Objective: To detect the mRNA expression of the cancer-testis antigens (CT) SSX1 and SSX4 gene in human hepatocellular carcinomas (HCCs) and to investigate the specificity of their expression in HCCs. Methods: The mRN...Objective: To detect the mRNA expression of the cancer-testis antigens (CT) SSX1 and SSX4 gene in human hepatocellular carcinomas (HCCs) and to investigate the specificity of their expression in HCCs. Methods: The mRNA expression of SSX1 and SSX4 in HCC tissues and the corresponding nearby liver tissues in 35 cases was detected by using RT-PCR; Six positive RT-PCR products were randomly selected and sequenced. Results: In all 35 HCC tissues, SSX1 in 27 cases (81%) and SSX4 in 23 cases (73%) were detected, and their expression was negative in the liver tissues nearby HCC and the non-tumor liver tissues (12 cirrhotic tissues and 15 normal tissues). In all 6 cases selected randomly, the results of DNA sequencing were identical with the cDNA sequence of SSX1 and SSX4 genes. The SSX1, SSX4 mRNA expression was not significantly correlated with age, sex, the tumor size, the level of tumor differentiation, the serum AFP level and the infection rate of HBV and HCV respectively (P>0.05). Conclusion: The SSX1, SSX4 mRNA expression was greatly specific in HCCs, which would not only provide the ideal target molecular sites for HCC tumor vaccines, but also establish the potential value of the polyvalent tumor-antigen vaccines for HCC therapy and its theory bases.展开更多
AIM:To evaluate the diagnostic value of cancer-testis antigen(CTA) mRNA in peripheral blood samples from hepatocellular carcinoma(HCC) patients.METHODS:Peripheral blood samples were taken from 90 patients with HCC bef...AIM:To evaluate the diagnostic value of cancer-testis antigen(CTA) mRNA in peripheral blood samples from hepatocellular carcinoma(HCC) patients.METHODS:Peripheral blood samples were taken from 90 patients with HCC before operation.Expression of melanoma antigen-1(MAGE-1),synovial sarcoma X breakpoint-1(SSX-1),and cancer-testis-associated protein of 11 kDa(CTp11) mRNA in peripheral blood mononuclear cells(PBMC) was tested by nested reverse transcriptspolymerase chain reaction(RT-PCR).Serum α-fetoprotein(AFP) in these patients was also determined.RESULTS:The positive rate of MAGE-1,SSX-1 and CTp11 transcripts was 37.7%,34.4%,31.1% in PBMC samples,and 74.4%,73.3%,62.2% in their resected tumor samples,respectively.The positive rate for at least one of the transcripts of three CTA genes was 66.7% in PBMC samples and 91.1% in their resected tumor samples.MAGE-1,SSX-1 and/or CTp11 mRNA were not detected in the PBMC of those patients from whom the resected tumor samples were MAGE-1,SSX-1 and/or CTp11 mRNA negative,nor in the PBMC samples from 20 healthy donors and 10 cirrhotic patients.Among the 90 patients,the serum AFP in 44 patients met the general diagnostic standard(AFP > 400 μg/L) for HCC,and was negative(AFP ≤ 20 μg/L) or positive with a low concentration(20 μg/L < AFP ≤ 400 μg/L) in the other patients.The positive rate for at least one of the transcripts of three CTA genes in PBMC samples from the AFP negative or positive patients with a low concentration was 69.2% and 45.0%,respectively.Of the 90 patients,71(78.9%) were diagnosed as HCC by nested RT-PCR and serum AFP.Although the positive rate for at least one of the transcripts of three CTA genes in PBMC samples from 53 patients at TNM stage or was obviously higher than that in PBMC samples from 37 patients at stage or(77.9% vs 51.4%,P = 0.010),the CTA mRNA was detected in 41.7% and 56.0% of PBMC samples from HCC patients at stages andrespectively.CONCLUSION:Detecting MAGE-1,SSX-1 and CTp11 mRNA in PBMC improves the total diagnostic rate of HCC.展开更多
AIM To assess cancer-testis antigens(CTAs) expression in gastric cancer patients and examined their associations with clinicopathological factors.METHODS Eighty-three gastric cancer patients were evaluated in this stu...AIM To assess cancer-testis antigens(CTAs) expression in gastric cancer patients and examined their associations with clinicopathological factors.METHODS Eighty-three gastric cancer patients were evaluated in this study. Gastric cancer specimens were evaluated for the gene expression of CTAs, Kitakyushu lung cancer antigen-1(KK-LC-1), melanoma antigen(MAGE)-A1, MAGE-A3 and New York esophageal cancer-1(NYESO-1), by reverse transcription PCR. Clinicopathological background information, such as gender, age, tumor size, macroscopic type, tumor histology, depth of invasion, lymph node metastasis, lymphatic invasion, venous invasion, and pathological stage, was obtained. Statistical comparisons between the expression of each CTA and each clinicopathological background were performed using the χ2 test. RESULTS The expression rates of KK-LC-1, MAGE-A1, MAGE-A3, and NY-ESO-1 were 79.5%, 32.5%, 39.8%, and 15.7%, respectively. In early stage gastric cancer specimens, the expression of KK-LC-1 was 79.4%, which is comparable to the 79.6% observed in advanced stage specimens. The expression of KK-LC-1 was not significantly associated with clinicopathological factors, while there were considerable differences in the expression rates of MAGE-A1 and MAGE-A3 with vs without lymphatic invasion(MAGE-A1, 39.3% vs 13.6%, P = 0.034; MAGE-A3, 47.5% vs 18.2%, P = 0.022) and/or vascular invasion(MAGE-A1, 41.5% vs 16.7%, P = 0.028; MAGE-A3, 49.1% vs 23.3%, P = 0.035) and, particularly, MAGE-A3, in patients with early vs advanced stage(36.5% vs 49.0%, P = 0.044), respectively. Patients expressing MAGE-A3 and NYESO-1 were older than those not expressing MAGE-A3 and NY-ESO-1(MAGE-A3, 73.7 ± 7.1 vs 67.4 ± 12.3, P = 0.009; NY-ESO-1, 75.5 ± 7.2 vs 68.8 ± 11.2, P = 0.042). CONCLUSION The KK-LC-1 expression rate was high even in patients with stage I cancer, suggesting that KK-LC-1 is a useful biomarker for early diagnosis of gastric cancer.展开更多
Recently, the immunotherapy has been highlighted among cancer treatments. Cancer-testis antigen （CTA） has been studied in a variety of solid tumors because of its specific expression in tumors, and testis, ovary and...Recently, the immunotherapy has been highlighted among cancer treatments. Cancer-testis antigen （CTA） has been studied in a variety of solid tumors because of its specific expression in tumors, and testis, ovary and placenta tissues, but not in other normal tissues. In order to provide a new ap- proach for multiple myeloma （MM） immunotherapy, we examined the CTA expression in MM cell lines, and primary myeloma cells in patients with MM. Reverse transcriptase-polymerase chain reaction （RT-PCR） was used to detect the mRNA expression of MAGE-C1/CT7, SSX1, SSX2 and SSX4 in MM cell lines of RPMI-8226 and U266, and bone marrow （BM） Cells of 25 MM patients and 18 healthy vol- unteers. The results showed that the 4 CTAs were expressed in RPMI-8226 and U266 cell lines. The positive expression rate of MAGE-C1/CT7, SSX1, SSX2 and SSX4 in the BM cells of 25 MM patients was 28% （7/25）, 80% （20/25）, 40% （10/25） and 68% （17/25）, respectively. In contrast, the expression of any member of the CTAs was not detected in BM cells of 18 healthy volunteers. The expression of two or more CTAs was detected in 80% （20/25） MM patients, and that of at least one CTA in 88% （22/25）. The mRNA expression levels of SSX1 and SSX4 were significantly higher in patients with MM at stage III than in those at stage I and II （P〈0.05）. No statistically significant differences were observed in the mRNA expression levels of MAGE-C 1/CT7 and SSX2 in further stratified analyses by age, gender, MM types and percentage of MM cells in BM （P〉0.05）. In conclusion, our present study showed that MAGE-C1/CT7, SSX1, SSX2 and SSX4 were co-expressed in MM cell lines and the primary myeloma cells in MM patients, but not expressed in BM cells of healthy subjects. The mRNA levels of SSX1 and SSX4 are associated with MM clinical stage. This work may provide a new insight into MM immuno- therapy in the future.展开更多
