cancer therapy in the foreseeable future.展开更多
Aldehyde dehydrogenase 2(ALDH2),a mitochondrial enzyme,is the main acetaldehyde dehydrogenase involved in the scavenging of alcohol-derived acetaldehyde and endogenous aldehydes.The ALDH2^(rs671)mutation affects 560 m...Aldehyde dehydrogenase 2(ALDH2),a mitochondrial enzyme,is the main acetaldehyde dehydrogenase involved in the scavenging of alcohol-derived acetaldehyde and endogenous aldehydes.The ALDH2^(rs671)mutation affects 560 million East Asians and is closely related to an increased risk of various human diseases.In addition to its well-known function in detoxifying alcohol-derived acetaldehyde and endogenous aldehydes,ALDH2 is implicated in human health through its regulation of autophagic machinery and multiple cell death pathways(e.g.,apoptosis,necroptosis,pyroptosis,ferroptosis,and NETosis).This review summarizes the current knowledge of ALDH2 and the regulatory mechanism through which ALDH2 regulates autophagy and cell death.In addition,we outline the potential role of ALDH2 in the regulation of autophagy and cell death during the occurrence and progression of human diseases,aiming to provide a novel theoretical framework for human disease treatment.展开更多
Introduction.Ischemic stroke,spinal cord injury(SCI),and acute primary angle-closure glaucoma constitute three major clinically prevalent and highly disabling central nervous system(CNS)disorders.Their core pathogenes...Introduction.Ischemic stroke,spinal cord injury(SCI),and acute primary angle-closure glaucoma constitute three major clinically prevalent and highly disabling central nervous system(CNS)disorders.Their core pathogenesis universally originates from ischemia/reperfusion(I/R)injury affecting the cerebral,spinal cord,and/or retina.展开更多
Disulfidptosis is a newly identified form of regulated cell death(RCD)first described in 2023,representing a significant advance in understanding programmed cell death pathways.This unique cell death modality is chara...Disulfidptosis is a newly identified form of regulated cell death(RCD)first described in 2023,representing a significant advance in understanding programmed cell death pathways.This unique cell death modality is characterized by abnormal intracellular accumulation of disulfide bonds and disruption of redox homeostasis,leading to cytoskeletal collapse without caspase activation.Disulfidptosis is primarily triggered by glucose deprivation in cells with high expression of solute carrier family 7 member 11(SLC7A11).Under these conditions,insufficient NADPH supply prevents the effective reduction of accumulated cystine to cysteine,thereby inducing disulfide stress.Distinct from apoptosis,ferroptosis,cuproptosis,or pyroptosis,disulfidptosis exhibits unique metabolic dependencies and a hallmark feature of cytoskeletal disintegration.Current evidence indicates that this mechanism is operative in various tumor types,including hepatocellular carcinoma,colorectal cancer,and lung adenocarcinoma,suggesting its potential therapeutic relevance.Therapeutic strategies targeting disulfidptosis include modulation of metabolic pathways—such as the use of GLUT1 or G6PD inhibitors—to selectively induce this form of cell death in cancer cells.This review systematically summarizes current understanding,aiming to elucidate the unique mechanisms and therapeutic potential of disulfidptosis,and provides a foundational framework for future studies and the development of innovative strategies targeting tumor metabolic vulnerabilities.展开更多
Background:That Central and Eastern Europe and Central Asia(CEECA)experienced a major mortality crisis in the 1990s is a well-established finding,with most analyses focusing on singular causes like alcohol-related dea...Background:That Central and Eastern Europe and Central Asia(CEECA)experienced a major mortality crisis in the 1990s is a well-established finding,with most analyses focusing on singular causes like alcohol-related deaths.However,the utility of the integrated“deaths of despair”framework,which views alcohol,drug,and suicide deaths as a unified socio-economic phenomenon,remains under-explored in this context.Crucially,the long-term evolution of the composition of despair within the region remains a largely unexplored area of inquiry.Therefore,this study aims to analyze the long-term trends,changing composition,and regional heterogeneity of deaths from despair in the CEECA region from 1980 to 2021.Methods:Using 2021 Global Burden of Disease(GBD)data(1980–2021),we analyzed deaths of despair mortality trends in 29 CEECA countries.We employed Joinpoint regression to identify significant trend changes and conducted stratified analyses by cause,gender,and age group.Results:The CEECA deaths of despair crisis began as an alcohol and suicide driven phenomenon concentrated in middle-aged men(50–74 years)during the 1990s,with mortality rates for alcohol use disorders and self-harm surging annually by 30.35%(p=0.002)and 13.44%(p=0.001),respectively,between 1991 and 1994.It has since evolved,marked by a contrasting and emerging threat in the 21st century:a rising proportion of drug-related deaths among the younger(15–49 years)male cohort,where the share of drug use disorders increased from 6.9%in 2000 to 11.8%in 2008.Conclusion:The deaths of despair crisis in the CEECA region is not a past event but an ongoing,evolving phenomenon.Its changing nature demands a shift in public health focus from solely historical drivers to new,generation-specific threats,particularly the rise of drug-related despair among youth.展开更多
Ischemia-reperfusion(I/R)injury induces region-specific neuronal vulnerability within the hippocampus,with the cornu ammonis 1(CA1)subfield particularly prone to delayed neuronal death.While intrinsic neuronal factors...Ischemia-reperfusion(I/R)injury induces region-specific neuronal vulnerability within the hippocampus,with the cornu ammonis 1(CA1)subfield particularly prone to delayed neuronal death.While intrinsic neuronal factors have been implicated,emerging evidence highlights the decisive contribution of astrocyte endfeet(AEF)—specialized perivascular structures that regulate ion and water homeostasis,glutamate clearance,and blood–brain barrier(BBB)stability.This review synthesizes structural and molecular alterations of AEF across the CA1-CA3 subfields following I/R and their correlation with neuronal fate.In CA1,AEF undergo early-onset swelling and detachment from the vascular basal lamina due to dysfunction of critical proteins such as aquaporin-4(AQP4)and Kir4.1.These changes impair glutamate uptake,metabolic support,and potassium buffering,contributing to neuronal hyperexcitability and degeneration.In contrast,AEF in CA3 preserves polarity and functional coupling of AQP4 and Kir4.1,conferring regional resilience.At the signaling level,AEF disruption activates mitogen-activated protein kinase(MAPK)/c-Jun N-terminal kinase(JNK)pathways,promotes reactive oxygen species(ROS)accumulation,and induces inducible nitric oxide synthase(iNOS)-mediated inflammation,amplifying neurotoxicity.Furthermore,subfield-specific astrocytic transcriptional profiles modulate inflammatory responses and gliovascular interactions.By reframing AEF not as passive scaffolds but as active regulators of neuronal survival,this review provides novel insight into the astrocyte-dependent mechanisms of hippocampal vulnerability.Therapeutic strategies that preserve AEF structure and function may offer targeted protection against delayed neuronal death in ischemic brain injury.展开更多
