In early of 1960s, I was a graduate student studying on tRNA biochemistry. In the course of the research, the magnesium ions stabilized the tertiary structure of tRNA, resulting in its resistance to enzymatic degradat...In early of 1960s, I was a graduate student studying on tRNA biochemistry. In the course of the research, the magnesium ions stabilized the tertiary structure of tRNA, resulting in its resistance to enzymatic degradation was discovered independently. The experiment of deaminated (denatured) tRNA obtained from native tRNA was designed and conducted and further proved the validity of this finding. It was found that magnesium ions could stabilize the tertiary structure of the natrive tRNA but could not stabilize structure of the deaminated tRNA. In term of the methodology, this stabilization technique has been widely applied in sequencing analysis of RNA and has greatly promoted the progress in the study of primary structure of RNA. More importantly, the stabilization of the tertiary structure of RNA by magnesium ions plays a key role both in the processing of messenger RNAs and the ribozyme activity. After our first article in Chinese was published in 1963, a paper of Nishimura & Novelli came into our note. The received date of their paper was March 22 of 1963, only 4 days earlier than that of our first paper. Thus, we and Nishimura & Novelli made almost at the same time the earliest discovery of the role of magnesium ions on stabilizing the tertiary structure of the transfer RNA and thus resulted in resistance of tRNA degradation by enzymes. However, this discovery was not initially appreciated for a period of time but was finally “visualized” and proved by X-ray crystal structure of yeast phenylalanine tRNA, which has provided more accurate information on the geometry of the magnesium-binding sites in tRNA.展开更多
Structure-based protein classification can be based on the similarities in primary, second or tertiary structures of proteins. A method using virtual-bond-angles series that transformed the protein space configuration...Structure-based protein classification can be based on the similarities in primary, second or tertiary structures of proteins. A method using virtual-bond-angles series that transformed the protein space configuration into a sequence was used for the classification of three-dimensional structures oi proteins. By transforming the main chains formed by C^a atoms of proteins into sequences, the series of virtual-bond-angles corresponding to the tertiary structure of the proteins were constructed. Then a distance-based hierarchical clustering method similar to Ward method was introduced to classify these virtual-bond-angles series of proteins. 200 files of protein structures were selected from Brookheaven protein data bank, and 11 clusters were classified.展开更多
Background:Tertiary lymphoid structures(TLSs)promote antitumor immunity and predict favorable immunotherapy outcomes in breast cancer.The study aimed to investigate how Tryptophan 2,3-dioxygenase(TDO2)-associated tryp...Background:Tertiary lymphoid structures(TLSs)promote antitumor immunity and predict favorable immunotherapy outcomes in breast cancer.The study aimed to investigate how Tryptophan 2,3-dioxygenase(TDO2)-associated tryptophan metabolism influences TLS maturation and B cell class switching in breast cancer.Methods:Bulk transcriptomic data from The Cancer Genome Atlas-Breast Invasive Carcinoma(TCGA-BRCA,n=1055)were analyzed using Gene Set Variation Analysis(GSVA)-based metabolic scoring,immune deconvolution,and TLS quantification.Single-cell RNA sequencing(scRNA-seq,n=26)and spatial transcriptomics(n=1)were applied to map TDO2 expression and TLS spatial organization.Validation was performed by immunohistochemistry(n=38)and multiplex immunofluorescence(n=12).Results:We identified that elevated tryptophan metabolism was predominantly enriched in the Luminal A subtype and delineates an immune-cold phenotype with less immunogenicity,associated with a distinct immune-dominant cellular microenvironment,particularly enriched in T and plasma cells.High expression of the tryptophan-metabolizing enzyme TDO2 was significantly enriched in TLS-low tumors and negatively correlated with TLS maturation signatures.Functional enrichment revealed suppressed B cell class switching and attenuated C-X-C motif chemokine ligand 9(CXCL9)expression in TLS-deficient tumors.Spatial transcriptomics and hotspot analysis demonstrated an inverse spatial correlation between TDO2 expression and TLS core components.Tumors with high tryptophan metabolism showed decreased cluster of differentiation 20(CD20)^(+)and CXCL9^(+)cell infiltration within TLS zones.Tumors with strong TDO2-kynurenine activity displayed impaired TLS organization and attenuated humoral immunity.Conditional spatial co-occurrence modeling confirmed reduced proximity between tryptophan metabolism hotspots and TLS-related immune features.Conclusion:In conclusion,our findings suggest that TDO2-associated tryptophan metabolism is linked to impaired TLS maturation and suppressed B cell class switching in breast cancer.Targeting the TDO2-kynurenine axis may represent a promising strategy to restore TLS formation and enhance immunotherapy responsiveness in breast cancer.展开更多
Background:Chronic inflammation is closely associated with the most common and socially significant prostate conditions,including benign prostatic hyperplasia(BPH),prostate cancer(PCa),and prostatitis syndromes.NIHcat...Background:Chronic inflammation is closely associated with the most common and socially significant prostate conditions,including benign prostatic hyperplasia(BPH),prostate cancer(PCa),and prostatitis syndromes.NIHcategory IV prostatitis(histologic prostatitis,HP)is defined as asymptomatic chronic inflammation of the prostate.The presence of lymphoid follicles,referred to as tertiary lymphoid structures(TLSs),along with benign lympho-epithelial lesions(BLELs),is among the key histological indicators of immune inflammation and can be assessed relatively easily.This study aimed to quantitatively assess TLSs and BLELs,as well as their relationship with the severity of HP.Methods:We investigated TLSs and BLELs in 110 prostatic specimens,including inflammatory and normal tissues,within the context of common prostate pathologies such as BPH and PCa.HP was graded as low-grade(LG)or high-grade(HG)based on the severity of inflammation.Results:TLSs were observed in 51 out of 110 cases(46.4%),while BLELs were identified in 78 cases(70.44%).Both TLSs and BLELs co-occurred in 45 cases(40.9%).Statistical analysis revealed a significant correlation between the presence of TLSs,BLELs(individually or combined),and HG-HP(p<0.001).Conclusions:This study is the first to quantitatively evaluate the immunopathologic patterns in the inflamed human prostate by analyzing the presence and cooccurrence of TLSs and BLELs.Their formation,likely triggered by antigenic stimuli and external factors,indicates a chronic inflammatory microenvironment.The strong association between TLSs,BLELs,and HG-HP underscores their potential role in HP aggressiveness.These findings suggest that TLSs and BLELs may be crucial contributors to the pathophysiology and morphogenesis of NIH-category IV prostatitis.Furthermore,TLS/BLEL formation may represent a hallmark of tissue autoimmunity,reflecting the immune or autoimmune phase of this prostatitis subtype.展开更多
Objective Cigarette smoking exacerbates the progression of pulmonary tuberculosis(TB).The role of tertiary lymphoid structures(TLS)in chronic lung diseases has gained attention;however,it remains unclear whether smoki...Objective Cigarette smoking exacerbates the progression of pulmonary tuberculosis(TB).The role of tertiary lymphoid structures(TLS)in chronic lung diseases has gained attention;however,it remains unclear whether smoking-exacerbated lung damage in TB is associated with TLS.This study aimed to analyze the characteristics of pulmonary TLS in smokers with TB and to explore the possible role of TLS in smoking-related lung injury in TB.Methods Lung tissues from 36 male patients(18 smokers and 18 non-smokers)who underwent surgical resection for pulmonary TB were included in this study.Pathological and immunohistological analyses were conducted to evaluate the quantity of TLS,and chest computed tomography(CT)was used to assess the severity of lung lesions.The correlation between the TLS quantity and TB lesion severity scores was analyzed.The immune cells and chemokines involved in TLS formation were also evaluated and compared between smokers and non-smokers.Results Smoker patients with TB had significantly higher TLS than non-smokers(P<0.001).The TLS quantity in both the lung parenchyma and peribronchial regions correlated with TB lesion severity on chest CT(parenchyma:r=0.5767;peribronchial:r=0.7373;both P<0.001).Immunohistochemical analysis showed increased B cells,T cells,and C-X-C motif chemokine ligand 13(CXCL13)expression in smoker patients with TB(P<0.001).Conclusion Smoker TB patients exhibited increased pulmonary TLS,which was associated with exacerbated lung lesions on chest CT,suggesting that cigarette smoking may exacerbate lung damage by promoting TLS formation.展开更多
