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
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
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
Riboswitches are conserved RNA elements that specifically recognize the cognate metabolites and regulate downstream gene expression involved in the metabolic pathways.To date,two classes of xanthine-responsive riboswi...Riboswitches are conserved RNA elements that specifically recognize the cognate metabolites and regulate downstream gene expression involved in the metabolic pathways.To date,two classes of xanthine-responsive riboswitches involved in xanthine homeostasis have been identified.The recently reported xanthine-II riboswitch originates from guanine riboswitch family,featuring a single U-to-G mutation and several nucleotide insertions.Here,we report the complex structure of xanthine-II riboswitch bound to xanthine.The tertiary structure of xanthine-II riboswitch adopts a three-way junction scaffold similar to that of guanine riboswitch.However,the distinctive mutation and insertions in xanthine-II riboswitch facilitate the formation of a highly specific binding pocket for xanthine,distinguishing it from guanine riboswitches.Xanthine is bound in the junction region,forming a base triple with C64 and the mutant nucleotide G37,and is sandwiched by one base pair U8-A38 and one base triple A7-C36-U65.Structural alignment and ligand recognition specificity of the xanthine-II riboswitch are further verified by ligand-binding assays of structure-based mutation using isothermal titration calorimetry.Furthermore,leveraging the ligand specificity of the xanthine-II riboswitch,we develop a highly specific and sensitive biosensor for xanthine detection by fusing xanthine-II riboswitch with Pepper fluorogenic aptamer,highlighting the potential applications of xanthine-II riboswitch in diagnosing diseases related to xanthine metabolism disorders.展开更多
Background:Tertiary lymphoid structures(TLS)are major components in the immune microenvironment,correlating with a favorable prognosis in colorectal cancer.However,the methods used to define and characterize TLS were ...Background:Tertiary lymphoid structures(TLS)are major components in the immune microenvironment,correlating with a favorable prognosis in colorectal cancer.However,the methods used to define and characterize TLS were not united,hindering its clinical application.This study aims to seek a more stable method to characterize TLS and clarify their prognostic value in larger multicenter cohorts.Methods:A total of 1609 patients from four hospitals and The Cancer Genome Atlas database were analyzed.We quantified the number and maximum length of TLS along the invasive margin of tumor using hematoxylin and eosin-stained whole-slide images(WSIs).Additionally,the length of the invasive margin was determined to calculate the TLs density.The prognostic value of TLS for overall survival was evaluated.In addition,we examined the association between TLS density and immune cell infltration using immunohistochemistry-stained WSIs.The performance for predicting overall survival was measured using hazard ratios(HR)with 95%confidence intervals(CI).Results:Among the three TLS quantification methods,TLS density has the strongest discriminative performance.Survival analysis indicated that higher TLS density correlated with better overall survival[HR for high vs.low 0.57(95%CI 0.42-0.78)in the primary cohort;0.49(0.35-0.69)in the validation cohort;0.35(0.18-0.67)in TCGA cohort].A high TLS density was associated with a high level of CD3+Tcell infiltration.Conclusions:Based on this comparative multicenter analysis,TLs density was identified as a simple,robust,and effective immune prognostic index for colorectal cancer.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
The sonic hedgehog protein not only plays a key role in early embryonic development, but also has essential effects on the adult nervous system, including neural stem cell proliferation, differentiation migration and ...The sonic hedgehog protein not only plays a key role in early embryonic development, but also has essential effects on the adult nervous system, including neural stem cell proliferation, differentiation migration and neuronal axon guidance. The N-terminal fragment of sonic hedgehog is the key functional element in this process. Therefore, this study aimed to clone and analyze the N-terminal fragment of the sonic hedgehog gene. Total RNA was extracted from the notochord of a Sprague-Dawley rat at embryonic day 9 and the N-terminal fragment of sonic hedgehog was amplified by nested reverse transcription-PCR. The N-terminal fragment of the sonic hedgehog gene was successfully cloned. The secondary and tertiary structures of the N-terminal fragment of the sonic hedgehog protein were predicted using Jpred and Phyre online.展开更多