BACKGROUND Death anxiety(DA)is a prevalent psychological challenge among oncology nurses that affects their emotional well-being and professional competence in coping with death-related situations.Death-related attitu...BACKGROUND Death anxiety(DA)is a prevalent psychological challenge among oncology nurses that affects their emotional well-being and professional competence in coping with death-related situations.Death-related attitudes and resilience are critical factors that may mediate the relationship between DA and coping with death competence(CDC).However,few studies have examined the chain-mediating effect of these factors among Chinese oncology nurses.This study aimed to investigate the association between DA and CDC among Chinese oncology nurses,with a focus on the mediating roles of death attitude and resilience.AIM To investigate the association between DA and CDC among Chinese oncology nurses.using an electronic questionnaire distributed in Wenjuanxing,China.In total,615 valid responses were obtained.The participants completed the Templer death anxiety scale,death attitude profile-revised,Connor-Davidson resilience scale,and coping with death scale.A chain mediation analysis was performed using the PROCESS macro in SPSS to examine the relationships between these variables.RESULTS The findings indicated that DA had a significant direct effect on CDC[effect=0.201,95%confidence interval(CI):0.112-0.322].In addition to this direct effect,three significant indirect pathways were observed:(1)Death attitude(effect=0.118,95%CI:0.056-0.163);(2)Resilience(effect=0.108,95%CI:0.032-0.176);and(3)A sequential mediation pathway involving both death attitude and resilience(effect=0.071,95%CI:0.042-0.123).The total indirect effects of the three mediation paths accounted for 29.7%of the relationship between DA and CDC.CONCLUSION Using a chain mediation model,this study explored the mechanisms linking DA,death attitude,resilience,and CDC among Chinese oncology nurses.These findings highlighted the crucial role of death attitude and resilience in mediating the relationship between DA and CDC.Interventions aimed at fostering adaptive attitudes toward death and enhancing resilience may improve nurses’ability to cope with death-related stressors,ultimately benefiting their psychological well-being and professional competence.展开更多
BACKGROUND Recent studies have indicated that an antibody against programmed cell death protein 1-ligand 1(PDCD1-LG1),a new marker of programmed cell death-ligand 1 expression,is promising for studying the mechanisms ...BACKGROUND Recent studies have indicated that an antibody against programmed cell death protein 1-ligand 1(PDCD1-LG1),a new marker of programmed cell death-ligand 1 expression,is promising for studying the mechanisms of breast cancer(BC)progression and resistance to chemotherapy.AIM To compare the features of PDCD1-LG1 expression in chemoresistant luminal A BC and BC with high Ki67 indices.METHODS This prospective single-center observational cohort study included 148 patients with newly diagnosed primary resectable BC.The tumor sections were stained with antibodies against PDCD1-LG1.The statistical calculations were performed using Statistica software version 12.0.P<0.05 was considered statistically significant.RESULTS Cytoplasmic PDCD1-LG1(cPDCD1-LG1)expression was detected in the nonneoplastic epithelium,tumor cells(TCs)and immune cells(ICs).A lack of cPDCD1-LG1 expression in≥20% of TCs and a PDCD1-LG1+IC score≥10%were associated with aggressive BC characteristics,including tumor G3,estrogen receptor-negative status,overexpression of human epidermal growth factor receptor 2(HER2+),luminal B HER2+BC,nonluminal HER2+BC and triplenegative BC.The lack of cPDCD1-LG1 expression in<20% of the TCs,in combination with a PDCD1-LG1+IC score<10% and G1,was characteristic of chemoresistant luminal A BC,whereas the lack of cPDCD1-LG1 expression in≥20% of the TCs,combined with a PDCD1-LG1+IC score≥10%,was a predictor of high BC sensitivity to chemotherapy.CONCLUSION These results indicate that both the lack of cPDCD1 LG1 in TCs and the PDCD1 LG1 IC score and their combination may be important for assessing BC prognosis and sensitivity to chemotherapy.展开更多
BACKGROUND We previously demonstrated that the antibody against programmed cell death protein 1 ligand 1(PDCD1 LG1)is a promising new marker of programmed death-ligand 1(PD-L1)expression that correlates with both brea...BACKGROUND We previously demonstrated that the antibody against programmed cell death protein 1 ligand 1(PDCD1 LG1)is a promising new marker of programmed death-ligand 1(PD-L1)expression that correlates with both breast cancer(BC)clinicopathological characteristics and tumor sensitivity to chemotherapy.However,the concordance of PDCD1 LG1 expression scoring with immunohistochemical(IHC)tests approved for clinical use and with the polymerase chain reaction(PCR)method has not been previously studied.AIM To evaluate the concordance of methods for assessing PD-L1 expression,IHC tests with anti-PD-L1(PDCD1 LG1)and anti-PD-L1(SP142)antibodies and PCR.METHODS This prospective single-center observational cohort study included 148 patients with BC.PD-L1 expression in immune cells was assessed by the IHC method with anti-PD-L1(PDCD1 LG1)and anti-PD-L1(SP142)antibodies and by PCR.The concordance of PD-L1 scores between tests was assessed with positive percentage agreement(PPA)and negative percentage agreement(NPA).The strength of the agreement between the methods was calculated via the Cohen kappa index.P<0.05 was considered statistically significant.RESULTS Regardless of the method used to assess marker expression,PD-L1 expression was significantly more often detected in patients with negative estrogen receptor status,human epidermal growth factor receptor-2-positive(HER2+)status,luminal B HER+BC,nonluminal HER+BC and triple-negative BC.PPA and NPA were 38.3%and 70.4%,respectively,for PD-L1(PDCD1 LG1)and PD-L1(SP142);26.3%and 63.3%,respectively,for PD-L1(PDCD1 LG1)and PD-L1(PCR);and 36.5%and 74.4%,respectively,for PD-L1(SP142)and PD-L1(PCR).Cohen's kappa index for PD-L1(PDCD1 LG1)and PD-L1(SP142)was 0.385(95%CI:0.304–0.466),that for PD-L1(PDCD1 LG1)and PD-L1(PCR)was 0.207(95%CI:0.127–0.287),and that for PD-L1(SP142)and PD-L1(PCR)was 0.389(95%CI:0.309–0.469).CONCLUSION Thus,all three markers of PD-L1 expression are associated with the characteristics of aggressive BC,demonstrating moderate concordance between the tests.展开更多
We read with great interest the advanced research article by He et al,which reported a marked upregulation of peroxiredoxin 1 mRNA and protein levels in colorectal cancer tissues.A central finding of this study was th...We read with great interest the advanced research article by He et al,which reported a marked upregulation of peroxiredoxin 1 mRNA and protein levels in colorectal cancer tissues.A central finding of this study was the demonstration of distinct heterogeneity in cell death mechanisms between normal and malignant cells.Current evidence indicates the existence of at least 12 subtypes of programmed cell death,each characterized by unique molecular signatures.The findings of this study have the potential to advance the development of personalized therapies that target cancer cells,representing a promising step forward in cancer treatment.Further advances in targeted mRNA therapy could be achieved by selectively shifting the regulation of cancer cells toward specific pathways of cellular death.展开更多