Summary:Cancer testis(CT)antigens have received particular attention in cancer immunotherapy.OY-TES-1 is a member of CT antigens.This study was to evaluate OY-TES-1 expression and immunogenicity in hepatocelluar carci...Summary:Cancer testis(CT)antigens have received particular attention in cancer immunotherapy.OY-TES-1 is a member of CT antigens.This study was to evaluate OY-TES-1 expression and immunogenicity in hepatocelluar carcinoma(HCC).OY-TES-1 mRNA expression was detected in 56 HCC tissues and 5 normal liver tissues by reverse transcriptase PCR(RT-PCR).Of the 56 cases of HCC tissues tested,37 cases had tumor and matched adjacent non-cancer tissues and were subjected to both RT-PCR and quantitative real-time PCR.OY-TES-1 protein was subsequently observed on a panel of tissue microarrays.Sera from patients were tested for OY-TES-1 antibody by ELISA.To identify OY-TES-1 capable of inducing cellular immune response,OY-TES-1 protein was used to sensitize dentritic cells and the cytotoxicity effect was measured in vitro.The results showed that OY-TES-1 mRNA was highly expressed in 41 of the 56(73.21%)HCC tissues,whereas none in 5 normal liver tissues.OY-TES-1 mRNA was frequently expressed not only in HCC tissues(72.97%,27/37),but also in paired adjacent non-cancer tissues(64.86%,24/37).But the mean expression level of OY-TES-1 mRNA in HCC tissues was significantly higher than that in adjacent non-cancer tissues(0.76854 vs.0.09834,P=0.021).Immunohistochemistry showed that OY-TES-1 protein expression was detected in 6 of the 49 cases of HCC tissues,and absent in 9 cases of normal liver and 6 cases of cirrhosis tissues.Seropositivity was detected in 10 of the 45 HCC patients,but not detected in 17 cirrhosis patients and 76 healthy donors.The specific cytotoxic T cells elicited by OY-TES-1 could kill HLA-A2^+HCC cell line which expressed OY-TES-1.The target lysis was mainly HLA class I-dependent and could be blocked by antibodies against monomorphic HLA class I but not HLA class II molecule.In summary,OY-TES-1 expression is upregulated in HCC tissues and can be recognized by humoral and cellular responses,which suggests that OY-TES-1 is an attractive target for tumor immunotherapy in HCC.展开更多
This study aimed to develop a multimodal imaging histological model based on computed tomography(CT)images and carcinoembryonic antigen(CEA)values to predict the efficacy of preoperative neoadjuvant therapy in rectal ...This study aimed to develop a multimodal imaging histological model based on computed tomography(CT)images and carcinoembryonic antigen(CEA)values to predict the efficacy of preoperative neoadjuvant therapy in rectal cancer patients.Data were obtained from the Database of Colorectal Cancer of West China Hospital of Sichuan University.A total of 155 patients were enrolled and categorized into good and poor response groups based on pathological evaluation using the tumor regression grade system.Radiomics features were extracted from CT images using PyRadiomics software,and CEA data were collected and processed.Three types of models—a clinical model,a pure radiomics model,and an integrated model—were constructed using logistic regression,support vector machine,random forest(RF),and XGBoost algorithms.The results showed that the integrated model,particularly the RF and XGBoost models,demonstrated the best predictive performance.The RF model achieved an area under the curve(AUC)value of 0.96 in the test set,with accuracy,sensitivity,and specificity of 0.88,0.50,and 1.00,respectively.The XGBoost model had the highest AUC value of 0.97 in the test set,with accuracy,sensitivity,and specificity of 0.91,0.70,and 0.97,respectively.This model can be integrated into existing clinical practice to provide clinicians with additional insights for guiding treatment decisions.Future studies should recruit a larger and more diverse patient population to validate and refine the model,and prospective validation is needed to assess its real-world applicability.展开更多
Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal malignancies,characterized by a highly immunosuppressive tumor microenvironment(TME),dense stromal architecture,and limited response to conventional...Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal malignancies,characterized by a highly immunosuppressive tumor microenvironment(TME),dense stromal architecture,and limited response to conventional therapies.This review comprehensively examines the emerging role of chimeric antigen receptor(CAR)-engineered immune cells,including chimeric antigen receptor-T(CAR-T),CAR-macrophages(CAR-M),and CAR-natural killer(CAR-NK)cells,as innovative immunotherapeutic strategies for PDAC.We delve into the mechanistic foundations of these platforms,highlighting their unique abilities to target tumor-associated antigens,overcome stromal barriers,and remodel the immunosuppressive TME.Recent preclinical and clinical advances demonstrate promising antitumor activity,particularly with targets such as mesothelin,claudin18.2,and human epidermal growth factor 2(HER2),though challenges related to antigen heterogeneity,TME suppression,and cell persistence remain.We further discuss synergistic approaches involving genetic engineering,microenvironment modulation,and combination therapies aimed at enhancing efficacy.Finally,we offer perspectives on the future direction of CARbased therapies,including the development of next-generation constructs,allogeneic“off-the-shelf”products,and personalized combination regimens,underscoring their potential in pancreatic cancer.展开更多
Objectives:B-cell maturation antigen(BCMA)-targeted antibody–drug conjugates(ADCs)have emerged as promising therapies for relapsed/refractory multiple myeloma(RRMM),but the overall efficacy and safety profile is uncl...Objectives:B-cell maturation antigen(BCMA)-targeted antibody–drug conjugates(ADCs)have emerged as promising therapies for relapsed/refractory multiple myeloma(RRMM),but the overall efficacy and safety profile is unclear.This study aimed to synthesize the available evidence on the safety and efficacy of BCMA-ADCs in development for RRMM.Methods:A systematic search was conducted using six bibliographic databases and ClinicalTrials.gov up to November 2024.Studies were eligible if they were human clinical trials or animal studies evaluating BCMA-ADCs and reported efficacy and safety outcomes.Data extraction and quality assessments were conducted using validated tools,including ROBINS-I and SYRCLE’s risk of bias tool.Results:A total of 21 studies were included:16 clinical trials and five animal studies.Key findings included that belantamab mafodotin demonstrated variable but generally durable response rates(32%–85%)and a broad range of progression-free survival(PFS)(2.8–36.6 months),albeit with ocular toxicities in 51%–96%.Among newer candidates,MEDI2228 showed median PFS 5.1–6.6 months with 14%discontinuation for ocular symptoms,while AMG 224 had an overall response rate(ORR)of 23%(9/40)with anemia 21%,thrombocytopenia 24%,and ocular adverse events(AEs)21%.Animal studies supported the tumor-eradicating potential of all BCMA-ADC candidates,although safety signals such as hepatic and renal toxicity were noted with HDP-101.The risk of bias assessment revealed generally moderate to serious concerns in human trials,while the overall quality of the animal studies was acceptable.Conclusions:BCMA-targeted ADC candidates show encouraging efficacy in RRMM,particularly belantamab mafodotin.However,frequent AEs,especially ocular and hematologic toxicities,underscore the need for optimization in ADC design.Further research should prioritize enhancing safety while maintaining clinical benefit.展开更多
Prostate-specific membrane antigen(PSMA)is a surface membrane antigen that is highly overexpressed in prostate cancer,with heterogenous expression throughout the natural history of the disease.This has generated signi...Prostate-specific membrane antigen(PSMA)is a surface membrane antigen that is highly overexpressed in prostate cancer,with heterogenous expression throughout the natural history of the disease.This has generated significant interest as a potential biomarker for use in early diagnosis and treatment of prostate cancer.We reviewed the literature surrounding PSMA and its current clinical applications in diagnosing and managing early prostate cancer that is confined to the prostate and local lymph nodes.A search on PubMed,Medline,and Web of Science was performed using the following keywords:“PSMA”,“Prostate Specific Membrane Antigen”,“Prostate cancer”,“Biomarker”,“Diagnosis”.We considered all available articles relevant to the topic of PSMA as a biomarker in early prostate cancer when developing this narrative review.Key articles assessing the biology of PSMA,as well as its use as a potential diagnostic and therapeutic target in early prostate cancer,were assessed.The role of PSMA PET as a potential diagnostic and risk stratification tool was assessed.The current use of antibody-drug conjugates and radioligand therapy targeting PSMA was assessed,along with any current evidence to support their use in early prostate cancer.PSMA is heavily expressed throughout the early stages of prostate cancer,and this has significant therapeutic implications.There is a growing body of evidence that shows PSMA PET can play a role in the diagnosis,risk stratification,and prognostication of localised prostate cancer.PSMA-targeted therapies such as Lu-177 currently do not have any proven benefit in treating early prostate cancer;however,this remains an area of ongoing research.展开更多