The recent explosion of biological data and the concomitant proliferation of distributed databases make it challenging for biologists and bioinformaticians to discover the best data resources for their needs, and the ...The recent explosion of biological data and the concomitant proliferation of distributed databases make it challenging for biologists and bioinformaticians to discover the best data resources for their needs, and the most efficient way to access and use them For the biologist, running bioinformatics analyses involve a time-consuming management of data and tools. Users need support to organize their work, retrieve parameters and reproduce their analyses. They also need to be able to combine their analytic tools using a safe data flow software mechanism. Finally we have designed a system, Bioinfo-Portal, to provide a flexible and usable web environment for defining and running bioinformatics analyses. It embeds simple yet powerful data management features that allow the user to reproduce analyses and to combine tools using an adobe flex tool. Bioinfo-Portal can also act as a front end to provide a unified view of already-existing collections of bioinformatics resources. Users can analyze genomic and proteomic data by using the tools that has been integrated in the portal （tools for alignments, dotplots, motif detection, domain analysis, profile searching and tertiary structure prediction）. The sequences that user obtained from portal＇s nucleotide and protein databases are easily analyzed by the portal tools on the same interface in no time. User can also take benefit from the animations.展开更多
Tertiary lymphoid structures(TLS)are ectopic lymphoid formations that form within nonlymphoid tissue.They share structural and functional characteristics with secondary lymphoid structures such as lymph nodes and can ...Tertiary lymphoid structures(TLS)are ectopic lymphoid formations that form within nonlymphoid tissue.They share structural and functional characteristics with secondary lymphoid structures such as lymph nodes and can contain B-cell follicles and germinal centers surrounded by a T-cell region.TLS have been described in several types of cancers and are usually associated with positive patient outcomes.However,TLS differ vastly in cellular composition and location within tissue types.In this review,we discuss factors confounding the interpretation of the evidence for a prognostic role for TLS in cancer and frame these factors in the context of translation to regular clinical use.展开更多
Tertiary lymphoid structures(TLS)often develop at sites of persistent inflammation,including cancers and autoimmune diseases.In most cases,the presence of TLS correlates with active immune responses.Because of their p...Tertiary lymphoid structures(TLS)often develop at sites of persistent inflammation,including cancers and autoimmune diseases.In most cases,the presence of TLS correlates with active immune responses.Because of their proximity to pathological loci,TLS are an intriguing target for the manipulation of immune responses.For several years,it has become clear that lymphotoxin(LT)signalling plays critical roles in lymphoid tissue organogenesis and maintenance.In the current review,we will discuss the role of LT signalling in the development of TLS.With a focus on cancers and autoimmune diseases,we will highlight the correlations between TLS and disease progression.We will also discuss the current efforts and potential directions for manipulating TLS for immunotherapies.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 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.
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supported by the National Key Research and Development Project of China (2021YFC2300300,2023YFC2604300)the National Natural Science Foundation of China (32325029,91940302,91640104)。
文摘Riboswitches are conserved RNA elements that specifically recognize the cognate metabolites and regulate downstream gene expression involved in the metabolic pathways.To date,two classes of xanthine-responsive riboswitches involved in xanthine homeostasis have been identified.The recently reported xanthine-II riboswitch originates from guanine riboswitch family,featuring a single U-to-G mutation and several nucleotide insertions.Here,we report the complex structure of xanthine-II riboswitch bound to xanthine.The tertiary structure of xanthine-II riboswitch adopts a three-way junction scaffold similar to that of guanine riboswitch.However,the distinctive mutation and insertions in xanthine-II riboswitch facilitate the formation of a highly specific binding pocket for xanthine,distinguishing it from guanine riboswitches.Xanthine is bound in the junction region,forming a base triple with C64 and the mutant nucleotide G37,and is sandwiched by one base pair U8-A38 and one base triple A7-C36-U65.Structural alignment and ligand recognition specificity of the xanthine-II riboswitch are further verified by ligand-binding assays of structure-based mutation using isothermal titration calorimetry.Furthermore,leveraging the ligand specificity of the xanthine-II riboswitch,we develop a highly specific and sensitive biosensor for xanthine detection by fusing xanthine-II riboswitch with Pepper fluorogenic aptamer,highlighting the potential applications of xanthine-II riboswitch in diagnosing diseases related to xanthine metabolism disorders.
基金supported by the National Science Fund for Distinguished Young Scholars of China(Grant No.81925023)Joint Funds of the National Natural Science Foundation of China(Grant No.U23A20478)the National Science Foundation for Young Scientists of China(Grant No.82202267,82101996).