Hepatocellular carcinoma(HCC)is the predominant form of primary liver cancer,accounting for 90%of all cases.Currently,early diagnosis of HCC can be achieved through serum alpha-fetoprotein detection,B-ultrasound,and c...Hepatocellular carcinoma(HCC)is the predominant form of primary liver cancer,accounting for 90%of all cases.Currently,early diagnosis of HCC can be achieved through serum alpha-fetoprotein detection,B-ultrasound,and computed tomography scanning;however,their specificity and sensitivity are suboptimal.Despite significant advancements in HCC biomarker detection,the prognosis for patients with HCC remains unfavorable due to tumor heterogeneity and limited understanding of its pathogenesis.Therefore,it is crucial to explore more sensitive HCC biomarkers for improved diagnosis,monitoring,and management of the disease.Long non-coding RNA(lncRNA)serves as an auxiliary carrier of genetic information and also plays diverse intricate regulatory roles that greatly contribute to genome complexity.Moreover,investigating gene expression regulation networks from the perspective of lncRNA may provide insights into the diagnosis and prognosis of HCC.We searched the PubMed database for literature,comprehensively classified regulated cell death mechanisms and systematically reviewed research progress on lncRNA-mediated cell death pathways in HCC cells.Furthermore,we prospectively summarize its potential implications in diagnosing and treating HCC.展开更多
BACKGROUND In recent years,emerging clinical research has prioritized assessment of combined therapeutic efficacy and safety parameters when programmed death 1 or its ligand(PD-1/L1)inhibitors are incorporated into fi...BACKGROUND In recent years,emerging clinical research has prioritized assessment of combined therapeutic efficacy and safety parameters when programmed death 1 or its ligand(PD-1/L1)inhibitors are incorporated into first-line standard-of-care(SOC)therapy for metastatic colorectal cancer(mCRC).However,data obtained from these trials demonstrated conflicting evidence concerning survival benefits and clinical outcomes.AIM To evaluate the therapeutic impact and safety parameters of combining PD-1/L1 inhibitors with SOC protocols as first-line treatment for mCRC.METHODS Four biomedical databases(PubMed,Embase,Cochrane Library,Web of Science)were systematically interrogated to identify eligible studies published up to October 12,2024.The analysis focused on evaluating the primary outcome of overall survival(OS)in the mCRC population with secondary outcomes of progression-free survival(PFS),overall response rate(ORR),and incidence rate of grade≥3 adverse events.Additionally,we performed exploratory analyses in the microsatellite stable/mismatch repair-proficient(MSS/pMMR)subpopulation,based on a subset of the included studies.Subgroup analyses according to PD-1/L1 inhibitor use were conducted in both the overall population and the MSS/pMMR subgroup.RESULTS This pooled analysis incorporated six randomized controlled trials involving 675 patients with mCRC receiving first-line therapy.The combination of PD-1/L1 inhibitors with SOC regimens demonstrated a significant PFS advantage over SOC monotherapy in intention-to-treat populations[hazard ratio(HR)=0.8,95%confidence interval(CI):0.65-0.98,P=0.033].Nevertheless,the MSS/pMMR subgroup showed no PFS benefit(HR=0.83,95%CI:0.67-1.03,P=0.091),and no cohort exhibited OS improvement(intention-to-treat:HR=0.84,95%CI:0.66-1.05,P=0.124;MSS/pMMR:HR=0.79,95%CI:0.60-1.03,P=0.083).Comparable outcomes were observed for ORR(risk ratio=1.03,95%CI:0.90-1.17,P=0.711)and incidence rate of grade≥3 adverse events(risk ratio=1.12,95%CI:0.93-1.36,P=0.245)between treatment arms.CONCLUSION The findings indicated that integrating PD-1/L1 blocking agents with SOC regimens for mCRC as first-line treatment failed to demonstrate significant improvements in ORR.Existing clinical data remain inadequate to establish OS advantages,particularly in patients with MSS/pMMR,despite exhibiting manageable toxicity profiles.Subsequent confirmation through rigorously designed phase III clinical trials remains essential to verify these therapeutic outcomes.展开更多
Melanomas are aggressive cancers,with a high rate of metastatic disease.Cutaneous(CM)and uveal(UM)melanomas are intrinsically different diseases,and most cell death inducers effective for CM do not function for UM.Thi...Melanomas are aggressive cancers,with a high rate of metastatic disease.Cutaneous(CM)and uveal(UM)melanomas are intrinsically different diseases,and most cell death inducers effective for CM do not function for UM.This is primarily due to the fact the eye is an immunologically privileged organ,and it fails to achieve the efficacy of immune checkpoint inhibitors(ICIs)comparable to that for CM.However,approaches utilizing specific melanomaassociated antigens are being developed for metastatic forms of CM and UM.The most promising to date are gp100 and tyrosinase related protein 1(TYRP1),primarily for the design of targeting chimeric molecules and for autologous T-/NK-cell products with a chimeric antigen receptor.The difference in the mutational profile of apoptosis-related genes in CM and UM also makes counterproductive the use of the same drugs re-activators of the intrinsic pathway of apoptosis.Therefore,the discovery of novel pathways of regulated cell death such as ferroptosis and cuproptosis may help in the development of new drugs for melanomas resistant to already available inducers of regulated cell death.Here we consistently discuss the latest advances in the therapy of melanomas,and above all-UM,which is classified as an orphan disease.展开更多
This editorial focuses on the recent article by Yang et al in the World Journal of Gastrointestinal Oncology,which highlights the role of interlukin-17A in promoting hepatocellular carcinoma(HCC)progression by up-regu...This editorial focuses on the recent article by Yang et al in the World Journal of Gastrointestinal Oncology,which highlights the role of interlukin-17A in promoting hepatocellular carcinoma(HCC)progression by up-regulated programmed cell death protein-1(PD-1)/programmed cell death protein ligand-1(PD-L1)expression.Previous,the high PD-1/PD-L1 level was due to hepatitis virus infection leading to systemic innate immune tolerance and cluster of differen-tiation 8+T cells exhaustion,ultimately leading to HCC.Recently,interesting studies have found that the malignant progression of metabolic dysfunction-associated steatotic/fatty liver disease(MASLD/MAFLD),that is former nonalcoholic fatty liver disease,was achieved by up-regulated PD-L1 level that was activated the cGAS-STING pathway under lipid accumulation with mito-chondrial DNA overflow and up-regulated PD-1/PD-L1 to promote MASLD malignant transformation via immune escape.These data suggested that PD-1 or PD-L1 should be a promising target for preventing or delaying non-viral liver disease malignant progression except of antiviral therapy for HCC.展开更多
基金supported by the Capital’s Funds for Health Improvement and Research(CFH2024-2G-40214)the CAMS Innovation Fund for Medical Sciences(2021-I2M-1-011,2021-I2M-1-061).