BACKGROUND Donor-specific antibodies(DSAs)against human leukocyte antigen(HLA)-DQ are increasingly recognized as major contributors to antibody-mediated rejection(AMR)and graft failure in kidney transplantation.Howeve...BACKGROUND Donor-specific antibodies(DSAs)against human leukocyte antigen(HLA)-DQ are increasingly recognized as major contributors to antibody-mediated rejection(AMR)and graft failure in kidney transplantation.However,their clinical impact remains understudied in Morocco.AIM To evaluate the presence and implications of anti-HLA-DQ DSAs in Moroccan kidney transplant recipients.METHODS We retrospectively analyzed the immunological profiles and clinical outcomes of kidney transplant recipients screened for anti-HLA antibodies between 2015 and 2020,who developed anti-HLA-DQ DSAs either before or after transplantation.Anti-HLA antibodies were identified using Luminex®single antigen bead technology,and clinical follow-up included graft function assessment,biopsy interpretation,and evaluation of immunosuppression.RESULTS In the pre-transplant group(n=6 with confirmed donor typing),patients with low to moderate median fluorescence intensity(MFI)anti-HLA-DQ DSAs(MFI 561-1581)underwent successful transplantation and maintained stable graft function under optimized immunosuppression.In contrast,in the post-transplant group(n=6 with confirmed donor typing),the emergence of de novo anti-HLA-DQ DSAs was consistently associated with AMR,with MFI values reaching up to 19473,with biopsy-proven AMR in 5 of 6 cases and suspicion of AMR in 1 case.Two representative cases are detailed to illustrate the clinical impact of DQ DSAs:one patient developed high-level anti-DQB1*02 de novo DSA(MFI 12029)with persistent AMR after 5 years,while another developed anti-DQA1*05:01 de novo DSA after an early AMR episode but maintained stable graft function after 5 years(creatinine 1.48 mg/dL).CONCLUSION Our findings underscore the clinical significance of anti-HLA-DQ DSAs in Moroccan kidney transplant recipients.While preformed DSAs with low immunogenicity may permit successful transplantation,de novo DSAs strongly correlate with AMR.Proactive monitoring,including routine DSA screening and HLA-DQ typing,could improve graft outcomes by enabling early intervention and better donor selection.展开更多
Loss of immune tolerance to central nervous system(CNS)antigens lies at the heart of multiple sclerosis(MS),the most common chronic autoimmune disease of the CNS.MS affects nearly2 million people wo rldwide and is cha...Loss of immune tolerance to central nervous system(CNS)antigens lies at the heart of multiple sclerosis(MS),the most common chronic autoimmune disease of the CNS.MS affects nearly2 million people wo rldwide and is chara cterized by focal areas of demyelination,inflammation,axonal injury,and neurodegeneration(Bronge et al.,2022;Magliozzi et al.,2023).展开更多
Highlights By conjugating the same anti-N monoclonal antibody(mAb4-mAb1)with colloidal gold or fluorescent microspheres,this study developed two rapid point-of-care antigen immunochromatographic strips for the detecti...Highlights By conjugating the same anti-N monoclonal antibody(mAb4-mAb1)with colloidal gold or fluorescent microspheres,this study developed two rapid point-of-care antigen immunochromatographic strips for the detection of porcine deltacoronavirus.The fluorescent microsphere-based lateral flow test strip demonstrated a sensitivity of 10^(1.7)TCID_(50)/0.1 mL,which is fourfold higher than that of the colloidal gold-based assay.Porcine deltacoronavirus(PDCoV)is a recently identified enteric coronavirus that causes an acute infectious disease in piglets,leading to diarrhea,vomiting,dehydration,and mortality(Hu et al.2015).展开更多
Objective:The newly defined cancer-testis(CT)gene,MEIOB,was previously found to play key roles in DNA double-strand break(DSB)repair.In this study,we aimed to investigate the effects and mechanisms of MEIOB in the car...Objective:The newly defined cancer-testis(CT)gene,MEIOB,was previously found to play key roles in DNA double-strand break(DSB)repair.In this study,we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers(TNBCs).Methods:The Cancer Genome Atlas database was used to quantify the expression of MEIOB.Cox regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human TNBC.The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in vitro.Patient-derived xenograft(PDX)models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors.Results:We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors,especially TNBCs.Its activation was significantly associated with poor survival in breast cancer patients[overall,hazard ratio(HR)=1.90(1.16–2.06);TNBCs:HR=7.05(1.16–41.80)].In addition,we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC cells.Further analysis showed that MEIOB participated in DSB repair in TNBCs.However,in contrast to its function in meiosis,it mediated homologous recombination deficiency(HRD)through the activation of poly ADP-ribose polymerase(PARP)1 by interacting with YBX1.Furthermore,activated MEIOB was shown to confer sensitivity to PARP inhibitors,which was confirmed in PDX models.Conclusions:MEIOB played an oncogenic role in TNBC through its involvement in HRD.In addition,dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors,so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC.展开更多
In this article,we comment on an article published in a recent issue of the World Journal of Gastroenterology.We specifically focus on the roles of human leukocyte antigen(HLA)and donor-specific antibodies(DSAs)in ped...In this article,we comment on an article published in a recent issue of the World Journal of Gastroenterology.We specifically focus on the roles of human leukocyte antigen(HLA)and donor-specific antibodies(DSAs)in pediatric liver transpl-antation(LT),as well as the relationship between immune rejection after LT and DSA.Currently,LT remains the standard of care for pediatric patients with end-stage liver disease or severe acute liver failure.However,acute and chronic re-jection continues to be a significant cause of graft dysfunction and loss.HLA mismatch significantly reduces graft survival and increases the risk of acute rejection.Among them,D→R one-way mismatch at three loci was significantly related to graft-versus-host disease incidence after LT.The adverse impact of HLA-DSAs on LT recipients is already established.Therefore,the evaluation of HLA and DSA is crucial in pediatric LT.展开更多
[Objective]To design and express a recombinant protein rMKIBV incorporating confirmed antigenic epitopes of infectious bronchitis virus(IBV)as a vaccine to provide comprehensive protection.Additionally,it explores the...[Objective]To design and express a recombinant protein rMKIBV incorporating confirmed antigenic epitopes of infectious bronchitis virus(IBV)as a vaccine to provide comprehensive protection.Additionally,it explores the potential of polyclonal yolk antibodies(IgY)harvested from laying hens immunized with the rMKIBV vaccine in the prevention and control of IBV.[Methods]The antigenic epitope sequences of IBV,obtained from online databases,were compared with sequences of representative IBV strains from GenBank.Flexible peptides were designed to link all antigenic peptides.The constructed amino acid sequence was analyzed,reverse-translated,codon-optimized,and then inserted into the pET-28a(+)cloning vector.The recombinant vector was introduced into Escherichia coli for expression.The purified,desalted,and endotoxin-removed rMKIBV protein was used as a vaccine to immunize animals for investigation of its immunogenicity and ability to stimulate specific IgY production in laying hens.[Results]The retrieved IBV antigenic epitope sequences showed high similarity with the published N and S protein sequences of 22 representative IBV strains.The predicted isoelectric point and molecular weight of rMKIBV were 10.25 and 63.39 kDa,respectively.The secondary structure of rMKIBV included a high proportion of random coils,which suggested strong antigenicity.High-purity rMKIBV was obtained from E.coli transformed with the recombinant plasmid pET-28a-mkibv.This protein specifically bound to anti-His-tag antibodies,N protein antibodies,and S protein antibodies.The mice immunized with this protein showed increases in the spleen index(P<0.05),elevations in the levels of serum-specific IgG antibodies(P<0.01)and IFN-γ(P<0.05),and no significant change in the IL-2 level.Immunized laying hens successfully produced IgY in egg yolks,with specific IgY antibody levels significantly increasing.Moreover,the IgY antibody titer gradually rose after immunization,reaching the peak after about 50 days and then gradually declining to reach a stable level.[Conclusion]We successfully constructed and expressed the recombinant protein rMKIBV.The protein demonstrated good immunogenicity,stimulating specific antibody production in both mice and laying hens.Notably,the IgY extracted from the yolks of immunized laying hens offers a novel approach to IBV prevention and control.These findings hold significant scientific and practical value for the development of vaccines against IBV.展开更多