Changes in the intestinal immune micro-environment of the gastrointestinal tract are indispensable in the occurrence and development of gastrointestinal cancer.Tertiary lymphoid structure(TLS)is an immune cell aggrega...Changes in the intestinal immune micro-environment of the gastrointestinal tract are indispensable in the occurrence and development of gastrointestinal cancer.Tertiary lymphoid structure(TLS)is an immune cell aggregation structure found around gastrointestinal cancer in recent years.More and more research proves that tertiary lymphoid structure plays a key biological role and clinical value in disease progression,patient prognosis,and adjuvant treatment.This review aims to explore the research progress,biological significance,and potential clinical applications of TLSs in gastrointestinal tumors.The formation,development,and interaction of TLSs with tumor microenvironment have been reviewed and analyzed in recent years.Meanwhile,this review not only evaluates the clinical value of TLSs as prognostic biomarkers and predictors of treatment response but also explores their role in guiding the formulation of immunotherapy strategies for gastrointestinal tumors.In addition,this review points out the main problems in the current research of TLSs and looks forward to their future development,especially their broad application prospects in the diagnosis,treatment,and prognostic evaluation of gastrointestinal tumors.展开更多
Objective:Recent studies have highlighted the distinct value of tertiary lymphoid structure(TLS)for immunotherapeutic response prediction.However,it remains unclear whether TLS could play such roles in gastric cancer(...Objective:Recent studies have highlighted the distinct value of tertiary lymphoid structure(TLS)for immunotherapeutic response prediction.However,it remains unclear whether TLS could play such roles in gastric cancer(GC).Methods:In this study,tumor tissue slices from 292 GC patients from Zhongshan Hospital were firstly reviewed to explore the correlation between TLS and clinical characteristics.Subsequently,we curated 38 reported genes that may function as triggers of TLS and performed consensus molecular subtyping in public RNA-seq datasets to determine TLS patterns in GC.Based on the differentially expressed genes acquired from two TLS patterns,we quantified TLS-related genes on the principal component analysis(PCA)algorithm to develop TLS score.A Zhongshan immunotherapy cohort including 13 patients who received programmed cell death 1(PD1)blockade therapy was established to conduct RNA sequencing analysis and multiplex immunohistochemistry(mIHC)tests using formalin-fixed and paraffin-embedded(FFPE)tissues.The corresponding TLS score and immune cell counts were further compared based on therapeutic response variations.Results:Mature TLS was revealed as an independent prognostic factor in 292 GC patients.Patients with higher TLS score was characterized by prolonged survival time and superior response to immunotherapy.TLS score was correlated with immunotherapy-related characters,such as microsatellite instability(MSI)and tumor mutation burden(TMB).In addition,RNA-seq data analysis in the Zhongshan immunotherapy cohort indicated that a higher TLS score was correlated with a superior response to PD1 blockade therapy.mIHC tests also revealed that PD1+CD8+T cell counts were significantly increased in the high-TLS score group.Conclusions:This study highlighted that TLS was significantly associated with immune landscape diversity and complexity.Quantitatively evaluating TLS patterns of individual tumor will strengthen our understanding of TME characteristics and promote more effective immunotherapy strategies.展开更多
Tertiary lymphoid structures(TLSs)are ectopic immune cell aggregations that develop in peripheral tissues in response to a wide range of chronic inflammatory conditions,including infection,autoimmune disease,and cance...Tertiary lymphoid structures(TLSs)are ectopic immune cell aggregations that develop in peripheral tissues in response to a wide range of chronic inflammatory conditions,including infection,autoimmune disease,and cancer.In the tumor microenvironment(TME),the structures of TLSs,including B-cell-and T-cell-enriched areas indicate that the TLSs might be the local site during the initiation and maintenance of humoral and cellular immune responses against cancers.Numerous studies have evaluated the expression of TLSs in different cancer patients and their association with prognoses of cancer patients.It was shown that welldeveloped TLSs characterized by mature B cells synthesized tumor specific antibodies,which were considered as specific markers for a good prognosis.However,there are still some immunosuppressive factors existing in the TLSs that may affect anti-tumor responses.These factors include dysfunctional B cells,regulatory T cells,and T follicular regulatory cells.The complexity and heterogeneity of the TLS composition may affect the function and activity of TLSs;it is therefore essential to fully understand the function and influencing factors in TLSs.It has been reported that checkpoint inhibitors and vaccines are currently being developed to reprogram the TME by establishing mature TLSs to improve cancer immunotherapies.In this review,we focused on recent advances in TLSs in human solid tumors,including structural characteristics and classes,antitumor mechanisms,immunosuppressive factors,and TLSbased therapeutic approaches.展开更多
Tumor-associated tertiary lymphoid structures(TLSs)are ectopic lymphoid formations within tumor tissue,with mainly B and T cell populations forming the organic aggregates.The presence of TLSs in tumors has been strong...Tumor-associated tertiary lymphoid structures(TLSs)are ectopic lymphoid formations within tumor tissue,with mainly B and T cell populations forming the organic aggregates.The presence of TLSs in tumors has been strongly associated with patient responsiveness to immunotherapy regimens and improving tumor prognosis.Researchers have been motivated to actively explore TLSs due to their bright clinical application prospects.Various studies have attempted to decipher TLSs regarding their formation mechanism,structural composition,induction generation,predictive markers,and clinical utilization.Meanwhile,the scientific approaches to qualitative and quantitative descriptions are crucial for TLS studies.In terms of detection,hematoxylin and eosin(H&E),multiplex immunohistochemistry(mIHC),multiplex immunofluorescence(mIF),and 12-chemokine gene signature have been the top approved methods.However,no standard methods exist for the quantitative analysis of TLSs,such as absolute TLS count,analysis of TLS constituent cells,structural features,TLS spatial location,density,and maturity.This study reviews the latest research progress on TLS detection and quantification,proposes new directions for TLS assessment,and addresses issues for the quantitative application of TLSs in the clinic.展开更多
Tertiary lymphoid structures(TLSs)are formations at sites with persistent inflammatory stimulation,including tumors.These ectopic lymphoid organs mainly consist of chemo-attracting B cells,T cells,and supporting dendr...Tertiary lymphoid structures(TLSs)are formations at sites with persistent inflammatory stimulation,including tumors.These ectopic lymphoid organs mainly consist of chemo-attracting B cells,T cells,and supporting dendritic cells(DCs).Mature TLSs exhibit functional organization for the optimal development and collaboration of adaptive immune response,delivering an augmented effect on the tumor microenvironment(TME).The description of the positive correlation between TLSs and tumor prognosis is reliable only under a certain condition involving the localization and maturation of TLSs.Emerging evidence suggests that underlying mechanisms of the anti-tumor effect of TLSs pave the way for novel immunotherapies.Several approaches have been developed to take advantage of intratumoral TLSs,either by combining it with therapeutic agents or by inducing the neogenesis of TLSs.展开更多