文摘Background:The level of premature deaths(deaths among those aged 30-69 years)caused by cancer is an important indicator of evaluating the level of cancer prevention and control.However,the current burden and temporal trends in cancer-related premature deaths,and their impact on life expectancy at the global,regional,and national levels are not clear.Methods:Cancer mortality data for 185 countries were obtained from the GLOBOCAN 2022 database.High-quality cancer mortality data and national population statistics for 47 countries were extracted from the United Nations and national cancer registry databases,covering the period 2003-2022.Countries were classified based on the human development index(HDI).The death probability,the year of life lost(YLL),and the potential gain in life expectancy(PGLE)attributable to premature deaths from site-specific and all-cancers combined were calculated.Results:Globally,the probability of premature cancer deaths was 6.49%(95%UI 6.49-6.50).The YLLs caused by cancer-related premature death were 163.86 million(95%UI 163.70-164.03),constituting 65.58%of the total cancer-related YLLs.The PGLEs were 1.16 years(95%UI 1.16-1.16).The premature death probability increased with higher HDI levels in men,but decreased in women.Cancer-related premature deaths as a proportion of total cancer deaths varied from 18.31%(95%UI 18.20-18.43)in Japan to 84.44%(95%UI 76.10-91.16)in São Toméand Príncipe.Lung cancer was the leading cause of cancer-related premature deaths in men,and breast cancer ranked first in women.By eradicating premature deaths attributable to lung,liver,colorectal,and stomach cancer in men,and to breast,cervical,and lung cancer in women,0.55 years(95%UI 0.55-0.55)and 0.49 years(95%UI 0.49-0.49)of PGLEs could be achieved,accounting for 48.67%and 42.24%of the total PGLEs,respectively.Cancer-related premature deaths decreased significantly in 38 countries during 2003-2022(P<0.05).The probability of premature cancer-related deaths decreased by more than 15.50%from 2015 to 2022 in 16 countries.Conclusions:Cancer-related premature deaths declined in many countries,with 16 of them having achieved the expected reduction by 2022.The current burden of cancer-related premature deaths is profound but varies around the world.Eliminating premature deaths from major cancer types could substantially increase life expectancy,underscoring the importance of prevention and treatment efforts for these cancers.
文摘Objective:This integrative review aims to synthesize observational evidence on the prevalence,predictors,and psychosocial correlates of death anxiety in patients with hear t failure(HF).Methods:A comprehensive literature search was conducted using 5 major databases:Scopus,Pub Med,Science Direct,Embase,and Pro Quest.Inclusion criteria were primary research studies published in English between January 2014 and March 2025 that quantitatively assessed death anxiety among patients with HF and explored its associations with demographic,clinical,or psychosocial variables.Results:A total of 12 eligible studies were identified and systematically reviewed,revealing that death anxiety is moderate to high among most samples.Key predictors of this anxiety included older age,feelings of loneliness,low socioeconomic status,and longer duration of HF.Additionally,several studies highlighted protective factors such as spiritual orientation,religious coping,and resilience.Interventions,including cognitive-behavioral therapy(CBT)and illness perception training,showed significant reductions in death anxiety.Conclusions:Death anxiety is a prevalent and impactful concern among Patients with HF,influenced by both individual and contextual factors.Routine assessment and integration of psychosocial and spiritual care—alongside evidence-based psychological interventions—are essential to address this critical aspect of HF management.
基金supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)(RS-2024-00351185, RS-2025-02219039)by the Korea Health Industry Development Institute (KHIDI)grant funded by the Korea government (MOHW)(RS-2023-KH135133)by Korea Drug Development Fund (KDDF)funded by Ministry of Science and ICT,Ministry of Trade,Industry,and Energy,and Ministry of Health and Welfare(RS-2025-02223093)。
文摘Highly potent chemotherapy provides rapid therapeutic efficacy in melanoma, but is often limited by drug resistance, off-target toxicity, and systemic toxicity. Combination therapy with chemotherapy and immunotherapy has attracted much attention but still faces challenges such as inconsistent immune responses and systemic toxicity. To address these limitations, we developed cathepsin B-activatable doxorubicin(DOX) prodrug nanoparticles(Cat B-NPs) for inducing tumor-specific immunogenic cell death(ICD), while minimizing off-target toxicity in normal tissues with low cathepsin B expression. The cathepsin Bactivatable DOX prodrug was synthesized by conjugating the cathepsin B-cleavable peptide(FRRL) to DOX, yielding FRRL-DOX. The amphiphilic FRRL-DOX formed stable nanoparticles(163.6 ± 13.5 nm) through intermolecular hydrophobic interaction and π-π stacking. In melanoma cells overexpressing cathepsin B, Cat B-NPs effectively induced cancer cellspecific ICD, while sparing normal cells and immune cells. When Cat B-NPs-treated B16F10cells were co-cultured with immune cells, Cat B-NPs enhanced the phagocytic activity of macrophages and induced the maturation of dendritic cells(DCs). In melanoma models,Cat B-NPs passively accumulated at tumor tissues through the enhanced permeability and retention effect and were selectively activated by intratumoral cathepsin B, enabling highdose treatment that induced robust ICD. Importantly, combination therapy with Cat B-NPs and anti-PD-L1 antibody enhanced ICD, DC maturation and T-cell activation, resulting in complete tumor regression in 50% of treated mice by converting the immunosuppressive tumor environment into an immune-responsive state. In a lung metastasis model, highdose Cat B-NPs with anti-PD-L1 also suppressed metastatic burden without systemic toxicity, supporting their potential as a safe and effective chemo-immunotherapy for melanoma.