Immune adjuvants are extremely important in tumor vaccines,which can amplify antigen-specific immune responses and enhance anti-tumor efficacy.Nevertheless,well-designed adjuvants and rational combination of adjuvants...Immune adjuvants are extremely important in tumor vaccines,which can amplify antigen-specific immune responses and enhance anti-tumor efficacy.Nevertheless,well-designed adjuvants and rational combination of adjuvants and antigens still remain a challenge in tumor vaccines.In this study,we designed and formulated carrier-free double-adjuvant nanoparticles(FPC-NPs)by self-assembling of fluoroalkane-grafted polyethylenimide(PEI)(Toll-like receptor 4(TLR4)agonist)and cytosine-phosphateguanine(CpG)(TLR9 agonist),and then obtained personalized tumor vaccines(FPC-NPs@TAAs)by electrostatic adsorption of tumor-associated antigens(TAAs)on the surface of FPC-NPs.The results showed that FPC-NPs@TAAs could promote cellular internalization of adjuvants,deliver antigens and adjuvants to the same antigen-presenting cell,which can effectively activate dendritic cells,encourage cross-presentation of antigens,and reduce the proportion of M2-type macrophages.Our work presents a simple method to realize the dual adjuvant combination of TLR4 and TLR9 via well-designed carrier-free nanoparticles,showing great promise for developing personalized tumor vaccines to enhance the efficacy of immunotherapy.展开更多
Chimeric antigen receptor T(CAR-T)cell therapy represents a major advance in cancer immunotherapy,offering targeted treatment options,particularly for hematologic malignancies.This review comprehensively explores the ...Chimeric antigen receptor T(CAR-T)cell therapy represents a major advance in cancer immunotherapy,offering targeted treatment options,particularly for hematologic malignancies.This review comprehensively explores the structural evolution,production processes,and cytotoxic mechanisms underlying CAR-T function.Therapy involves engineering autologous T cells with synthetic receptors that allow major histocompatibility complex-independent recognition of tumor-associated antigens.Key structural components such as antigen recognition domains,spacers,transmembrane,and intracellular domains are optimized to enhance specificity,persistence,and cytotoxicity.CAR-T therapy exerts antitumor effects via granzyme-perforin degranulation,Fas/Fas ligand signaling,and cytokine secretion.Over time,the development of second-to fifth-generation CARs has incorporated costimulatory molecules,transcriptional regulation,and logic-gated control to improve efficacy and safety.Additionally,novel engineering strategies such as dual CARs,tandem CARs,SynNotch systems,and universal or inhibitory CARs have expanded antigen targeting and reduced offtumor toxicity.Emerging gene delivery technologies,including viral vectors,transposons,CRISPR/Cas9,and RNA-based electroporation,are improving CART production.Despite notable clinical success,particularly in CD19-and B-cell maturation antigen-targeted therapies,CAR-T applications face challenges,including cell exhaustion,antigen escape,and therapy-induced toxicities,such as cytokine release syndrome and neurotoxicity.Ongoing efforts in engineering innovation,clinical trials,and regulatory support continue to shape CAR-T therapy into a safer,more precise tool for cancer treatment.This review highlights current advances while outlining the barriers and future prospects of CAR-T immunotherapy.展开更多
BACKGROUND Metastatic colorectal cancer(mCRC)is a global health challenge with a poor prognosis.Prognostic markers are critical for survival prediction.METHODS This multicenter,retrospective study measured baseline ca...BACKGROUND Metastatic colorectal cancer(mCRC)is a global health challenge with a poor prognosis.Prognostic markers are critical for survival prediction.METHODS This multicenter,retrospective study measured baseline carcinoembryonic antigen and carbohydrate antigen 19-9 levels to calculate a TMI as the geometric mean of values normalized to their upper limits of normal.Receiver operating characteristic curve analysis assessed TMI’s prognostic accuracy,and patients were stratified into high-TMI(≥1.39)and low-TMI(<1.39)groups.The primary endpoint was overall survival(OS),with progression-free survival and treatment response as secondary endpoints.RESULTS The study included 305 mCRC patients with a median follow-up of 22.9 months.The median OS for high-TMI patients was 29.5 months,significantly lower than the 45.6 months observed in the low-TMI group(P=0.02).The 2-year OS rates for the high-and low-TMI groups were 59.4%and 72.9%,respectively.Median progression-free survival was also shorter for the high-TMI group(14.0 vs 16.0 months,P=0.84).High TMI is an independent prognostic factor for worse OS.CONCLUSION TMI is a simple,cost-effective prognostic tool for mCRC,with high TMI associated with poorer survival outcomes.展开更多
Chimeric antigen receptor-T(CAR-T)cell therapy is a precise immunotherapy for lymphoma.However,its long-term efficacy faces many challenges related to tumor cell heterogeneity,interference from immunosuppressive micro...Chimeric antigen receptor-T(CAR-T)cell therapy is a precise immunotherapy for lymphoma.However,its long-term efficacy faces many challenges related to tumor cell heterogeneity,interference from immunosuppressive microenvironments,CAR-T cell exhaustion,and unmanageable adverse events.Diverse modifications have been introduced into conventional CAR-T cells to overcome these obstacles;examples include addition of recognition sites to prevent immune escape,coupling of cytokine domains to enhance killing ability,blocking of immune checkpoint signals to resist tumor microenvironments,and inclusion of suicide systems or safety switches to improve safety and flexibility.With increasing understanding of the importance of metabolism and epigenetics in cancer and cytotherapy,glycolysis,methylation,and acetylation have become crucial CAR-T cell therapeutic targets.Universal and in situ CAR-T cells are also expected to be used in clinical applications,thus providing hope to patients with relapsed/refractory lymphomas.展开更多
Mycobacterium tuberculosis(Mtb)employs multiple mechanisms,such as phagocytosis and autophagy,to evade innate immune clearance and establish infection.In the present study,we identified the ESX-1 secretion-associated ...Mycobacterium tuberculosis(Mtb)employs multiple mechanisms,such as phagocytosis and autophagy,to evade innate immune clearance and establish infection.In the present study,we identified the ESX-1 secretion-associated protein EspL,which promotes Mtb survival by inhibiting phagosome maturation and autophagy initiation.EspL knockout decreased Mtb intracellular survival,while EspL overexpression increased bacterial survival by interfering with phagocytosis and autophagy.EspL interacts with ULK1 and promotes its phosphorylation at Ser^(757),leading to the inhibition of autophagy initiation.Additionally,overexpression of EspL reduced antigen presentation and T-cell responses both in vitro and in vivo.Our findings revealed that EspL interferes with autophagy and antigen presenta-tion by suppressing ULK1 activation.These insights provide a novel understanding of Mtb pathogenicity.展开更多
文摘Objective: To detect the mRNA expression of the cancer-testis antigens (CT) SSX1 and SSX4 gene in human hepatocellular carcinomas (HCCs) and to investigate the specificity of their expression in HCCs. Methods: The mRNA expression of SSX1 and SSX4 in HCC tissues and the corresponding nearby liver tissues in 35 cases was detected by using RT-PCR; Six positive RT-PCR products were randomly selected and sequenced. Results: In all 35 HCC tissues, SSX1 in 27 cases (81%) and SSX4 in 23 cases (73%) were detected, and their expression was negative in the liver tissues nearby HCC and the non-tumor liver tissues (12 cirrhotic tissues and 15 normal tissues). In all 6 cases selected randomly, the results of DNA sequencing were identical with the cDNA sequence of SSX1 and SSX4 genes. The SSX1, SSX4 mRNA expression was not significantly correlated with age, sex, the tumor size, the level of tumor differentiation, the serum AFP level and the infection rate of HBV and HCV respectively (P>0.05). Conclusion: The SSX1, SSX4 mRNA expression was greatly specific in HCCs, which would not only provide the ideal target molecular sites for HCC tumor vaccines, but also establish the potential value of the polyvalent tumor-antigen vaccines for HCC therapy and its theory bases.