文摘Background:Tertiary lymphoid structures(TLS)are major components in the immune microenvironment,correlating with a favorable prognosis in colorectal cancer.However,the methods used to define and characterize TLS were not united,hindering its clinical application.This study aims to seek a more stable method to characterize TLS and clarify their prognostic value in larger multicenter cohorts.Methods:A total of 1609 patients from four hospitals and The Cancer Genome Atlas database were analyzed.We quantified the number and maximum length of TLS along the invasive margin of tumor using hematoxylin and eosin-stained whole-slide images(WSIs).Additionally,the length of the invasive margin was determined to calculate the TLs density.The prognostic value of TLS for overall survival was evaluated.In addition,we examined the association between TLS density and immune cell infltration using immunohistochemistry-stained WSIs.The performance for predicting overall survival was measured using hazard ratios(HR)with 95%confidence intervals(CI).Results:Among the three TLS quantification methods,TLS density has the strongest discriminative performance.Survival analysis indicated that higher TLS density correlated with better overall survival[HR for high vs.low 0.57(95%CI 0.42-0.78)in the primary cohort;0.49(0.35-0.69)in the validation cohort;0.35(0.18-0.67)in TCGA cohort].A high TLS density was associated with a high level of CD3+Tcell infiltration.Conclusions:Based on this comparative multicenter analysis,TLs density was identified as a simple,robust,and effective immune prognostic index for colorectal cancer.
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.
基金sponsored by the Guangdong Provincial Natural Science Foundation,No.S2012010009592the Science and Technology Talent Foundation of Guangdong Provincial Natural Science Foundation,No.30900725+2 种基金the Joint Research Program by Southern Medical University-Shunde Guizhou Hospital,No.09000608the Science Foshan Municipal Key Project in Medical Sciences,No.201008063and the Shunde Medical Research Program,No.2011050
文摘The sonic hedgehog protein not only plays a key role in early embryonic development, but also has essential effects on the adult nervous system, including neural stem cell proliferation, differentiation migration and neuronal axon guidance. The N-terminal fragment of sonic hedgehog is the key functional element in this process. Therefore, this study aimed to clone and analyze the N-terminal fragment of the sonic hedgehog gene. Total RNA was extracted from the notochord of a Sprague-Dawley rat at embryonic day 9 and the N-terminal fragment of sonic hedgehog was amplified by nested reverse transcription-PCR. The N-terminal fragment of the sonic hedgehog gene was successfully cloned. The secondary and tertiary structures of the N-terminal fragment of the sonic hedgehog protein were predicted using Jpred and Phyre online.
文摘The recent explosion of biological data and the concomitant proliferation of distributed databases make it challenging for biologists and bioinformaticians to discover the best data resources for their needs, and the most efficient way to access and use them For the biologist, running bioinformatics analyses involve a time-consuming management of data and tools. Users need support to organize their work, retrieve parameters and reproduce their analyses. They also need to be able to combine their analytic tools using a safe data flow software mechanism. Finally we have designed a system, Bioinfo-Portal, to provide a flexible and usable web environment for defining and running bioinformatics analyses. It embeds simple yet powerful data management features that allow the user to reproduce analyses and to combine tools using an adobe flex tool. Bioinfo-Portal can also act as a front end to provide a unified view of already-existing collections of bioinformatics resources. Users can analyze genomic and proteomic data by using the tools that has been integrated in the portal （tools for alignments, dotplots, motif detection, domain analysis, profile searching and tertiary structure prediction）. The sequences that user obtained from portal＇s nucleotide and protein databases are easily analyzed by the portal tools on the same interface in no time. User can also take benefit from the animations.
基金supported by the Maurice Wilkins Centre for Biodiscovery,New Zealandsupported by a Health Research Council Clinical Fellowship.
文摘Tertiary lymphoid structures(TLS)are ectopic lymphoid formations that form within nonlymphoid tissue.They share structural and functional characteristics with secondary lymphoid structures such as lymph nodes and can contain B-cell follicles and germinal centers surrounded by a T-cell region.TLS have been described in several types of cancers and are usually associated with positive patient outcomes.However,TLS differ vastly in cellular composition and location within tissue types.In this review,we discuss factors confounding the interpretation of the evidence for a prognostic role for TLS in cancer and frame these factors in the context of translation to regular clinical use.
基金by the US National Institutes of Health through National Cancer Institute grants CA141975 and CA97296,CPRIT grant RR150072,grants from the Chinese Academy of Sciences(XDA09030303)grants from the Chinese Ministry of Science and Technology(2012ZX10002006,2011DFA31250 and 2012AA020701)to YXF and a Cancer Resarch Institute Irvington Fellowship to HT.
文摘Tertiary lymphoid structures(TLS)often develop at sites of persistent inflammation,including cancers and autoimmune diseases.In most cases,the presence of TLS correlates with active immune responses.Because of their proximity to pathological loci,TLS are an intriguing target for the manipulation of immune responses.For several years,it has become clear that lymphotoxin(LT)signalling plays critical roles in lymphoid tissue organogenesis and maintenance.In the current review,we will discuss the role of LT signalling in the development of TLS.With a focus on cancers and autoimmune diseases,we will highlight the correlations between TLS and disease progression.We will also discuss the current efforts and potential directions for manipulating TLS for immunotherapies.