基金supported by the National Natural Science Foundation of China(82372552)the Excellent Youth of Natural Science Research Projects in Anhui Province Universities(2023AH030060)+1 种基金Anhui Provincial Natural Science Foundation(2408085Y016)Anhui Province Excellent Research and Innovation Team Project(2024AH010013)。
文摘The development of highly efficient and multifunctional nanozymes holds promise for addressing the challenges posed by drugresistant bacteria.Here,copper single-atom-loaded MoS_(2) nanozymes(CuSAs/MoS_(2))were developed to effectively combat drug-resistant bacteria by synergistically integrating the triple strategies of oxidative damage,cuproptosis-like death and disruption of cell wall synthesis.Density functional theory revealed that each Cu center coordinated with three sulfur ligands,enhancing the adsorption of H_(2)O_(2),which reduced the activation energy of the key step by 17%,thereby improving peroxidase-like(PODlike)activity.The generation of reactive oxygen species in combination with CuSAs/MoS_(2) glutathione peroxidase-like(GSH-Px-like)for glutathione scavenging resulted in an imbalance in redox homeostasis within bacteria.CuSAs/MoS_(2),which act as nanopioneers,drive oxidative stress to initiate the process of cuproptosis-like death,leading to abnormal aggregation of lipoylated proteins and inactivation of iron-sulfur cluster proteins.Moreover,CuSAs/MoS_(2) inhibited the biosynthesis of the peptidoglycan synthesis precursors D-glutamate and m-diaminopimelic acid and disrupted the peptidoglycan cross-linking process mediated by penicillin-binding proteins,effectively blocking the compensatory cell wall remodeling pathway ofβ-lactam-resistant bacteria.Overall,CuSAs/MoS_(2) with multiple functions can not only efficiently kill bacteria but also decelerate the development of bacterial resistance to combat drug-resistant bacterial infections.
基金The National Natural Science Foundation of China(Nos.82473864,82400095)the Natural Science Foundation of Jiangsu Province(No.BK20231009)+2 种基金the National Center of Technology Innovation for Biopharmaceuticals(No.NCTIB2022HS01015)“Double First-Class”Initiative Program in China Pharmaceutical Universitythe National Innovation and Entrepreneurship Training Program for Undergraduate(Nos.202310316007Z,2023103161133,2023103161333).
文摘Doxorubicin(DOX)is known to elicit potent antitumor immune responses through the induction of immunogenic cell death(ICD).However,its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell death ligand 1(PD-L1),which hijacked the antitumor immunity.In this study,we developed a reactive oxygen species(ROS)-responsive dihydroartemisinin(DHA)prodrug to facilitate the delivery of DOX via hydrophobic and electrostatic interactions.Upon internalization by tumor cells,the nanoparticles(NPs)preferentially accumulated in endoplasmic reticulum(ER),exacerbating ER stress and amplifying ICD to enhance tumor immunogenicity.Simultaneously,the oxidative intracellular environment trigged the degradation of NPs,releasing DHA,which downregulated PD-L1 by disrupting signal transducer and activator of transcription 3(STAT3)phosphorylation and inactivating the nuclear factor kappa-B(NF-κB)pathway.Consequently,the effective PD-L1 blockade and robust ICD response,synergistically inhibited breast cancer progression,significantly enhancing the chemo-immunotherapy efficacy of doxorubicin.
基金Project for Cultivating Technological Innovation Talents in Yunnan Province(Project No.:202405AD350026)Special Project for Medical and Health Talents under the“Xingdian Talent Support Program”in Yunnan Province(Project No.:XDYC-YLWS-2024-0065)Young Talent Cultivation and Funding Program of the Yunnan Institute of Endemic Disease Control and Prevention(Project No.:YIEDC-G202104)。
文摘Objective:To investigate the correlation between the occurrences of unexplained sudden death in Yunnan Province and the pathogen spectrum by using real-time fluorescent quantitative reverse transcription PCR,metagenomic next-generation sequencing(mNGS),and virus isolation techniques to test autopsy samples from cases of unexplained sudden death and fecal specimens from populations in affected areas.Methods:Real-time fluorescent quantitative reverse transcription PCR and Sanger sequencing were performed on 101 fecal samples collected from populations in affected areas.Virus isolation was conducted on fecal and gastric content samples from individuals who died suddenly.Additionally,metavirome sequencing and pathogen spectrum abundance detection were performed on 50 autopsy organ samples.Results:No specific fragments of enteroviruses were detected in 101 fecal samples from the population in the affected wards,and no viruses were isolated from fecal and gastric content samples of sudden death victims.Among the 50 autopsy organ samples,29 were successfully sequenced.High-throughput sequencing revealed low-abundance enterovirus reads in 11 samples(relative abundance≤0.91%in all cases);Enterovirus A114 was detected in 6 samples(with relative abundances of 0.211%,0.571%,0.910%,0.013%,0.002%,and 0.0000263%,respectively);Coxsackievirus A2 in 9 samples(with relative abundances of 0.111%,0.192%,0.051%,0.291%,0.007%,0.00019%,0.00342%,0.000551%,and 0.0000368%,respectively);and Coxsackievirus B3 in 9 samples(with relative abundances of 0.312%,0.486%,0.120%,0.765%,0.001%,0.001%,0.001%,0.0000999%,and 0.00000848%,respectively).Coexistence of 2-3 types of enteroviruses was observed in some samples.Genomic annotation results indicated that high-abundance bacteria were primarily Paeniclostridium sordellii and Escherichia coli,while viral species could not be successfully assembled due to their low abundance.Conclusion:Enterovirus infection may be one of the causes of some unexplained sudden deaths in Yunnan,and the possibility of varying degrees of enterovirus infection cannot be ruled out in some populations in the affected areas.The detection of bacteria may be attributed to the normal intestinal flora of the human body or contamination during the autopsy sampling process.
基金financially supported by the Natural Science Foundation of Jiangsu Province (No.BK20200709)the Natural Science Foundation of China (Nos.62288102,32201127 and 82270113)+2 种基金the Natural Science Foundation of Guangdong Province (No.2023A1515011386)the Natural Science Foundation of the Jiangsu Higher Education Institutes (No.20KJB430031)the startup fund from Nanjing Tech University,and Disciplinary Fund of School of Pharmaceutical Sciences (2024)。
文摘The field of nanomedicine has been revolutionized by the concept of immunogenic cell death(ICD)-enhanced cancer therapy,which holds immense promise for the efficient treatment of cancer.However,precise delivery of ICD inducer is severely hindered by complex biological barriers.How to design and build intelligent nanoplatform for adaptive and dynamic cancer therapy remains a big challenge.Herein,this article presents the design and preparation of CD44-targeting and ZIF-8 gated gold nanocage(Au@ZH) for programmed delivery of the 1,2-diaminocyclohexane-Pt(Ⅱ)(DACHPt) as ICD inducer.After actively targeting the CD44 on the surface of 4T1 tumor cell,this Pt-Au@ZH can be effectively endocytosed by the 4T1 cell and release the DACHPt in tumor acidic environment,resulting in ICD effect and superior antitumor efficacy both in vitro and in vivo in the presence of mild 808 nm laser irradiation.By integration of internal and external stimuli intelligently,this programmed nanoplatform is poised to become a cornerstone in the pursuit of effective and targeted cancer therapy in the foreseeable future.