基金Supported by National Natural Science Foundation of China,No 30200271
文摘AIM:To evaluate the diagnostic value of cancer-testis antigen(CTA) mRNA in peripheral blood samples from hepatocellular carcinoma(HCC) patients.METHODS:Peripheral blood samples were taken from 90 patients with HCC before operation.Expression of melanoma antigen-1(MAGE-1),synovial sarcoma X breakpoint-1(SSX-1),and cancer-testis-associated protein of 11 kDa(CTp11) mRNA in peripheral blood mononuclear cells(PBMC) was tested by nested reverse transcriptspolymerase chain reaction(RT-PCR).Serum α-fetoprotein(AFP) in these patients was also determined.RESULTS:The positive rate of MAGE-1,SSX-1 and CTp11 transcripts was 37.7%,34.4%,31.1% in PBMC samples,and 74.4%,73.3%,62.2% in their resected tumor samples,respectively.The positive rate for at least one of the transcripts of three CTA genes was 66.7% in PBMC samples and 91.1% in their resected tumor samples.MAGE-1,SSX-1 and/or CTp11 mRNA were not detected in the PBMC of those patients from whom the resected tumor samples were MAGE-1,SSX-1 and/or CTp11 mRNA negative,nor in the PBMC samples from 20 healthy donors and 10 cirrhotic patients.Among the 90 patients,the serum AFP in 44 patients met the general diagnostic standard(AFP > 400 μg/L) for HCC,and was negative(AFP ≤ 20 μg/L) or positive with a low concentration(20 μg/L < AFP ≤ 400 μg/L) in the other patients.The positive rate for at least one of the transcripts of three CTA genes in PBMC samples from the AFP negative or positive patients with a low concentration was 69.2% and 45.0%,respectively.Of the 90 patients,71(78.9%) were diagnosed as HCC by nested RT-PCR and serum AFP.Although the positive rate for at least one of the transcripts of three CTA genes in PBMC samples from 53 patients at TNM stage or was obviously higher than that in PBMC samples from 37 patients at stage or(77.9% vs 51.4%,P = 0.010),the CTA mRNA was detected in 41.7% and 56.0% of PBMC samples from HCC patients at stages andrespectively.CONCLUSION:Detecting MAGE-1,SSX-1 and CTp11 mRNA in PBMC improves the total diagnostic rate of HCC.
基金Supported by Grant-in-Aid for research by Kitasato University Medical Center,No.H25-0006 and the JSPS,KAKENHI,No.26670609 to Futawatari Nthe JSPS,KAKENHI,No.21700510 and No.17K16578,Takeda Science Foundation and Kitasato University Research Grant for Young Researchers to Fukuyama T
文摘AIM To assess cancer-testis antigens(CTAs) expression in gastric cancer patients and examined their associations with clinicopathological factors.METHODS Eighty-three gastric cancer patients were evaluated in this study. Gastric cancer specimens were evaluated for the gene expression of CTAs, Kitakyushu lung cancer antigen-1(KK-LC-1), melanoma antigen(MAGE)-A1, MAGE-A3 and New York esophageal cancer-1(NYESO-1), by reverse transcription PCR. Clinicopathological background information, such as gender, age, tumor size, macroscopic type, tumor histology, depth of invasion, lymph node metastasis, lymphatic invasion, venous invasion, and pathological stage, was obtained. Statistical comparisons between the expression of each CTA and each clinicopathological background were performed using the χ2 test. RESULTS The expression rates of KK-LC-1, MAGE-A1, MAGE-A3, and NY-ESO-1 were 79.5%, 32.5%, 39.8%, and 15.7%, respectively. In early stage gastric cancer specimens, the expression of KK-LC-1 was 79.4%, which is comparable to the 79.6% observed in advanced stage specimens. The expression of KK-LC-1 was not significantly associated with clinicopathological factors, while there were considerable differences in the expression rates of MAGE-A1 and MAGE-A3 with vs without lymphatic invasion(MAGE-A1, 39.3% vs 13.6%, P = 0.034; MAGE-A3, 47.5% vs 18.2%, P = 0.022) and/or vascular invasion(MAGE-A1, 41.5% vs 16.7%, P = 0.028; MAGE-A3, 49.1% vs 23.3%, P = 0.035) and, particularly, MAGE-A3, in patients with early vs advanced stage(36.5% vs 49.0%, P = 0.044), respectively. Patients expressing MAGE-A3 and NYESO-1 were older than those not expressing MAGE-A3 and NY-ESO-1(MAGE-A3, 73.7 ± 7.1 vs 67.4 ± 12.3, P = 0.009; NY-ESO-1, 75.5 ± 7.2 vs 68.8 ± 11.2, P = 0.042). CONCLUSION The KK-LC-1 expression rate was high even in patients with stage I cancer, suggesting that KK-LC-1 is a useful biomarker for early diagnosis of gastric cancer.
基金supported by the Natural Science Foundation of Hubei Province,China(No.2012FK04452)
文摘Recently, the immunotherapy has been highlighted among cancer treatments. Cancer-testis antigen （CTA） has been studied in a variety of solid tumors because of its specific expression in tumors, and testis, ovary and placenta tissues, but not in other normal tissues. In order to provide a new ap- proach for multiple myeloma （MM） immunotherapy, we examined the CTA expression in MM cell lines, and primary myeloma cells in patients with MM. Reverse transcriptase-polymerase chain reaction （RT-PCR） was used to detect the mRNA expression of MAGE-C1/CT7, SSX1, SSX2 and SSX4 in MM cell lines of RPMI-8226 and U266, and bone marrow （BM） Cells of 25 MM patients and 18 healthy vol- unteers. The results showed that the 4 CTAs were expressed in RPMI-8226 and U266 cell lines. The positive expression rate of MAGE-C1/CT7, SSX1, SSX2 and SSX4 in the BM cells of 25 MM patients was 28% （7/25）, 80% （20/25）, 40% （10/25） and 68% （17/25）, respectively. In contrast, the expression of any member of the CTAs was not detected in BM cells of 18 healthy volunteers. The expression of two or more CTAs was detected in 80% （20/25） MM patients, and that of at least one CTA in 88% （22/25）. The mRNA expression levels of SSX1 and SSX4 were significantly higher in patients with MM at stage III than in those at stage I and II （P〈0.05）. No statistically significant differences were observed in the mRNA expression levels of MAGE-C 1/CT7 and SSX2 in further stratified analyses by age, gender, MM types and percentage of MM cells in BM （P〉0.05）. In conclusion, our present study showed that MAGE-C1/CT7, SSX1, SSX2 and SSX4 were co-expressed in MM cell lines and the primary myeloma cells in MM patients, but not expressed in BM cells of healthy subjects. The mRNA levels of SSX1 and SSX4 are associated with MM clinical stage. This work may provide a new insight into MM immuno- therapy in the future.