Transfer RNAs(tRNAs)adopt a stable L-shaped tertiary structure crucial for their involvement in protein translation.Among various divalent metal ions,magnesium ions play a pivotal role in preserving the tertiary struc...Transfer RNAs(tRNAs)adopt a stable L-shaped tertiary structure crucial for their involvement in protein translation.Among various divalent metal ions,magnesium ions play a pivotal role in preserving the tertiary structure of tRNA.However,the precise location of the Mg^(2+)binding pocket in human tRNA remains elusive.In this investigation,we identified the Mg^(2+)binding site within human tRNAGln using suppressor tRNA^(Gln).This variant of tRNA recognizes premature stop codons(specificlly UAG)and facilitates the expression of fll-length proteis.By mutating sites 8 and C72 in supprssr tRNAcl,we assessed the decoding efficiency of the resulting mutant suppressor tRNAs,which serves as a measure of tRNA's ability to decode genetic information.Our analysis revealed that the U8C mutant suppressor tRNA exhibited a significantly lower Mg^(2+)content compared to the C72U mutant.Furthermore,we observed a notable reduction in decoding efficiency in the U8-mutated suppressor tRNA,as evidenced by GFP fluorescence and Western blotting analysis.Conversely,mutations at the C72 site had a comparatively minor impact on decoding efficiency.These findings underscored the tight binding of Mg^(2+)to the U8 site of human tRNAGln,crucial for maintaining the stability of tRNA tertiary structure and translation efficacy.Additionally,our investigation delved into the influence of glutamine availability on tRNA decoding efficiency at the cellular level.The results indicated that both the concentration of amino acids and the codon context of TAG could modulate tRNA decoding efficiency.This study provided valuable insights into the structure and function of tRNA,laying the groundwork for further exploration in this field.展开更多
The recent publication by Amisaki et al.in Nature highlights a novel and druggable mechanism by which IL-33-activated innate lymphoid cells type 2(ILC2s)induce the formation of tertiary lymphoid structures(TLSs)within...The recent publication by Amisaki et al.in Nature highlights a novel and druggable mechanism by which IL-33-activated innate lymphoid cells type 2(ILC2s)induce the formation of tertiary lymphoid structures(TLSs)within the tumor microenvironment(TME)of pancreatic cancer.These findings open new avenues for therapeutic strategies aimed at enhancing TLS-mediated antitumor immunity and suggest lymphoneogenesis as a potential tool for immunotherapy.展开更多
Objective To evaluate the expression of tertiary lymphoid structures (TLS) in renal tissues,and the relationship between TLS and clinicopathological changes and prognosis in idiopathic membranous nephropathy(IMN) pati...Objective To evaluate the expression of tertiary lymphoid structures (TLS) in renal tissues,and the relationship between TLS and clinicopathological changes and prognosis in idiopathic membranous nephropathy(IMN) patients.Methods It was a single center retrospective study.展开更多
Tertiary lymphoid structures(TLS),also referred to as tertiary lymphoid organs or ectopic lymphoid structures,are organized aggregates of immune cells that develop in non-lymphoid tissues in response to certain diseas...Tertiary lymphoid structures(TLS),also referred to as tertiary lymphoid organs or ectopic lymphoid structures,are organized aggregates of immune cells that develop in non-lymphoid tissues in response to certain disease processes^(1).They are typically observed in chronically inflamed tissues that are persistently exposed to antigens,such as in autoimmune diseases,chronic infections,and cancers^(2).In many tumor types,the presence and higher density of TLS are strongly correlated with improved pa-tient prognosis^(3).展开更多
Background:Tertiary lymphoid structure(TLS),ectopic lymphoid aggregates formed in response to chronic inflammation,have emerged as potential prognostic biomarkers and mediators of anti-tumor immunity in various cancer...Background:Tertiary lymphoid structure(TLS),ectopic lymphoid aggregates formed in response to chronic inflammation,have emerged as potential prognostic biomarkers and mediators of anti-tumor immunity in various cancers.However,the heterogeneity of TLS spatial distribution,maturity,and their prognostic and immunological significance in prostate cancer(PCa)remain poorly characterized.Methods:We utilized immunohistochemistry,multispectral fluorescence immunohistochemistry(mIHC)and spatial multi-omics analyses to evaluate the heterogeneity of TLS and its relationship with immune components in the tumor microenvironment(TME).Prognostic implications were assessed in 701 PCa patients from the TCGA and Fudan University Shanghai Cancer Center cohorts.The association between TLS heterogeneity and immunoreactivity was assessed through the quantification of immune cell infiltration.CellTreck and robust cell type decomposition deconvolution algorithms were used to decipher the colocalization features of each cell,cell-cell communication and ligand-receptor features within TLS regions.Results:In PCa,TLSs were detected in approximately 20%of patients across both cohorts,with intratumoral TLS(intra-TLS)being twice as prevalent as peritumoral TLS(peri-TLS).Patients harboring intra-TLS exhibited significantly longer disease-free and progression-free survival.Compared to peri-TLS,intra-TLS were more mature,characterized by increased T-effector cell infiltration,activation of interferon pathways,and the presence of follicular dendritic cell centers and B cell aggregates.Notably,compared with immature TLS,mature TLS were markedly associated with reduced PD-L1 expression,lower regulatory T cells(Tregs)infiltration,and increased high endothelial venules(HEVs)density,indicative of an immunologically active microenvironment.Spatial multi-omics analysis revealed that mature TLS exhibited enriched immune cell diversity and HEVs density,suggesting enhanced anti-tumor immunity.Furthermore,cell-cell communication analysis identified significant interactions between CCL5+dendritic cells and ACKR1+activated B cells within mature TLS,reflecting the enhanced capacity of mature TLS to orchestrate robust antigen presentation and B-cell-driven immune responses.Conclusions:In conclusion,this study highlights the prognostic and immunological implications of TLS heterogeneity in PCa,demonstrating that the spatial distribution and maturity of TLSs are closely linked to TME activation and improved clinical outcomes.These findings provide novel insights into the immune landscape of PCa and establish a foundation for immune-based precision stratification and therapeutic development.展开更多
Background For patients with locally advanced esophagogastric cancer,the standard of care in the UK is neoadjuvant chemotherapy(NAC)followed by surgery.Prehabilitation exercise training can improve physiological funct...Background For patients with locally advanced esophagogastric cancer,the standard of care in the UK is neoadjuvant chemotherapy(NAC)followed by surgery.Prehabilitation exercise training can improve physiological function and fitness.If such improvements translate to increased immune infiltration of tumors,exercise could be prescribed as an immune adjuvant during NAC and potentially improve clinical outcomes.As such,we aimed to determine whether prehabilitation increased tumor infiltrating lymphocytes(TILs).Methods We assessed 22 patients with locally advanced esophageal cancer on a randomized control trial comparing 16 weeks of low-to-moderate intensity twice weekly supervised and thrice weekly home-based exercise(Prehab:n=11)to no prehabilitation(Control:n=11).Our primary outcome was to compare tumor-immune responses between Controls and Prehab.We compared formalin-fixed paraffin-embedded tumors by high-resolution multispectral immunohistochemistry(mIHC)and NanoString spatial transcriptomics.Secondarily,we determined relationships between changes in fitness to the exercise training and tumor-immune measures.Specifically,we assessed percentage changes in peak cardiorespiratory fitness as assessed by peak oxygen uptake(VO_(2peak))before NAC(Baseline)and after 8 weeks of NAC(Post-NAC),and changes between Baseline and following 8 weeks of NAC recovery before surgery(Pre-surgery)and correlated changes in fitness with tumor-immune responses.Finally,as an exploratory aim,we assessed clinical outcomes between groups,including survival,therapy tolerance,and tumor regrading.Results We observed that Prehab had significantly more CD8+lymphocytes in their tumors(mean difference(diff.)