Human colorectal cancer(CRC) is the third most commonly diagnosed malignancies and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although new chemotherapeutic regimen improves surv...Human colorectal cancer(CRC) is the third most commonly diagnosed malignancies and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although new chemotherapeutic regimen improves survival rates, therapy with better efficacy and less adverse effects is drastically needed. Immunotherapy has been investigated in human CRC for decades with limited success. However, recent developments of immunotherapy, particularly immune checkpoint inhibitor therapy, have achieved promising clinical benefits in many types of cancer and revived the hope for utilizing such therapy in human CRC. In this review, we will discuss important immunological landscape within the CRC microenvironment and introduce immunoscore system to better describe immunophenotyping in CRC. We will also discuss different immunotherapeutic approaches currently utilized in different phases of clinical trials. Some of those completed or ongoing trials are summarized. Finally, we provide a brief prospective on the future human CRC immunotherapy.展开更多
AIM: To study the effect of 5-Aza-2’-deoxycytidine (5-Aza-CdR) on heat shock protein 70 (HSP70), human leucocyte antigen-Ⅰ (HLA-Ⅰ) and NY-ESO-1 proteins in exosomes produced by hepatoma cells, HepG2 and Hep3B. METH...AIM: To study the effect of 5-Aza-2’-deoxycytidine (5-Aza-CdR) on heat shock protein 70 (HSP70), human leucocyte antigen-Ⅰ (HLA-Ⅰ) and NY-ESO-1 proteins in exosomes produced by hepatoma cells, HepG2 and Hep3B. METHODS: Exosomes derived from HepG2 and Hep3B cells treated with or without 5-aza-CdR were isolated and purified by ultrafiltration centrifugation and sucrose gradient ultracentrifugation. The number of exosomes was counted under electron microscope. Concentration of proteins in exosomes was measured by bicinchoninic acid protein assay. Expression of HSP70, HLA-Ⅰ and NY-ESO-1 proteins in exosomes was detected by Western blotting and immunoelectron microscopy. mRNA expression of p53 gene was detected by reverse transcription polymerase chain reaction.RESULTS: The mRNA expression of p53 gene was increased in both hepatoma cell lines after treatment with 5-Aza-CdR. The number of exosomes and the concentration of total proteins in exosomes were increased signifi cantly after treatment with 5-aza-CdR (P < 0.05). After treatment with 5-Aza-CdR, immunoelectron microscopy and Western blotting showed that the HSP70, HLA-Ⅰ and NY-ESO-1 proteins were increased in exosomes produced by both hepatoma cell lines. CONCLUSION: 5-aza-CdR, an inhibitor of DNA methyltransferase, can increase exosomes produced by hepatoma cells and immune-associated protein component of exosomes, which may be mediated by p53 gene upregulation and 5-Aza-CdR demethylation.展开更多
Despite of the promising achievements of immune checkpoints blockade therapy(ICB) in the clinic,which was often limited by low objective responses and severe side effects.Herein,we explored a synergistic strategy to c...Despite of the promising achievements of immune checkpoints blockade therapy(ICB) in the clinic,which was often limited by low objective responses and severe side effects.Herein,we explored a synergistic strategy to combine in situ vaccination and gene-mediated anti-PD therapy,which was generated by unmethylated cytosine-phosphate-guanine(CpG) and pshPD-L1 gene co-delivery.PEI worked as the delivery carrier to co-deliver the CpG and pshPD-L1 genes,the formed PDC(PEI/DNA/CpG)nanoparticles were further shielded by aldehyde modified polyethylene glycol(OHC-PEG-CHO) via pH responsive Schiff base reaction for OHC-PEG-CHO-PEI/DNA/CpG nanoparticles(P(PDC) NPs) prepa ration.All steps could be finished within 30 min.Such simple nanoparticles achieved the synergistic antitumor efficacy in B16 F10 tumor-bearing mice,and the amplified T cell responses,together with enhanced NK cells infiltration were observed after the combined treatments.In addition,the pH responsive delivery system reduced the side effects triggered by anti-PD therapy.The facile and effective combination strategy we presented here might provide a novel treatment for tumor inhibition.展开更多