基金supported by the State Key Program of the National Natural Science Foundation of China(82030059)the National Science and Technology Major Project(2023ZD0505501)+2 种基金the National Natural Science Foundation of China(81701952 and 82172127)the National Key Research and Development Program of China(2020YFC1512700)the Key Research and Development Program of Shandong Province(2021SFGC0503 and 2022ZLGX03).
文摘Aldehyde dehydrogenase 2(ALDH2),a mitochondrial enzyme,is the main acetaldehyde dehydrogenase involved in the scavenging of alcohol-derived acetaldehyde and endogenous aldehydes.The ALDH2^(rs671)mutation affects 560 million East Asians and is closely related to an increased risk of various human diseases.In addition to its well-known function in detoxifying alcohol-derived acetaldehyde and endogenous aldehydes,ALDH2 is implicated in human health through its regulation of autophagic machinery and multiple cell death pathways(e.g.,apoptosis,necroptosis,pyroptosis,ferroptosis,and NETosis).This review summarizes the current knowledge of ALDH2 and the regulatory mechanism through which ALDH2 regulates autophagy and cell death.In addition,we outline the potential role of ALDH2 in the regulation of autophagy and cell death during the occurrence and progression of human diseases,aiming to provide a novel theoretical framework for human disease treatment.
基金supported by the National Natural Science Foundation of China(Grant nos.62576136 to Yan Huang82372507,82572869 to Kun Xiongthe National Natural Science Foundation of Hunan Province(Grant no.2026JJ30177).
文摘Introduction.Ischemic stroke,spinal cord injury(SCI),and acute primary angle-closure glaucoma constitute three major clinically prevalent and highly disabling central nervous system(CNS)disorders.Their core pathogenesis universally originates from ischemia/reperfusion(I/R)injury affecting the cerebral,spinal cord,and/or retina.
文摘Disulfidptosis is a newly identified form of regulated cell death(RCD)first described in 2023,representing a significant advance in understanding programmed cell death pathways.This unique cell death modality is characterized by abnormal intracellular accumulation of disulfide bonds and disruption of redox homeostasis,leading to cytoskeletal collapse without caspase activation.Disulfidptosis is primarily triggered by glucose deprivation in cells with high expression of solute carrier family 7 member 11(SLC7A11).Under these conditions,insufficient NADPH supply prevents the effective reduction of accumulated cystine to cysteine,thereby inducing disulfide stress.Distinct from apoptosis,ferroptosis,cuproptosis,or pyroptosis,disulfidptosis exhibits unique metabolic dependencies and a hallmark feature of cytoskeletal disintegration.Current evidence indicates that this mechanism is operative in various tumor types,including hepatocellular carcinoma,colorectal cancer,and lung adenocarcinoma,suggesting its potential therapeutic relevance.Therapeutic strategies targeting disulfidptosis include modulation of metabolic pathways—such as the use of GLUT1 or G6PD inhibitors—to selectively induce this form of cell death in cancer cells.This review systematically summarizes current understanding,aiming to elucidate the unique mechanisms and therapeutic potential of disulfidptosis,and provides a foundational framework for future studies and the development of innovative strategies targeting tumor metabolic vulnerabilities.
基金supported by grants from the National Research Foundation of Korea(NRF)under the Ministry of Science and Information and Communication Technology(grant number:RS-2023-00249082)Korea University(grant number:K2225791).
文摘Background:That Central and Eastern Europe and Central Asia(CEECA)experienced a major mortality crisis in the 1990s is a well-established finding,with most analyses focusing on singular causes like alcohol-related deaths.However,the utility of the integrated“deaths of despair”framework,which views alcohol,drug,and suicide deaths as a unified socio-economic phenomenon,remains under-explored in this context.Crucially,the long-term evolution of the composition of despair within the region remains a largely unexplored area of inquiry.Therefore,this study aims to analyze the long-term trends,changing composition,and regional heterogeneity of deaths from despair in the CEECA region from 1980 to 2021.Methods:Using 2021 Global Burden of Disease(GBD)data(1980–2021),we analyzed deaths of despair mortality trends in 29 CEECA countries.We employed Joinpoint regression to identify significant trend changes and conducted stratified analyses by cause,gender,and age group.Results:The CEECA deaths of despair crisis began as an alcohol and suicide driven phenomenon concentrated in middle-aged men(50–74 years)during the 1990s,with mortality rates for alcohol use disorders and self-harm surging annually by 30.35%(p=0.002)and 13.44%(p=0.001),respectively,between 1991 and 1994.It has since evolved,marked by a contrasting and emerging threat in the 21st century:a rising proportion of drug-related deaths among the younger(15–49 years)male cohort,where the share of drug use disorders increased from 6.9%in 2000 to 11.8%in 2008.Conclusion:The deaths of despair crisis in the CEECA region is not a past event but an ongoing,evolving phenomenon.Its changing nature demands a shift in public health focus from solely historical drivers to new,generation-specific threats,particularly the rise of drug-related despair among youth.
文摘Ischemia-reperfusion(I/R)injury induces region-specific neuronal vulnerability within the hippocampus,with the cornu ammonis 1(CA1)subfield particularly prone to delayed neuronal death.While intrinsic neuronal factors have been implicated,emerging evidence highlights the decisive contribution of astrocyte endfeet(AEF)—specialized perivascular structures that regulate ion and water homeostasis,glutamate clearance,and blood–brain barrier(BBB)stability.This review synthesizes structural and molecular alterations of AEF across the CA1-CA3 subfields following I/R and their correlation with neuronal fate.In CA1,AEF undergo early-onset swelling and detachment from the vascular basal lamina due to dysfunction of critical proteins such as aquaporin-4(AQP4)and Kir4.1.These changes impair glutamate uptake,metabolic support,and potassium buffering,contributing to neuronal hyperexcitability and degeneration.In contrast,AEF in CA3 preserves polarity and functional coupling of AQP4 and Kir4.1,conferring regional resilience.At the signaling level,AEF disruption activates mitogen-activated protein kinase(MAPK)/c-Jun N-terminal kinase(JNK)pathways,promotes reactive oxygen species(ROS)accumulation,and induces inducible nitric oxide synthase(iNOS)-mediated inflammation,amplifying neurotoxicity.Furthermore,subfield-specific astrocytic transcriptional profiles modulate inflammatory responses and gliovascular interactions.By reframing AEF not as passive scaffolds but as active regulators of neuronal survival,this review provides novel insight into the astrocyte-dependent mechanisms of hippocampal vulnerability.Therapeutic strategies that preserve AEF structure and function may offer targeted protection against delayed neuronal death in ischemic brain injury.