=1.79,95%confidence interval(95%CI):0.76‒2.82,p<0.001)and their stroma(mean diff.=1.59,95%CI:0.66‒2.52,p<0.001)than the Controls.When normalized to total numbers of TILs,Prehab had higher levels of CD56+natural killer(NK)cells(median diff.=0.87,95%CI:0.25‒2.18),p=0.0274),consisting primarily of CD56^(dim)NK cells(median diff.=0.48,95%CI:0.03‒2.53),p=0.0464).Evaluation of the presence and localization of tumor-associated tertiary lymphoid structures(TLS)in the esophageal tumors revealed that most TLS were in the peritumoral regions.Prehab had a higher TLS cell density(cells/mm^(2);median diff.=18,959,95%CI:13,518‒22,635),p<0.001)and more clearly defined germinal centers indicative of mature TLS visually.We observed that Prehab maintained their VO_(2peak)during NAC while the Controls’VO_(2peak)reduced by 9.0%±10.2%(mean±SD)(Post-NAC:p=0.018).Pre-surgery,Prehab VO_(2peak)was a clinically meaningful 3.27±1.31 mL/kg/min higher than Controls(p=0.022).Between Baseline and Post-NAC,where the Prehab maintained VO_(2peak)better than Controls,there were significant positive associations with percentage changes in VO_(2peak)and the frequencies of CD8+TILs(r=0.531,p=0.016),programmed death-ligand 1+(PDL1+)cells(r=0.566,p=0.009),and granzyme B+(GrzB+)TILs(r=0.582,p=0.007).Similar relationships were observed for changes in VO_(2peak)from Baseline to Pre-Surgery only in the Prehab group.We observed no differences between groups regarding clinical outcomes such as survival,therapy tolerance,or tumor regrading.Conclusion We show that exercise training during NAC,which promotes higher levels of cardiorespiratory fitness than no exercise,is associated with increased frequencies of TILs and maturity of TLS.These data suggest that exercise during NAC enhances the immune system.Future studies are warranted to understand the clinical consequences of this.展开更多
Globally,ovarian cancer(OvCa)is the deadliest gynecological malignancy,which threatens women's health.1 Despite innovations in cancer treatments,nearly 70%of OvCa patients still suffered tumor recurrence and poor ...Globally,ovarian cancer(OvCa)is the deadliest gynecological malignancy,which threatens women's health.1 Despite innovations in cancer treatments,nearly 70%of OvCa patients still suffered tumor recurrence and poor survival after standard therapy.1 Therefore,further research is urgently needed to identify prognostic biomarkers and explore specific mechanisms for OvCa.Tertiary lymphoid structure(TLS),a newly acknowledged form of ectopic lymphoid tissues,plays a crucial role against cancer,though have not been validated in OvCa yet.2 Here,we developed and validated a TLS-related gene(TRG)signature to predict drug sensitivity and prognosis for OvCa patients via bioinformatics analysis.Moreover,through PCR and multiplex immunohistochemical analyses,we validated the importance of TLS and the related signature,particularly STAT5A(signal transducer and activator of transcription 5 A),thus assisting clinical decision-making for OvCa precision treatment.展开更多
This study aimed to investigate the impact of tertiary-lymphoid-structure-related genes on the clinical prognosis and tumor immune environment of patients with gastric cancer.Using The Cancer Genome Atlas data,23 diff...This study aimed to investigate the impact of tertiary-lymphoid-structure-related genes on the clinical prognosis and tumor immune environment of patients with gastric cancer.Using The Cancer Genome Atlas data,23 differentially expressed genes associated with the tumor microenvironment were identified and used to develop a prognostic model.Univariate and multivariate Cox regression analyses were conducted to assess the prognostic value of the model.The results revealed that high-risk patients presented increased activity in hypoxia,angiogenesis,epithelial-mesenchymal transition,and transforming-growthfactor-beta-signaling-related pathways,whereas low-risk patients presented increased activity in CD4+T-cell-infiltration-related pathways.High-risk patients had lower survival rates and a worse response to immunotherapy.This model serves as an independent predictor of the survival of gastric cancer patients and can aid in immunotherapy decision-making.展开更多
Tertiary lymphoid structures(TLSs)are ectopic lymphoid aggregates that form in non-lymphoid organs,frequently observed in conditions such as cancer,autoimmune diseases,transplant rejection,and chronic inflammation.Gro...Tertiary lymphoid structures(TLSs)are ectopic lymphoid aggregates that form in non-lymphoid organs,frequently observed in conditions such as cancer,autoimmune diseases,transplant rejection,and chronic inflammation.Growing evidence suggests that TLSs are beneficial for patients’prognosis with higher TLS density generally correlating with improved therapeutic response and survival outcomes across malignancies and might serve as a novel therapeutic target for cancer immunotherapy.However,the correlation between TLSs and tumor development is still ambiguous.The exact timing of TLS formation during tumorigenesis and their dynamic evolution throughout tumor progression remain under investigation.Recent studies have identified potential strategies for inducing TLSs,but there remains a considerable distance from clinical application.More advanced techniques such as high-resolution spatial multi-omics technologies combined with big data analysis will benefit understanding the complex interactions within TLSs and developing novel immunotherapies.展开更多
With the progress of plant genome research, more than 50 plant metallothionein_like (MT_L) genes have been found, but only several MT_L proteins have been detected and no experimental structural information for MT_L p...With the progress of plant genome research, more than 50 plant metallothionein_like (MT_L) genes have been found, but only several MT_L proteins have been detected and no experimental structural information for MT_L proteins has been reported so far. Since detailed knowledge of the protein tertiary structure is required to understand its biological function, a method is needed to determine the structure of these proteins. In this study, the structural data of known mammal MT was used to determine the interatomic distance constraints of the CXC and CXXC motifs and the metal_sulfur chelating cluster. Then several possible MT conformations were predicted using a distance geometry algorithm. The statistical analysis was used to select those with much lower target function values and lower conformation energies as the predicted tertiary structural models of the cysteine_rich (CR) domains of these proteins. A suitable prediction method for modeling the CR domain of the plant MT_L protein was constructed. The accurately predicted result for the known structure of an MT protein from blue crab suggests that this method is practicable. The tertiary structures of CR domains of rape MT_L protein LSC54 was then modeled with this method.展开更多
文摘In early of 1960s, I was a graduate student studying on tRNA biochemistry. In the course of the research, the magnesium ions stabilized the tertiary structure of tRNA, resulting in its resistance to enzymatic degradation was discovered independently. The experiment of deaminated (denatured) tRNA obtained from native tRNA was designed and conducted and further proved the validity of this finding. It was found that magnesium ions could stabilize the tertiary structure of the natrive tRNA but could not stabilize structure of the deaminated tRNA. In term of the methodology, this stabilization technique has been widely applied in sequencing analysis of RNA and has greatly promoted the progress in the study of primary structure of RNA. More importantly, the stabilization of the tertiary structure of RNA by magnesium ions plays a key role both in the processing of messenger RNAs and the ribozyme activity. After our first article in Chinese was published in 1963, a paper of Nishimura & Novelli came into our note. The received date of their paper was March 22 of 1963, only 4 days earlier than that of our first paper. Thus, we and Nishimura & Novelli made almost at the same time the earliest discovery of the role of magnesium ions on stabilizing the tertiary structure of the transfer RNA and thus resulted in resistance of tRNA degradation by enzymes. However, this discovery was not initially appreciated for a period of time but was finally “visualized” and proved by X-ray crystal structure of yeast phenylalanine tRNA, which has provided more accurate information on the geometry of the magnesium-binding sites in tRNA.