Oral prescription medical foods have long been used in hospital settings but are also appropriate therapies for gastrointestinal disorders in outpatient medical practice.Oral serum-derived bovine immunoglobulin/protei...Oral prescription medical foods have long been used in hospital settings but are also appropriate therapies for gastrointestinal disorders in outpatient medical practice.Oral serum-derived bovine immunoglobulin/protein isolate(SBI) has been shown in clinical studies to reduce loose stools and improve stool consistency as well as other symptoms(i.e.,abdominal pain,bloating,and urgency) in patients with irritable bowel syndrome with diarrhea(IBS-D) and human immunodeficiency virus-associated enteropathy.This case series reports the outcomes of 14 IBS patients who received SBI as an addition to standard of care at an individual physician's clinical practice.The patients:2 IBS with constipation(IBS-C),7 IBS-D,2 mixed diarrhea and constipation IBS(IBS-M) and 3 undefined IBS(IBS-U; also described by some physicians as IBS-Bloating),ranged in age from 22-87 years.SBI(5 g or 10 g daily dose) was added to the patient's current standard care and followed for several weeks to determine if symptoms were improved with the addition of SBI.Overall,12 of the 14 patients indicated some level of improvement through direct questioning of the patients regarding changes from the prior visit.One IBS-Bloating patient had a resolution of symptoms and two patients(1 IBS-Bloating and 1 IBS-C) discontinued therapy because of insufficient relief.The 12 patients who continued on therapy reported an overall improvement in symptoms with better stool consistency,decreased frequency as well as reductions in abdominal pain,bloating,distention,and incontinence.In most cases,therapeutic effects of SBI were seen within the first four weeks of therapy with continued improvements at subsequent visits.SBI has a multifaceted mechanism of action and may help to manage IBS by providing a distinct protein source required to normalize bowel function,gastrointestinal microbiota,and nutritionally enhance tight junction protein expression between intestinal epithelial cells.SBI as a medical food provides a safe option for patients with IBS-D but may have application in other forms of IBS.展开更多
田边制药公司宣布收买美国Immunetech公司的研究部,改名为美国Tanabe Research Laboratories USA公司(TRL,加利福尼亚州).是该公司的第一个海外研究所.是日本企业收买的第四个生物技术风险企业. 1988年8月田边制药公司就有资本参加到Imm...田边制药公司宣布收买美国Immunetech公司的研究部,改名为美国Tanabe Research Laboratories USA公司(TRL,加利福尼亚州).是该公司的第一个海外研究所.是日本企业收买的第四个生物技术风险企业. 1988年8月田边制药公司就有资本参加到Immunetech公司.这次的收买费用没有公开,估计有50亿日元左右,属于高价购买.TRL的资金为100万美元,有Immunetech公司的20名研究人员,加上田边制药派出的和新录用的共计30名.研究费一年约5亿日元.TRL的研究领域是由Immun公司延续下来的免疫和过敏症药物.公司的负责人由原Immunetech公司负责研究开发的副经理Gerald J.Yakatan、田边制药应用生物化学研究所土佐哲也、田边制药基础生物研究所长岩泽义郎三人担任.展开更多
Reactive oxygen signaling regulates numerous biological processes,including stress responses in plants.Redox sensors transduce reactive oxygen signals into cellular responses.Here,we present biochemical evidence that ...Reactive oxygen signaling regulates numerous biological processes,including stress responses in plants.Redox sensors transduce reactive oxygen signals into cellular responses.Here,we present biochemical evidence that a plant quiescin sulfhydryl oxidase homolog(QSOX1)is a redox sensor that negatively regulates plant immunity against a bacterial pathogen.The expression level of QSOX1 is inversely correlated with pathogen-induced reactive oxygen species(ROS)accumulation.Interestingly,QSOX1 both senses and regulates ROS levels by interactingn with and mediating redox regulation of S-nitrosoglutathione reductase,which,consistent with previous findings,influences reactive nitrogen-mediated regulation of ROS generation.Collectively,our data indicate that QSOX1 is a redox sensorthat negatively regulates plant immunity by linking reactive oxygen and reactive nitrogen signaling to limit ROS production.展开更多
Objective To investigate the prevalence of antiendothelial cell antib odies and its possible role in the pathogenesis in lupus nephritis Methods Sera from 58 patients with lupus nephritis were studied Cellu l ar enzy...Objective To investigate the prevalence of antiendothelial cell antib odies and its possible role in the pathogenesis in lupus nephritis Methods Sera from 58 patients with lupus nephritis were studied Cellu l ar enzyme linked immunoabsaborbent assay was used to detect antiendothelia l cell a ntibodies, and immunoblotting technique was performed to determine its specific endothelial target antigens Results 362% of the patients with lupus nephritis had elevated IgG is o type antiendothelial cell antibodies The association was revealed between th e presence of antiendothelial cell antibodies (AECA) and some laboratory and re nal biopsy features, such as thrombocytopenia, higher serum IgG level, lower ser um C3 level, higher erythrocyte sedimentation rate (ESR), presence of antin uc lear antibody (ANA), antidsDNA antibodies and glomerular thrombosis Antien d othelial cell antibodies were consisted of a group of heterogeneous antibodies, and reacted with different endothelial cell antigens which ranged from 12-90?kD in molecular size in immunoblot A correlation was demonstrated between heavy p roteinuria (>35?g/24?hr) and the existence of antibodies against both 27 and 29 ?kD endothelial cell antigens, an association between the presence of glomerula r capillary thrombi and antibody against the 29?kD endothelial cell antigen was also found Conclusions Lupus nephritis patients with antiendothelial cell antibo dies showed a complex autoimmune disorder and clinical disease activity, and the results also provided an indirect evidence that antiendothelial cell antibodi es might contribute to the pathogenesis of lupus nephritis展开更多