基金Supported by the Hunan Provincial Natural Science Foundation of China,No.2025JJ80410.
文摘BACKGROUND Death anxiety(DA)is a prevalent psychological challenge among oncology nurses that affects their emotional well-being and professional competence in coping with death-related situations.Death-related attitudes and resilience are critical factors that may mediate the relationship between DA and coping with death competence(CDC).However,few studies have examined the chain-mediating effect of these factors among Chinese oncology nurses.This study aimed to investigate the association between DA and CDC among Chinese oncology nurses,with a focus on the mediating roles of death attitude and resilience.AIM To investigate the association between DA and CDC among Chinese oncology nurses.using an electronic questionnaire distributed in Wenjuanxing,China.In total,615 valid responses were obtained.The participants completed the Templer death anxiety scale,death attitude profile-revised,Connor-Davidson resilience scale,and coping with death scale.A chain mediation analysis was performed using the PROCESS macro in SPSS to examine the relationships between these variables.RESULTS The findings indicated that DA had a significant direct effect on CDC[effect=0.201,95%confidence interval(CI):0.112-0.322].In addition to this direct effect,three significant indirect pathways were observed:(1)Death attitude(effect=0.118,95%CI:0.056-0.163);(2)Resilience(effect=0.108,95%CI:0.032-0.176);and(3)A sequential mediation pathway involving both death attitude and resilience(effect=0.071,95%CI:0.042-0.123).The total indirect effects of the three mediation paths accounted for 29.7%of the relationship between DA and CDC.CONCLUSION Using a chain mediation model,this study explored the mechanisms linking DA,death attitude,resilience,and CDC among Chinese oncology nurses.These findings highlighted the crucial role of death attitude and resilience in mediating the relationship between DA and CDC.Interventions aimed at fostering adaptive attitudes toward death and enhancing resilience may improve nurses’ability to cope with death-related stressors,ultimately benefiting their psychological well-being and professional competence.
基金Supported by the Russian Science Foundation,No.23-25-00183.
文摘BACKGROUND Recent studies have indicated that an antibody against programmed cell death protein 1-ligand 1(PDCD1-LG1),a new marker of programmed cell death-ligand 1 expression,is promising for studying the mechanisms of breast cancer(BC)progression and resistance to chemotherapy.AIM To compare the features of PDCD1-LG1 expression in chemoresistant luminal A BC and BC with high Ki67 indices.METHODS This prospective single-center observational cohort study included 148 patients with newly diagnosed primary resectable BC.The tumor sections were stained with antibodies against PDCD1-LG1.The statistical calculations were performed using Statistica software version 12.0.P<0.05 was considered statistically significant.RESULTS Cytoplasmic PDCD1-LG1(cPDCD1-LG1)expression was detected in the nonneoplastic epithelium,tumor cells(TCs)and immune cells(ICs).A lack of cPDCD1-LG1 expression in≥20% of TCs and a PDCD1-LG1+IC score≥10%were associated with aggressive BC characteristics,including tumor G3,estrogen receptor-negative status,overexpression of human epidermal growth factor receptor 2(HER2+),luminal B HER2+BC,nonluminal HER2+BC and triplenegative BC.The lack of cPDCD1-LG1 expression in<20% of the TCs,in combination with a PDCD1-LG1+IC score<10% and G1,was characteristic of chemoresistant luminal A BC,whereas the lack of cPDCD1-LG1 expression in≥20% of the TCs,combined with a PDCD1-LG1+IC score≥10%,was a predictor of high BC sensitivity to chemotherapy.CONCLUSION These results indicate that both the lack of cPDCD1 LG1 in TCs and the PDCD1 LG1 IC score and their combination may be important for assessing BC prognosis and sensitivity to chemotherapy.
基金Supported by Russian Science Foundation,No.23-25-00183.
文摘BACKGROUND We previously demonstrated that the antibody against programmed cell death protein 1 ligand 1(PDCD1 LG1)is a promising new marker of programmed death-ligand 1(PD-L1)expression that correlates with both breast cancer(BC)clinicopathological characteristics and tumor sensitivity to chemotherapy.However,the concordance of PDCD1 LG1 expression scoring with immunohistochemical(IHC)tests approved for clinical use and with the polymerase chain reaction(PCR)method has not been previously studied.AIM To evaluate the concordance of methods for assessing PD-L1 expression,IHC tests with anti-PD-L1(PDCD1 LG1)and anti-PD-L1(SP142)antibodies and PCR.METHODS This prospective single-center observational cohort study included 148 patients with BC.PD-L1 expression in immune cells was assessed by the IHC method with anti-PD-L1(PDCD1 LG1)and anti-PD-L1(SP142)antibodies and by PCR.The concordance of PD-L1 scores between tests was assessed with positive percentage agreement(PPA)and negative percentage agreement(NPA).The strength of the agreement between the methods was calculated via the Cohen kappa index.P<0.05 was considered statistically significant.RESULTS Regardless of the method used to assess marker expression,PD-L1 expression was significantly more often detected in patients with negative estrogen receptor status,human epidermal growth factor receptor-2-positive(HER2+)status,luminal B HER+BC,nonluminal HER+BC and triple-negative BC.PPA and NPA were 38.3%and 70.4%,respectively,for PD-L1(PDCD1 LG1)and PD-L1(SP142);26.3%and 63.3%,respectively,for PD-L1(PDCD1 LG1)and PD-L1(PCR);and 36.5%and 74.4%,respectively,for PD-L1(SP142)and PD-L1(PCR).Cohen's kappa index for PD-L1(PDCD1 LG1)and PD-L1(SP142)was 0.385(95%CI:0.304–0.466),that for PD-L1(PDCD1 LG1)and PD-L1(PCR)was 0.207(95%CI:0.127–0.287),and that for PD-L1(SP142)and PD-L1(PCR)was 0.389(95%CI:0.309–0.469).CONCLUSION Thus,all three markers of PD-L1 expression are associated with the characteristics of aggressive BC,demonstrating moderate concordance between the tests.
基金Supported by Russian Science Foundation,No.24-64-00028.