基金This work was supported by grants from the National Natural Science Foundation of China(No.81860445,No.81960453,No.81560408,and No.81660429)Natural Science Foundation of Guangxi Province(No.2016GXNSFBA380159,No.2018GXNSFAA281251,No.2018GXNSFAA050151,No.2017GXNSFAA198001,No.2018GXNSFAA281050,and No.2018GXNSFBA281187)+2 种基金Key Laboratory ofEarly Prevention and Treatment for Regional High Frequency Tumor(Guangxi Medical University)Ministry ofEducation(No.GK2018-09,No.GKE 2019-08,and No.K2015-TKF03)Basic Ability Improvement Project for Young and Middle-aged Teachers in Colleges and Universities of Guangxi Province(No.2018KY0109).
文摘Summary:Cancer testis(CT)antigens have received particular attention in cancer immunotherapy.OY-TES-1 is a member of CT antigens.This study was to evaluate OY-TES-1 expression and immunogenicity in hepatocelluar carcinoma(HCC).OY-TES-1 mRNA expression was detected in 56 HCC tissues and 5 normal liver tissues by reverse transcriptase PCR(RT-PCR).Of the 56 cases of HCC tissues tested,37 cases had tumor and matched adjacent non-cancer tissues and were subjected to both RT-PCR and quantitative real-time PCR.OY-TES-1 protein was subsequently observed on a panel of tissue microarrays.Sera from patients were tested for OY-TES-1 antibody by ELISA.To identify OY-TES-1 capable of inducing cellular immune response,OY-TES-1 protein was used to sensitize dentritic cells and the cytotoxicity effect was measured in vitro.The results showed that OY-TES-1 mRNA was highly expressed in 41 of the 56(73.21%)HCC tissues,whereas none in 5 normal liver tissues.OY-TES-1 mRNA was frequently expressed not only in HCC tissues(72.97%,27/37),but also in paired adjacent non-cancer tissues(64.86%,24/37).But the mean expression level of OY-TES-1 mRNA in HCC tissues was significantly higher than that in adjacent non-cancer tissues(0.76854 vs.0.09834,P=0.021).Immunohistochemistry showed that OY-TES-1 protein expression was detected in 6 of the 49 cases of HCC tissues,and absent in 9 cases of normal liver and 6 cases of cirrhosis tissues.Seropositivity was detected in 10 of the 45 HCC patients,but not detected in 17 cirrhosis patients and 76 healthy donors.The specific cytotoxic T cells elicited by OY-TES-1 could kill HLA-A2^+HCC cell line which expressed OY-TES-1.The target lysis was mainly HLA class I-dependent and could be blocked by antibodies against monomorphic HLA class I but not HLA class II molecule.In summary,OY-TES-1 expression is upregulated in HCC tissues and can be recognized by humoral and cellular responses,which suggests that OY-TES-1 is an attractive target for tumor immunotherapy in HCC.
基金supported by the 1-3-5 projects for artificial intelligence(Grant No.:ZYAI24067)West China Hospital,Sichuan University and the medical research project(Grant No.:S2024045),Sichuan Medical Association.
文摘This study aimed to develop a multimodal imaging histological model based on computed tomography(CT)images and carcinoembryonic antigen(CEA)values to predict the efficacy of preoperative neoadjuvant therapy in rectal cancer patients.Data were obtained from the Database of Colorectal Cancer of West China Hospital of Sichuan University.A total of 155 patients were enrolled and categorized into good and poor response groups based on pathological evaluation using the tumor regression grade system.Radiomics features were extracted from CT images using PyRadiomics software,and CEA data were collected and processed.Three types of models—a clinical model,a pure radiomics model,and an integrated model—were constructed using logistic regression,support vector machine,random forest(RF),and XGBoost algorithms.The results showed that the integrated model,particularly the RF and XGBoost models,demonstrated the best predictive performance.The RF model achieved an area under the curve(AUC)value of 0.96 in the test set,with accuracy,sensitivity,and specificity of 0.88,0.50,and 1.00,respectively.The XGBoost model had the highest AUC value of 0.97 in the test set,with accuracy,sensitivity,and specificity of 0.91,0.70,and 0.97,respectively.This model can be integrated into existing clinical practice to provide clinicians with additional insights for guiding treatment decisions.Future studies should recruit a larger and more diverse patient population to validate and refine the model,and prospective validation is needed to assess its real-world applicability.
文摘Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal malignancies,characterized by a highly immunosuppressive tumor microenvironment(TME),dense stromal architecture,and limited response to conventional therapies.This review comprehensively examines the emerging role of chimeric antigen receptor(CAR)-engineered immune cells,including chimeric antigen receptor-T(CAR-T),CAR-macrophages(CAR-M),and CAR-natural killer(CAR-NK)cells,as innovative immunotherapeutic strategies for PDAC.We delve into the mechanistic foundations of these platforms,highlighting their unique abilities to target tumor-associated antigens,overcome stromal barriers,and remodel the immunosuppressive TME.Recent preclinical and clinical advances demonstrate promising antitumor activity,particularly with targets such as mesothelin,claudin18.2,and human epidermal growth factor 2(HER2),though challenges related to antigen heterogeneity,TME suppression,and cell persistence remain.We further discuss synergistic approaches involving genetic engineering,microenvironment modulation,and combination therapies aimed at enhancing efficacy.Finally,we offer perspectives on the future direction of CARbased therapies,including the development of next-generation constructs,allogeneic“off-the-shelf”products,and personalized combination regimens,underscoring their potential in pancreatic cancer.
文摘Objectives:B-cell maturation antigen(BCMA)-targeted antibody–drug conjugates(ADCs)have emerged as promising therapies for relapsed/refractory multiple myeloma(RRMM),but the overall efficacy and safety profile is unclear.This study aimed to synthesize the available evidence on the safety and efficacy of BCMA-ADCs in development for RRMM.Methods:A systematic search was conducted using six bibliographic databases and ClinicalTrials.gov up to November 2024.Studies were eligible if they were human clinical trials or animal studies evaluating BCMA-ADCs and reported efficacy and safety outcomes.Data extraction and quality assessments were conducted using validated tools,including ROBINS-I and SYRCLE’s risk of bias tool.Results:A total of 21 studies were included:16 clinical trials and five animal studies.Key findings included that belantamab mafodotin demonstrated variable but generally durable response rates(32%–85%)and a broad range of progression-free survival(PFS)(2.8–36.6 months),albeit with ocular toxicities in 51%–96%.Among newer candidates,MEDI2228 showed median PFS 5.1–6.6 months with 14%discontinuation for ocular symptoms,while AMG 224 had an overall response rate(ORR)of 23%(9/40)with anemia 21%,thrombocytopenia 24%,and ocular adverse events(AEs)21%.Animal studies supported the tumor-eradicating potential of all BCMA-ADC candidates,although safety signals such as hepatic and renal toxicity were noted with HDP-101.The risk of bias assessment revealed generally moderate to serious concerns in human trials,while the overall quality of the animal studies was acceptable.Conclusions:BCMA-targeted ADC candidates show encouraging efficacy in RRMM,particularly belantamab mafodotin.However,frequent AEs,especially ocular and hematologic toxicities,underscore the need for optimization in ADC design.Further research should prioritize enhancing safety while maintaining clinical benefit.