文摘Structure-based protein classification can be based on the similarities in primary, second or tertiary structures of proteins. A method using virtual-bond-angles series that transformed the protein space configuration into a sequence was used for the classification of three-dimensional structures oi proteins. By transforming the main chains formed by C^a atoms of proteins into sequences, the series of virtual-bond-angles corresponding to the tertiary structure of the proteins were constructed. Then a distance-based hierarchical clustering method similar to Ward method was introduced to classify these virtual-bond-angles series of proteins. 200 files of protein structures were selected from Brookheaven protein data bank, and 11 clusters were classified.
基金supported by grants from the Beijing Xisike Clinical Oncology Research Foundation(No.Y-Young2024-0138)China Postdoctoral Science Foundation(No.2024M750538)Qingdao Chengyang People’s Hospital Fund Project(No.202510300).
文摘Background:Tertiary lymphoid structures(TLSs)promote antitumor immunity and predict favorable immunotherapy outcomes in breast cancer.The study aimed to investigate how Tryptophan 2,3-dioxygenase(TDO2)-associated tryptophan metabolism influences TLS maturation and B cell class switching in breast cancer.Methods:Bulk transcriptomic data from The Cancer Genome Atlas-Breast Invasive Carcinoma(TCGA-BRCA,n=1055)were analyzed using Gene Set Variation Analysis(GSVA)-based metabolic scoring,immune deconvolution,and TLS quantification.Single-cell RNA sequencing(scRNA-seq,n=26)and spatial transcriptomics(n=1)were applied to map TDO2 expression and TLS spatial organization.Validation was performed by immunohistochemistry(n=38)and multiplex immunofluorescence(n=12).Results:We identified that elevated tryptophan metabolism was predominantly enriched in the Luminal A subtype and delineates an immune-cold phenotype with less immunogenicity,associated with a distinct immune-dominant cellular microenvironment,particularly enriched in T and plasma cells.High expression of the tryptophan-metabolizing enzyme TDO2 was significantly enriched in TLS-low tumors and negatively correlated with TLS maturation signatures.Functional enrichment revealed suppressed B cell class switching and attenuated C-X-C motif chemokine ligand 9(CXCL9)expression in TLS-deficient tumors.Spatial transcriptomics and hotspot analysis demonstrated an inverse spatial correlation between TDO2 expression and TLS core components.Tumors with high tryptophan metabolism showed decreased cluster of differentiation 20(CD20)^(+)and CXCL9^(+)cell infiltration within TLS zones.Tumors with strong TDO2-kynurenine activity displayed impaired TLS organization and attenuated humoral immunity.Conditional spatial co-occurrence modeling confirmed reduced proximity between tryptophan metabolism hotspots and TLS-related immune features.Conclusion:In conclusion,our findings suggest that TDO2-associated tryptophan metabolism is linked to impaired TLS maturation and suppressed B cell class switching in breast cancer.Targeting the TDO2-kynurenine axis may represent a promising strategy to restore TLS formation and enhance immunotherapy responsiveness in breast cancer.
文摘Background:Chronic inflammation is closely associated with the most common and socially significant prostate conditions,including benign prostatic hyperplasia(BPH),prostate cancer(PCa),and prostatitis syndromes.NIHcategory IV prostatitis(histologic prostatitis,HP)is defined as asymptomatic chronic inflammation of the prostate.The presence of lymphoid follicles,referred to as tertiary lymphoid structures(TLSs),along with benign lympho-epithelial lesions(BLELs),is among the key histological indicators of immune inflammation and can be assessed relatively easily.This study aimed to quantitatively assess TLSs and BLELs,as well as their relationship with the severity of HP.Methods:We investigated TLSs and BLELs in 110 prostatic specimens,including inflammatory and normal tissues,within the context of common prostate pathologies such as BPH and PCa.HP was graded as low-grade(LG)or high-grade(HG)based on the severity of inflammation.Results:TLSs were observed in 51 out of 110 cases(46.4%),while BLELs were identified in 78 cases(70.44%).Both TLSs and BLELs co-occurred in 45 cases(40.9%).Statistical analysis revealed a significant correlation between the presence of TLSs,BLELs(individually or combined),and HG-HP(p<0.001).Conclusions:This study is the first to quantitatively evaluate the immunopathologic patterns in the inflamed human prostate by analyzing the presence and cooccurrence of TLSs and BLELs.Their formation,likely triggered by antigenic stimuli and external factors,indicates a chronic inflammatory microenvironment.The strong association between TLSs,BLELs,and HG-HP underscores their potential role in HP aggressiveness.These findings suggest that TLSs and BLELs may be crucial contributors to the pathophysiology and morphogenesis of NIH-category IV prostatitis.Furthermore,TLS/BLEL formation may represent a hallmark of tissue autoimmunity,reflecting the immune or autoimmune phase of this prostatitis subtype.