文摘We read with great interest the advanced research article by He et al,which reported a marked upregulation of peroxiredoxin 1 mRNA and protein levels in colorectal cancer tissues.A central finding of this study was the demonstration of distinct heterogeneity in cell death mechanisms between normal and malignant cells.Current evidence indicates the existence of at least 12 subtypes of programmed cell death,each characterized by unique molecular signatures.The findings of this study have the potential to advance the development of personalized therapies that target cancer cells,representing a promising step forward in cancer treatment.Further advances in targeted mRNA therapy could be achieved by selectively shifting the regulation of cancer cells toward specific pathways of cellular death.
基金Supported by Science Project of Hunan Provincial Healthy Commission,No.20230844.
文摘Hepatocellular carcinoma(HCC)is the predominant form of primary liver cancer,accounting for 90%of all cases.Currently,early diagnosis of HCC can be achieved through serum alpha-fetoprotein detection,B-ultrasound,and computed tomography scanning;however,their specificity and sensitivity are suboptimal.Despite significant advancements in HCC biomarker detection,the prognosis for patients with HCC remains unfavorable due to tumor heterogeneity and limited understanding of its pathogenesis.Therefore,it is crucial to explore more sensitive HCC biomarkers for improved diagnosis,monitoring,and management of the disease.Long non-coding RNA(lncRNA)serves as an auxiliary carrier of genetic information and also plays diverse intricate regulatory roles that greatly contribute to genome complexity.Moreover,investigating gene expression regulation networks from the perspective of lncRNA may provide insights into the diagnosis and prognosis of HCC.We searched the PubMed database for literature,comprehensively classified regulated cell death mechanisms and systematically reviewed research progress on lncRNA-mediated cell death pathways in HCC cells.Furthermore,we prospectively summarize its potential implications in diagnosing and treating HCC.
文摘BACKGROUND In recent years,emerging clinical research has prioritized assessment of combined therapeutic efficacy and safety parameters when programmed death 1 or its ligand(PD-1/L1)inhibitors are incorporated into first-line standard-of-care(SOC)therapy for metastatic colorectal cancer(mCRC).However,data obtained from these trials demonstrated conflicting evidence concerning survival benefits and clinical outcomes.AIM To evaluate the therapeutic impact and safety parameters of combining PD-1/L1 inhibitors with SOC protocols as first-line treatment for mCRC.METHODS Four biomedical databases(PubMed,Embase,Cochrane Library,Web of Science)were systematically interrogated to identify eligible studies published up to October 12,2024.The analysis focused on evaluating the primary outcome of overall survival(OS)in the mCRC population with secondary outcomes of progression-free survival(PFS),overall response rate(ORR),and incidence rate of grade≥3 adverse events.Additionally,we performed exploratory analyses in the microsatellite stable/mismatch repair-proficient(MSS/pMMR)subpopulation,based on a subset of the included studies.Subgroup analyses according to PD-1/L1 inhibitor use were conducted in both the overall population and the MSS/pMMR subgroup.RESULTS This pooled analysis incorporated six randomized controlled trials involving 675 patients with mCRC receiving first-line therapy.The combination of PD-1/L1 inhibitors with SOC regimens demonstrated a significant PFS advantage over SOC monotherapy in intention-to-treat populations[hazard ratio(HR)=0.8,95%confidence interval(CI):0.65-0.98,P=0.033].Nevertheless,the MSS/pMMR subgroup showed no PFS benefit(HR=0.83,95%CI:0.67-1.03,P=0.091),and no cohort exhibited OS improvement(intention-to-treat:HR=0.84,95%CI:0.66-1.05,P=0.124;MSS/pMMR:HR=0.79,95%CI:0.60-1.03,P=0.083).Comparable outcomes were observed for ORR(risk ratio=1.03,95%CI:0.90-1.17,P=0.711)and incidence rate of grade≥3 adverse events(risk ratio=1.12,95%CI:0.93-1.36,P=0.245)between treatment arms.CONCLUSION The findings indicated that integrating PD-1/L1 blocking agents with SOC regimens for mCRC as first-line treatment failed to demonstrate significant improvements in ORR.Existing clinical data remain inadequate to establish OS advantages,particularly in patients with MSS/pMMR,despite exhibiting manageable toxicity profiles.Subsequent confirmation through rigorously designed phase III clinical trials remains essential to verify these therapeutic outcomes.
基金supported by the Russian Science Foundation,project no.23-14-00285。
文摘Melanomas are aggressive cancers,with a high rate of metastatic disease.Cutaneous(CM)and uveal(UM)melanomas are intrinsically different diseases,and most cell death inducers effective for CM do not function for UM.This is primarily due to the fact the eye is an immunologically privileged organ,and it fails to achieve the efficacy of immune checkpoint inhibitors(ICIs)comparable to that for CM.However,approaches utilizing specific melanomaassociated antigens are being developed for metastatic forms of CM and UM.The most promising to date are gp100 and tyrosinase related protein 1(TYRP1),primarily for the design of targeting chimeric molecules and for autologous T-/NK-cell products with a chimeric antigen receptor.The difference in the mutational profile of apoptosis-related genes in CM and UM also makes counterproductive the use of the same drugs re-activators of the intrinsic pathway of apoptosis.Therefore,the discovery of novel pathways of regulated cell death such as ferroptosis and cuproptosis may help in the development of new drugs for melanomas resistant to already available inducers of regulated cell death.Here we consistently discuss the latest advances in the therapy of melanomas,and above all-UM,which is classified as an orphan disease.
基金Supported by National Natural Science Foundation of China,No.81673241 and No.32470985.
文摘This editorial focuses on the recent article by Yang et al in the World Journal of Gastrointestinal Oncology,which highlights the role of interlukin-17A in promoting hepatocellular carcinoma(HCC)progression by up-regulated programmed cell death protein-1(PD-1)/programmed cell death protein ligand-1(PD-L1)expression.Previous,the high PD-1/PD-L1 level was due to hepatitis virus infection leading to systemic innate immune tolerance and cluster of differen-tiation 8+T cells exhaustion,ultimately leading to HCC.Recently,interesting studies have found that the malignant progression of metabolic dysfunction-associated steatotic/fatty liver disease(MASLD/MAFLD),that is former nonalcoholic fatty liver disease,was achieved by up-regulated PD-L1 level that was activated the cGAS-STING pathway under lipid accumulation with mito-chondrial DNA overflow and up-regulated PD-1/PD-L1 to promote MASLD malignant transformation via immune escape.These data suggested that PD-1 or PD-L1 should be a promising target for preventing or delaying non-viral liver disease malignant progression except of antiviral therapy for HCC.