文摘Prostate-specific membrane antigen(PSMA)is a surface membrane antigen that is highly overexpressed in prostate cancer,with heterogenous expression throughout the natural history of the disease.This has generated significant interest as a potential biomarker for use in early diagnosis and treatment of prostate cancer.We reviewed the literature surrounding PSMA and its current clinical applications in diagnosing and managing early prostate cancer that is confined to the prostate and local lymph nodes.A search on PubMed,Medline,and Web of Science was performed using the following keywords:“PSMA”,“Prostate Specific Membrane Antigen”,“Prostate cancer”,“Biomarker”,“Diagnosis”.We considered all available articles relevant to the topic of PSMA as a biomarker in early prostate cancer when developing this narrative review.Key articles assessing the biology of PSMA,as well as its use as a potential diagnostic and therapeutic target in early prostate cancer,were assessed.The role of PSMA PET as a potential diagnostic and risk stratification tool was assessed.The current use of antibody-drug conjugates and radioligand therapy targeting PSMA was assessed,along with any current evidence to support their use in early prostate cancer.PSMA is heavily expressed throughout the early stages of prostate cancer,and this has significant therapeutic implications.There is a growing body of evidence that shows PSMA PET can play a role in the diagnosis,risk stratification,and prognostication of localised prostate cancer.PSMA-targeted therapies such as Lu-177 currently do not have any proven benefit in treating early prostate cancer;however,this remains an area of ongoing research.
基金Supported by the National Science and Technology Research Center(Morocco)“PhD-Associate Scholarship-PASS”Program,No.88UH2C2023.
文摘BACKGROUND Donor-specific antibodies(DSAs)against human leukocyte antigen(HLA)-DQ are increasingly recognized as major contributors to antibody-mediated rejection(AMR)and graft failure in kidney transplantation.However,their clinical impact remains understudied in Morocco.AIM To evaluate the presence and implications of anti-HLA-DQ DSAs in Moroccan kidney transplant recipients.METHODS We retrospectively analyzed the immunological profiles and clinical outcomes of kidney transplant recipients screened for anti-HLA antibodies between 2015 and 2020,who developed anti-HLA-DQ DSAs either before or after transplantation.Anti-HLA antibodies were identified using Luminex®single antigen bead technology,and clinical follow-up included graft function assessment,biopsy interpretation,and evaluation of immunosuppression.RESULTS In the pre-transplant group(n=6 with confirmed donor typing),patients with low to moderate median fluorescence intensity(MFI)anti-HLA-DQ DSAs(MFI 561-1581)underwent successful transplantation and maintained stable graft function under optimized immunosuppression.In contrast,in the post-transplant group(n=6 with confirmed donor typing),the emergence of de novo anti-HLA-DQ DSAs was consistently associated with AMR,with MFI values reaching up to 19473,with biopsy-proven AMR in 5 of 6 cases and suspicion of AMR in 1 case.Two representative cases are detailed to illustrate the clinical impact of DQ DSAs:one patient developed high-level anti-DQB1*02 de novo DSA(MFI 12029)with persistent AMR after 5 years,while another developed anti-DQA1*05:01 de novo DSA after an early AMR episode but maintained stable graft function after 5 years(creatinine 1.48 mg/dL).CONCLUSION Our findings underscore the clinical significance of anti-HLA-DQ DSAs in Moroccan kidney transplant recipients.While preformed DSAs with low immunogenicity may permit successful transplantation,de novo DSAs strongly correlate with AMR.Proactive monitoring,including routine DSA screening and HLA-DQ typing,could improve graft outcomes by enabling early intervention and better donor selection.
文摘Loss of immune tolerance to central nervous system(CNS)antigens lies at the heart of multiple sclerosis(MS),the most common chronic autoimmune disease of the CNS.MS affects nearly2 million people wo rldwide and is chara cterized by focal areas of demyelination,inflammation,axonal injury,and neurodegeneration(Bronge et al.,2022;Magliozzi et al.,2023).
基金financially supported by the National Key Research and Development Program of China(2021YFF0703600)。
文摘Highlights By conjugating the same anti-N monoclonal antibody(mAb4-mAb1)with colloidal gold or fluorescent microspheres,this study developed two rapid point-of-care antigen immunochromatographic strips for the detection of porcine deltacoronavirus.The fluorescent microsphere-based lateral flow test strip demonstrated a sensitivity of 10^(1.7)TCID_(50)/0.1 mL,which is fourfold higher than that of the colloidal gold-based assay.Porcine deltacoronavirus(PDCoV)is a recently identified enteric coronavirus that causes an acute infectious disease in piglets,leading to diarrhea,vomiting,dehydration,and mortality(Hu et al.2015).
基金supported by the National Natural Science Foundation of China(Grant Nos.81902836 and 81572602)the China Postdoctoral Science Foundation(Grant Nos.2017M610339 and 2018M630584)。
文摘Objective:The newly defined cancer-testis(CT)gene,MEIOB,was previously found to play key roles in DNA double-strand break(DSB)repair.In this study,we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers(TNBCs).Methods:The Cancer Genome Atlas database was used to quantify the expression of MEIOB.Cox regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human TNBC.The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in vitro.Patient-derived xenograft(PDX)models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors.Results:We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors,especially TNBCs.Its activation was significantly associated with poor survival in breast cancer patients[overall,hazard ratio(HR)=1.90(1.16–2.06);TNBCs:HR=7.05(1.16–41.80)].In addition,we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC cells.Further analysis showed that MEIOB participated in DSB repair in TNBCs.However,in contrast to its function in meiosis,it mediated homologous recombination deficiency(HRD)through the activation of poly ADP-ribose polymerase(PARP)1 by interacting with YBX1.Furthermore,activated MEIOB was shown to confer sensitivity to PARP inhibitors,which was confirmed in PDX models.Conclusions:MEIOB played an oncogenic role in TNBC through its involvement in HRD.In addition,dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors,so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC.
文摘In this article,we comment on an article published in a recent issue of the World Journal of Gastroenterology.We specifically focus on the roles of human leukocyte antigen(HLA)and donor-specific antibodies(DSAs)in pediatric liver transpl-antation(LT),as well as the relationship between immune rejection after LT and DSA.Currently,LT remains the standard of care for pediatric patients with end-stage liver disease or severe acute liver failure.However,acute and chronic re-jection continues to be a significant cause of graft dysfunction and loss.HLA mismatch significantly reduces graft survival and increases the risk of acute rejection.Among them,D→R one-way mismatch at three loci was significantly related to graft-versus-host disease incidence after LT.The adverse impact of HLA-DSAs on LT recipients is already established.Therefore,the evaluation of HLA and DSA is crucial in pediatric LT.