基金supported by the Peking University Medicine Fund of Fostering Young Scholars'Scientific&Technological Innovation[grant number BMU2024YFJHPY014]the Fundamental Research Funds for the Central Universities+1 种基金the Key Clinical Projects of Peking University Third Hospital[grant number BYSYZD2022014]the Capital’s Funds for Health Improvement and Research[grant number 2022-2G-40910]。
文摘Objective Cigarette smoking exacerbates the progression of pulmonary tuberculosis(TB).The role of tertiary lymphoid structures(TLS)in chronic lung diseases has gained attention;however,it remains unclear whether smoking-exacerbated lung damage in TB is associated with TLS.This study aimed to analyze the characteristics of pulmonary TLS in smokers with TB and to explore the possible role of TLS in smoking-related lung injury in TB.Methods Lung tissues from 36 male patients(18 smokers and 18 non-smokers)who underwent surgical resection for pulmonary TB were included in this study.Pathological and immunohistological analyses were conducted to evaluate the quantity of TLS,and chest computed tomography(CT)was used to assess the severity of lung lesions.The correlation between the TLS quantity and TB lesion severity scores was analyzed.The immune cells and chemokines involved in TLS formation were also evaluated and compared between smokers and non-smokers.Results Smoker patients with TB had significantly higher TLS than non-smokers(P<0.001).The TLS quantity in both the lung parenchyma and peribronchial regions correlated with TB lesion severity on chest CT(parenchyma:r=0.5767;peribronchial:r=0.7373;both P<0.001).Immunohistochemical analysis showed increased B cells,T cells,and C-X-C motif chemokine ligand 13(CXCL13)expression in smoker patients with TB(P<0.001).Conclusion Smoker TB patients exhibited increased pulmonary TLS,which was associated with exacerbated lung lesions on chest CT,suggesting that cigarette smoking may exacerbate lung damage by promoting TLS formation.
文摘Changes in the intestinal immune micro-environment of the gastrointestinal tract are indispensable in the occurrence and development of gastrointestinal cancer.Tertiary lymphoid structure(TLS)is an immune cell aggregation structure found around gastrointestinal cancer in recent years.More and more research proves that tertiary lymphoid structure plays a key biological role and clinical value in disease progression,patient prognosis,and adjuvant treatment.This review aims to explore the research progress,biological significance,and potential clinical applications of TLSs in gastrointestinal tumors.The formation,development,and interaction of TLSs with tumor microenvironment have been reviewed and analyzed in recent years.Meanwhile,this review not only evaluates the clinical value of TLSs as prognostic biomarkers and predictors of treatment response but also explores their role in guiding the formulation of immunotherapy strategies for gastrointestinal tumors.In addition,this review points out the main problems in the current research of TLSs and looks forward to their future development,especially their broad application prospects in the diagnosis,treatment,and prognostic evaluation of gastrointestinal tumors.
基金supported by grants from the National Natural Science Foundation of China(No.82172803 and No.82072679)the 2020 Zhongshan Hospital Clinical Research Special Fund(No.2020ZSLC15)。
文摘Objective:Recent studies have highlighted the distinct value of tertiary lymphoid structure(TLS)for immunotherapeutic response prediction.However,it remains unclear whether TLS could play such roles in gastric cancer(GC).Methods:In this study,tumor tissue slices from 292 GC patients from Zhongshan Hospital were firstly reviewed to explore the correlation between TLS and clinical characteristics.Subsequently,we curated 38 reported genes that may function as triggers of TLS and performed consensus molecular subtyping in public RNA-seq datasets to determine TLS patterns in GC.Based on the differentially expressed genes acquired from two TLS patterns,we quantified TLS-related genes on the principal component analysis(PCA)algorithm to develop TLS score.A Zhongshan immunotherapy cohort including 13 patients who received programmed cell death 1(PD1)blockade therapy was established to conduct RNA sequencing analysis and multiplex immunohistochemistry(mIHC)tests using formalin-fixed and paraffin-embedded(FFPE)tissues.The corresponding TLS score and immune cell counts were further compared based on therapeutic response variations.Results:Mature TLS was revealed as an independent prognostic factor in 292 GC patients.Patients with higher TLS score was characterized by prolonged survival time and superior response to immunotherapy.TLS score was correlated with immunotherapy-related characters,such as microsatellite instability(MSI)and tumor mutation burden(TMB).In addition,RNA-seq data analysis in the Zhongshan immunotherapy cohort indicated that a higher TLS score was correlated with a superior response to PD1 blockade therapy.mIHC tests also revealed that PD1+CD8+T cell counts were significantly increased in the high-TLS score group.Conclusions:This study highlighted that TLS was significantly associated with immune landscape diversity and complexity.Quantitatively evaluating TLS patterns of individual tumor will strengthen our understanding of TME characteristics and promote more effective immunotherapy strategies.
基金This study was supported by grants from the National Key R&D Program of China(Grant No.2018YFC1313400)the National Natural Science Foundation of China(Grant No.U20A20375).
文摘Tertiary lymphoid structures(TLSs)are ectopic immune cell aggregations that develop in peripheral tissues in response to a wide range of chronic inflammatory conditions,including infection,autoimmune disease,and cancer.In the tumor microenvironment(TME),the structures of TLSs,including B-cell-and T-cell-enriched areas indicate that the TLSs might be the local site during the initiation and maintenance of humoral and cellular immune responses against cancers.Numerous studies have evaluated the expression of TLSs in different cancer patients and their association with prognoses of cancer patients.It was shown that welldeveloped TLSs characterized by mature B cells synthesized tumor specific antibodies,which were considered as specific markers for a good prognosis.However,there are still some immunosuppressive factors existing in the TLSs that may affect anti-tumor responses.These factors include dysfunctional B cells,regulatory T cells,and T follicular regulatory cells.The complexity and heterogeneity of the TLS composition may affect the function and activity of TLSs;it is therefore essential to fully understand the function and influencing factors in TLSs.It has been reported that checkpoint inhibitors and vaccines are currently being developed to reprogram the TME by establishing mature TLSs to improve cancer immunotherapies.In this review,we focused on recent advances in TLSs in human solid tumors,including structural characteristics and classes,antitumor mechanisms,immunosuppressive factors,and TLSbased therapeutic approaches.
基金supported by the Key Projects of Sichuan Natural Science Foundation(No.2022NSFSC0051)the Clinical Scientist Program of Sichuan Cancer Hospital(No.YB2022003)the Chengdu Technology Innovation R&D Project(No.2021YF0501659SN),China.
文摘Tumor-associated tertiary lymphoid structures(TLSs)are ectopic lymphoid formations within tumor tissue,with mainly B and T cell populations forming the organic aggregates.The presence of TLSs in tumors has been strongly associated with patient responsiveness to immunotherapy regimens and improving tumor prognosis.Researchers have been motivated to actively explore TLSs due to their bright clinical application prospects.Various studies have attempted to decipher TLSs regarding their formation mechanism,structural composition,induction generation,predictive markers,and clinical utilization.Meanwhile,the scientific approaches to qualitative and quantitative descriptions are crucial for TLS studies.In terms of detection,hematoxylin and eosin(H&E),multiplex immunohistochemistry(mIHC),multiplex immunofluorescence(mIF),and 12-chemokine gene signature have been the top approved methods.However,no standard methods exist for the quantitative analysis of TLSs,such as absolute TLS count,analysis of TLS constituent cells,structural features,TLS spatial location,density,and maturity.This study reviews the latest research progress on TLS detection and quantification,proposes new directions for TLS assessment,and addresses issues for the quantitative application of TLSs in the clinic.
基金supported by the Zhejiang Provincial Key Project of Research and Development(No.2019C03043)the National Natural Science Foundation of China(Nos.32030035,31870874,32000623,and 32100693)the Zhejiang Provincial Natural Science Foundation(No.LZ21C080001)of China。
文摘Tertiary lymphoid structures(TLSs)are formations at sites with persistent inflammatory stimulation,including tumors.These ectopic lymphoid organs mainly consist of chemo-attracting B cells,T cells,and supporting dendritic cells(DCs).Mature TLSs exhibit functional organization for the optimal development and collaboration of adaptive immune response,delivering an augmented effect on the tumor microenvironment(TME).The description of the positive correlation between TLSs and tumor prognosis is reliable only under a certain condition involving the localization and maturation of TLSs.Emerging evidence suggests that underlying mechanisms of the anti-tumor effect of TLSs pave the way for novel immunotherapies.Several approaches have been developed to take advantage of intratumoral TLSs,either by combining it with therapeutic agents or by inducing the neogenesis of TLSs.
基金National Natural Science Foundation of China(Grant No.U23A20106)National Key Research and Development Program of China(Grant No.91510100MA6CG8UJ4K)。
文摘Transfer RNAs(tRNAs)adopt a stable L-shaped tertiary structure crucial for their involvement in protein translation.Among various divalent metal ions,magnesium ions play a pivotal role in preserving the tertiary structure of tRNA.However,the precise location of the Mg^(2+)binding pocket in human tRNA remains elusive.In this investigation,we identified the Mg^(2+)binding site within human tRNAGln using suppressor tRNA^(Gln).This variant of tRNA recognizes premature stop codons(specificlly UAG)and facilitates the expression of fll-length proteis.By mutating sites 8 and C72 in supprssr tRNAcl,we assessed the decoding efficiency of the resulting mutant suppressor tRNAs,which serves as a measure of tRNA's ability to decode genetic information.Our analysis revealed that the U8C mutant suppressor tRNA exhibited a significantly lower Mg^(2+)content compared to the C72U mutant.Furthermore,we observed a notable reduction in decoding efficiency in the U8-mutated suppressor tRNA,as evidenced by GFP fluorescence and Western blotting analysis.Conversely,mutations at the C72 site had a comparatively minor impact on decoding efficiency.These findings underscored the tight binding of Mg^(2+)to the U8 site of human tRNAGln,crucial for maintaining the stability of tRNA tertiary structure and translation efficacy.Additionally,our investigation delved into the influence of glutamine availability on tRNA decoding efficiency at the cellular level.The results indicated that both the concentration of amino acids and the codon context of TAG could modulate tRNA decoding efficiency.This study provided valuable insights into the structure and function of tRNA,laying the groundwork for further exploration in this field.
基金supported by the Rainald und Regine Pohl StiftungA.A.is part of the Cancer Core Europe(CCE)Training program of Young leaders in TRAnslational Cancer research(TRYTRAC).
文摘The recent publication by Amisaki et al.in Nature highlights a novel and druggable mechanism by which IL-33-activated innate lymphoid cells type 2(ILC2s)induce the formation of tertiary lymphoid structures(TLSs)within the tumor microenvironment(TME)of pancreatic cancer.These findings open new avenues for therapeutic strategies aimed at enhancing TLS-mediated antitumor immunity and suggest lymphoneogenesis as a potential tool for immunotherapy.
文摘Objective To evaluate the expression of tertiary lymphoid structures (TLS) in renal tissues,and the relationship between TLS and clinicopathological changes and prognosis in idiopathic membranous nephropathy(IMN) patients.Methods It was a single center retrospective study.
基金supported by the National Key Research and Development Plan(2022YFC3500202,China)the National Natural Science Foundation of China(No.U24A20794).
文摘Tertiary lymphoid structures(TLS),also referred to as tertiary lymphoid organs or ectopic lymphoid structures,are organized aggregates of immune cells that develop in non-lymphoid tissues in response to certain disease processes^(1).They are typically observed in chronically inflamed tissues that are persistently exposed to antigens,such as in autoimmune diseases,chronic infections,and cancers^(2).In many tumor types,the presence and higher density of TLS are strongly correlated with improved pa-tient prognosis^(3).
基金supported by grants from Non-communicable Chronic Diseases-National Science and Technology Major Project(grant number:2023ZD0510300)National Natural Science Foundation of China(grant numbers:82403377,82473192,82474506,81760463)+4 种基金China Postdoctoral Science Foundation(grant number:2024M750538)Shanghai Anticancer Association EYAS PROJECT(grant numbers:SACA-CY23A02,SACA-CY23C04)Beijing Xisike Clinical Oncology Research Foundation(grant numbers:Y-Young2024-0138,Y-HR2020MS-0948)Central Government Funds for Guiding Local Scientific and Technological Development(grant number:2021ZY0037)Natural Science Found of In-ner Mongolia(grant number:2023MS08015).
文摘Background:Tertiary lymphoid structure(TLS),ectopic lymphoid aggregates formed in response to chronic inflammation,have emerged as potential prognostic biomarkers and mediators of anti-tumor immunity in various cancers.However,the heterogeneity of TLS spatial distribution,maturity,and their prognostic and immunological significance in prostate cancer(PCa)remain poorly characterized.Methods:We utilized immunohistochemistry,multispectral fluorescence immunohistochemistry(mIHC)and spatial multi-omics analyses to evaluate the heterogeneity of TLS and its relationship with immune components in the tumor microenvironment(TME).Prognostic implications were assessed in 701 PCa patients from the TCGA and Fudan University Shanghai Cancer Center cohorts.The association between TLS heterogeneity and immunoreactivity was assessed through the quantification of immune cell infiltration.CellTreck and robust cell type decomposition deconvolution algorithms were used to decipher the colocalization features of each cell,cell-cell communication and ligand-receptor features within TLS regions.Results:In PCa,TLSs were detected in approximately 20%of patients across both cohorts,with intratumoral TLS(intra-TLS)being twice as prevalent as peritumoral TLS(peri-TLS).Patients harboring intra-TLS exhibited significantly longer disease-free and progression-free survival.Compared to peri-TLS,intra-TLS were more mature,characterized by increased T-effector cell infiltration,activation of interferon pathways,and the presence of follicular dendritic cell centers and B cell aggregates.Notably,compared with immature TLS,mature TLS were markedly associated with reduced PD-L1 expression,lower regulatory T cells(Tregs)infiltration,and increased high endothelial venules(HEVs)density,indicative of an immunologically active microenvironment.Spatial multi-omics analysis revealed that mature TLS exhibited enriched immune cell diversity and HEVs density,suggesting enhanced anti-tumor immunity.Furthermore,cell-cell communication analysis identified significant interactions between CCL5+dendritic cells and ACKR1+activated B cells within mature TLS,reflecting the enhanced capacity of mature TLS to orchestrate robust antigen presentation and B-cell-driven immune responses.Conclusions:In conclusion,this study highlights the prognostic and immunological implications of TLS heterogeneity in PCa,demonstrating that the spatial distribution and maturity of TLSs are closely linked to TME activation and improved clinical outcomes.These findings provide novel insights into the immune landscape of PCa and establish a foundation for immune-based precision stratification and therapeutic development.