文摘[Objective]To design and express a recombinant protein rMKIBV incorporating confirmed antigenic epitopes of infectious bronchitis virus(IBV)as a vaccine to provide comprehensive protection.Additionally,it explores the potential of polyclonal yolk antibodies(IgY)harvested from laying hens immunized with the rMKIBV vaccine in the prevention and control of IBV.[Methods]The antigenic epitope sequences of IBV,obtained from online databases,were compared with sequences of representative IBV strains from GenBank.Flexible peptides were designed to link all antigenic peptides.The constructed amino acid sequence was analyzed,reverse-translated,codon-optimized,and then inserted into the pET-28a(+)cloning vector.The recombinant vector was introduced into Escherichia coli for expression.The purified,desalted,and endotoxin-removed rMKIBV protein was used as a vaccine to immunize animals for investigation of its immunogenicity and ability to stimulate specific IgY production in laying hens.[Results]The retrieved IBV antigenic epitope sequences showed high similarity with the published N and S protein sequences of 22 representative IBV strains.The predicted isoelectric point and molecular weight of rMKIBV were 10.25 and 63.39 kDa,respectively.The secondary structure of rMKIBV included a high proportion of random coils,which suggested strong antigenicity.High-purity rMKIBV was obtained from E.coli transformed with the recombinant plasmid pET-28a-mkibv.This protein specifically bound to anti-His-tag antibodies,N protein antibodies,and S protein antibodies.The mice immunized with this protein showed increases in the spleen index(P<0.05),elevations in the levels of serum-specific IgG antibodies(P<0.01)and IFN-γ(P<0.05),and no significant change in the IL-2 level.Immunized laying hens successfully produced IgY in egg yolks,with specific IgY antibody levels significantly increasing.Moreover,the IgY antibody titer gradually rose after immunization,reaching the peak after about 50 days and then gradually declining to reach a stable level.[Conclusion]We successfully constructed and expressed the recombinant protein rMKIBV.The protein demonstrated good immunogenicity,stimulating specific antibody production in both mice and laying hens.Notably,the IgY extracted from the yolks of immunized laying hens offers a novel approach to IBV prevention and control.These findings hold significant scientific and practical value for the development of vaccines against IBV.
基金supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project(No.2023ZD0500800)National Natural Science Foundation of China(Nos.82302390,82172090 and 82072059)+4 种基金CAMS Innovation Fund for Medical Sciences(Nos.2021-I2M-1-058,2022-I2M-2-003 and 2023-I2M-2-008)China Postdoctoral Science Foundation(No.2022M720502)Tianjin Municipal Natural Science Foundation(Nos.22JCQNJC00070 and 24ZXZSSS00200)CAMS Union Young Scholars Support Program(No.2022051)Fundamental Research Funds for the Central Universities(No.2019PT320028).
文摘Immune adjuvants are extremely important in tumor vaccines,which can amplify antigen-specific immune responses and enhance anti-tumor efficacy.Nevertheless,well-designed adjuvants and rational combination of adjuvants and antigens still remain a challenge in tumor vaccines.In this study,we designed and formulated carrier-free double-adjuvant nanoparticles(FPC-NPs)by self-assembling of fluoroalkane-grafted polyethylenimide(PEI)(Toll-like receptor 4(TLR4)agonist)and cytosine-phosphateguanine(CpG)(TLR9 agonist),and then obtained personalized tumor vaccines(FPC-NPs@TAAs)by electrostatic adsorption of tumor-associated antigens(TAAs)on the surface of FPC-NPs.The results showed that FPC-NPs@TAAs could promote cellular internalization of adjuvants,deliver antigens and adjuvants to the same antigen-presenting cell,which can effectively activate dendritic cells,encourage cross-presentation of antigens,and reduce the proportion of M2-type macrophages.Our work presents a simple method to realize the dual adjuvant combination of TLR4 and TLR9 via well-designed carrier-free nanoparticles,showing great promise for developing personalized tumor vaccines to enhance the efficacy of immunotherapy.
文摘Chimeric antigen receptor T(CAR-T)cell therapy represents a major advance in cancer immunotherapy,offering targeted treatment options,particularly for hematologic malignancies.This review comprehensively explores the structural evolution,production processes,and cytotoxic mechanisms underlying CAR-T function.Therapy involves engineering autologous T cells with synthetic receptors that allow major histocompatibility complex-independent recognition of tumor-associated antigens.Key structural components such as antigen recognition domains,spacers,transmembrane,and intracellular domains are optimized to enhance specificity,persistence,and cytotoxicity.CAR-T therapy exerts antitumor effects via granzyme-perforin degranulation,Fas/Fas ligand signaling,and cytokine secretion.Over time,the development of second-to fifth-generation CARs has incorporated costimulatory molecules,transcriptional regulation,and logic-gated control to improve efficacy and safety.Additionally,novel engineering strategies such as dual CARs,tandem CARs,SynNotch systems,and universal or inhibitory CARs have expanded antigen targeting and reduced offtumor toxicity.Emerging gene delivery technologies,including viral vectors,transposons,CRISPR/Cas9,and RNA-based electroporation,are improving CART production.Despite notable clinical success,particularly in CD19-and B-cell maturation antigen-targeted therapies,CAR-T applications face challenges,including cell exhaustion,antigen escape,and therapy-induced toxicities,such as cytokine release syndrome and neurotoxicity.Ongoing efforts in engineering innovation,clinical trials,and regulatory support continue to shape CAR-T therapy into a safer,more precise tool for cancer treatment.This review highlights current advances while outlining the barriers and future prospects of CAR-T immunotherapy.
文摘BACKGROUND Metastatic colorectal cancer(mCRC)is a global health challenge with a poor prognosis.Prognostic markers are critical for survival prediction.METHODS This multicenter,retrospective study measured baseline carcinoembryonic antigen and carbohydrate antigen 19-9 levels to calculate a TMI as the geometric mean of values normalized to their upper limits of normal.Receiver operating characteristic curve analysis assessed TMI’s prognostic accuracy,and patients were stratified into high-TMI(≥1.39)and low-TMI(<1.39)groups.The primary endpoint was overall survival(OS),with progression-free survival and treatment response as secondary endpoints.RESULTS The study included 305 mCRC patients with a median follow-up of 22.9 months.The median OS for high-TMI patients was 29.5 months,significantly lower than the 45.6 months observed in the low-TMI group(P=0.02).The 2-year OS rates for the high-and low-TMI groups were 59.4%and 72.9%,respectively.Median progression-free survival was also shorter for the high-TMI group(14.0 vs 16.0 months,P=0.84).High TMI is an independent prognostic factor for worse OS.CONCLUSION TMI is a simple,cost-effective prognostic tool for mCRC,with high TMI associated with poorer survival outcomes.
基金supported by grants from the Science Technology Department of Zhejiang Province(Grant No.2021C03117)Noncommunicable Chronic DiseasesNational Science and Technology Major Project(Grant No.2023ZD0501300)+1 种基金National Natural Science Foundation of China(Grant No.82170219)Zhejiang Provincial Natural Science Foundation of China(Grant No.LQ24H080009)。
文摘Chimeric antigen receptor-T(CAR-T)cell therapy is a precise immunotherapy for lymphoma.However,its long-term efficacy faces many challenges related to tumor cell heterogeneity,interference from immunosuppressive microenvironments,CAR-T cell exhaustion,and unmanageable adverse events.Diverse modifications have been introduced into conventional CAR-T cells to overcome these obstacles;examples include addition of recognition sites to prevent immune escape,coupling of cytokine domains to enhance killing ability,blocking of immune checkpoint signals to resist tumor microenvironments,and inclusion of suicide systems or safety switches to improve safety and flexibility.With increasing understanding of the importance of metabolism and epigenetics in cancer and cytotherapy,glycolysis,methylation,and acetylation have become crucial CAR-T cell therapeutic targets.Universal and in situ CAR-T cells are also expected to be used in clinical applications,thus providing hope to patients with relapsed/refractory lymphomas.
基金supported by the National Natural Science Foundation of China under grant number U21A20259the National Key Research and Development Program of China under grant number 2021YFD1800401.
文摘Mycobacterium tuberculosis(Mtb)employs multiple mechanisms,such as phagocytosis and autophagy,to evade innate immune clearance and establish infection.In the present study,we identified the ESX-1 secretion-associated protein EspL,which promotes Mtb survival by inhibiting phagosome maturation and autophagy initiation.EspL knockout decreased Mtb intracellular survival,while EspL overexpression increased bacterial survival by interfering with phagocytosis and autophagy.EspL interacts with ULK1 and promotes its phosphorylation at Ser^(757),leading to the inhibition of autophagy initiation.Additionally,overexpression of EspL reduced antigen presentation and T-cell responses both in vitro and in vivo.Our findings revealed that EspL interferes with autophagy and antigen presenta-tion by suppressing ULK1 activation.These insights provide a novel understanding of Mtb pathogenicity.