文摘Background For patients with locally advanced esophagogastric cancer,the standard of care in the UK is neoadjuvant chemotherapy(NAC)followed by surgery.Prehabilitation exercise training can improve physiological function and fitness.If such improvements translate to increased immune infiltration of tumors,exercise could be prescribed as an immune adjuvant during NAC and potentially improve clinical outcomes.As such,we aimed to determine whether prehabilitation increased tumor infiltrating lymphocytes(TILs).Methods We assessed 22 patients with locally advanced esophageal cancer on a randomized control trial comparing 16 weeks of low-to-moderate intensity twice weekly supervised and thrice weekly home-based exercise(Prehab:n=11)to no prehabilitation(Control:n=11).Our primary outcome was to compare tumor-immune responses between Controls and Prehab.We compared formalin-fixed paraffin-embedded tumors by high-resolution multispectral immunohistochemistry(mIHC)and NanoString spatial transcriptomics.Secondarily,we determined relationships between changes in fitness to the exercise training and tumor-immune measures.Specifically,we assessed percentage changes in peak cardiorespiratory fitness as assessed by peak oxygen uptake(VO_(2peak))before NAC(Baseline)and after 8 weeks of NAC(Post-NAC),and changes between Baseline and following 8 weeks of NAC recovery before surgery(Pre-surgery)and correlated changes in fitness with tumor-immune responses.Finally,as an exploratory aim,we assessed clinical outcomes between groups,including survival,therapy tolerance,and tumor regrading.Results We observed that Prehab had significantly more CD8+lymphocytes in their tumors(mean difference(diff.)=1.79,95%confidence interval(95%CI):0.76‒2.82,p<0.001)and their stroma(mean diff.=1.59,95%CI:0.66‒2.52,p<0.001)than the Controls.When normalized to total numbers of TILs,Prehab had higher levels of CD56+natural killer(NK)cells(median diff.=0.87,95%CI:0.25‒2.18),p=0.0274),consisting primarily of CD56^(dim)NK cells(median diff.=0.48,95%CI:0.03‒2.53),p=0.0464).Evaluation of the presence and localization of tumor-associated tertiary lymphoid structures(TLS)in the esophageal tumors revealed that most TLS were in the peritumoral regions.Prehab had a higher TLS cell density(cells/mm^(2);median diff.=18,959,95%CI:13,518‒22,635),p<0.001)and more clearly defined germinal centers indicative of mature TLS visually.We observed that Prehab maintained their VO_(2peak)during NAC while the Controls’VO_(2peak)reduced by 9.0%±10.2%(mean±SD)(Post-NAC:p=0.018).Pre-surgery,Prehab VO_(2peak)was a clinically meaningful 3.27±1.31 mL/kg/min higher than Controls(p=0.022).Between Baseline and Post-NAC,where the Prehab maintained VO_(2peak)better than Controls,there were significant positive associations with percentage changes in VO_(2peak)and the frequencies of CD8+TILs(r=0.531,p=0.016),programmed death-ligand 1+(PDL1+)cells(r=0.566,p=0.009),and granzyme B+(GrzB+)TILs(r=0.582,p=0.007).Similar relationships were observed for changes in VO_(2peak)from Baseline to Pre-Surgery only in the Prehab group.We observed no differences between groups regarding clinical outcomes such as survival,therapy tolerance,or tumor regrading.Conclusion We show that exercise training during NAC,which promotes higher levels of cardiorespiratory fitness than no exercise,is associated with increased frequencies of TILs and maturity of TLS.These data suggest that exercise during NAC enhances the immune system.Future studies are warranted to understand the clinical consequences of this.
基金supported by the Science and Technology Commission of Shanghai Municipality,China(No.23YF1433600)the National Natural Science Foundation of China(No.82303652).
文摘Globally,ovarian cancer(OvCa)is the deadliest gynecological malignancy,which threatens women's health.1 Despite innovations in cancer treatments,nearly 70%of OvCa patients still suffered tumor recurrence and poor survival after standard therapy.1 Therefore,further research is urgently needed to identify prognostic biomarkers and explore specific mechanisms for OvCa.Tertiary lymphoid structure(TLS),a newly acknowledged form of ectopic lymphoid tissues,plays a crucial role against cancer,though have not been validated in OvCa yet.2 Here,we developed and validated a TLS-related gene(TRG)signature to predict drug sensitivity and prognosis for OvCa patients via bioinformatics analysis.Moreover,through PCR and multiplex immunohistochemical analyses,we validated the importance of TLS and the related signature,particularly STAT5A(signal transducer and activator of transcription 5 A),thus assisting clinical decision-making for OvCa precision treatment.
基金funded by the 2022 Baotou Health Science and Technology Program Project Subjects(wsjkkj 2022002)the 2022“Grassland Talent”Project Special Funding Support Program(CYYC230416)+1 种基金the 2024 Project of the Natural Science Foundation of the Inner Mongolia Autonomous Region(2024MS08047)the 2024 Inner Mongolia Academy of Medical Sciences Project Subjects(2024GLLH0748).
文摘This study aimed to investigate the impact of tertiary-lymphoid-structure-related genes on the clinical prognosis and tumor immune environment of patients with gastric cancer.Using The Cancer Genome Atlas data,23 differentially expressed genes associated with the tumor microenvironment were identified and used to develop a prognostic model.Univariate and multivariate Cox regression analyses were conducted to assess the prognostic value of the model.The results revealed that high-risk patients presented increased activity in hypoxia,angiogenesis,epithelial-mesenchymal transition,and transforming-growthfactor-beta-signaling-related pathways,whereas low-risk patients presented increased activity in CD4+T-cell-infiltration-related pathways.High-risk patients had lower survival rates and a worse response to immunotherapy.This model serves as an independent predictor of the survival of gastric cancer patients and can aid in immunotherapy decision-making.
基金supported by the National Key R&D Program of China(2023YFF1205900)National Natural Science Foundation of China(82425039,82173020).
文摘Tertiary lymphoid structures(TLSs)are ectopic lymphoid aggregates that form in non-lymphoid organs,frequently observed in conditions such as cancer,autoimmune diseases,transplant rejection,and chronic inflammation.Growing evidence suggests that TLSs are beneficial for patients’prognosis with higher TLS density generally correlating with improved therapeutic response and survival outcomes across malignancies and might serve as a novel therapeutic target for cancer immunotherapy.However,the correlation between TLSs and tumor development is still ambiguous.The exact timing of TLS formation during tumorigenesis and their dynamic evolution throughout tumor progression remain under investigation.Recent studies have identified potential strategies for inducing TLSs,but there remains a considerable distance from clinical application.More advanced techniques such as high-resolution spatial multi-omics technologies combined with big data analysis will benefit understanding the complex interactions within TLSs and developing novel immunotherapies.
文摘With the progress of plant genome research, more than 50 plant metallothionein_like (MT_L) genes have been found, but only several MT_L proteins have been detected and no experimental structural information for MT_L proteins has been reported so far. Since detailed knowledge of the protein tertiary structure is required to understand its biological function, a method is needed to determine the structure of these proteins. In this study, the structural data of known mammal MT was used to determine the interatomic distance constraints of the CXC and CXXC motifs and the metal_sulfur chelating cluster. Then several possible MT conformations were predicted using a distance geometry algorithm. The statistical analysis was used to select those with much lower target function values and lower conformation energies as the predicted tertiary structural models of the cysteine_rich (CR) domains of these proteins. A suitable prediction method for modeling the CR domain of the plant MT_L protein was constructed. The accurately predicted result for the known structure of an MT protein from blue crab suggests that this method is practicable. The tertiary structures of CR domains of rape MT_L protein LSC54 was then modeled with this method.