文摘Human colorectal cancer(CRC) is the third most commonly diagnosed malignancies and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although new chemotherapeutic regimen improves survival rates, therapy with better efficacy and less adverse effects is drastically needed. Immunotherapy has been investigated in human CRC for decades with limited success. However, recent developments of immunotherapy, particularly immune checkpoint inhibitor therapy, have achieved promising clinical benefits in many types of cancer and revived the hope for utilizing such therapy in human CRC. In this review, we will discuss important immunological landscape within the CRC microenvironment and introduce immunoscore system to better describe immunophenotyping in CRC. We will also discuss different immunotherapeutic approaches currently utilized in different phases of clinical trials. Some of those completed or ongoing trials are summarized. Finally, we provide a brief prospective on the future human CRC immunotherapy.
基金Supported by Capital Medical Development Scientif ic Research Fund, No. 2005-3086
文摘AIM: To study the effect of 5-Aza-2’-deoxycytidine (5-Aza-CdR) on heat shock protein 70 (HSP70), human leucocyte antigen-Ⅰ (HLA-Ⅰ) and NY-ESO-1 proteins in exosomes produced by hepatoma cells, HepG2 and Hep3B. METHODS: Exosomes derived from HepG2 and Hep3B cells treated with or without 5-aza-CdR were isolated and purified by ultrafiltration centrifugation and sucrose gradient ultracentrifugation. The number of exosomes was counted under electron microscope. Concentration of proteins in exosomes was measured by bicinchoninic acid protein assay. Expression of HSP70, HLA-Ⅰ and NY-ESO-1 proteins in exosomes was detected by Western blotting and immunoelectron microscopy. mRNA expression of p53 gene was detected by reverse transcription polymerase chain reaction.RESULTS: The mRNA expression of p53 gene was increased in both hepatoma cell lines after treatment with 5-Aza-CdR. The number of exosomes and the concentration of total proteins in exosomes were increased signifi cantly after treatment with 5-aza-CdR (P < 0.05). After treatment with 5-Aza-CdR, immunoelectron microscopy and Western blotting showed that the HSP70, HLA-Ⅰ and NY-ESO-1 proteins were increased in exosomes produced by both hepatoma cell lines. CONCLUSION: 5-aza-CdR, an inhibitor of DNA methyltransferase, can increase exosomes produced by hepatoma cells and immune-associated protein component of exosomes, which may be mediated by p53 gene upregulation and 5-Aza-CdR demethylation.
基金The authors are thankful to the National Natural Science Foundation of China(Nos.51925305,51803210,51520105004,51873208,51973217 and 51833010)Jilin province science and technology development program(Nos.20200201075JC,20180414027GH)National Science and Technology Major Projects for Major New Drugs Innovation and Development(No.2018ZX09711003-012).
文摘Despite of the promising achievements of immune checkpoints blockade therapy(ICB) in the clinic,which was often limited by low objective responses and severe side effects.Herein,we explored a synergistic strategy to combine in situ vaccination and gene-mediated anti-PD therapy,which was generated by unmethylated cytosine-phosphate-guanine(CpG) and pshPD-L1 gene co-delivery.PEI worked as the delivery carrier to co-deliver the CpG and pshPD-L1 genes,the formed PDC(PEI/DNA/CpG)nanoparticles were further shielded by aldehyde modified polyethylene glycol(OHC-PEG-CHO) via pH responsive Schiff base reaction for OHC-PEG-CHO-PEI/DNA/CpG nanoparticles(P(PDC) NPs) prepa ration.All steps could be finished within 30 min.Such simple nanoparticles achieved the synergistic antitumor efficacy in B16 F10 tumor-bearing mice,and the amplified T cell responses,together with enhanced NK cells infiltration were observed after the combined treatments.In addition,the pH responsive delivery system reduced the side effects triggered by anti-PD therapy.The facile and effective combination strategy we presented here might provide a novel treatment for tumor inhibition.
文摘Oral prescription medical foods have long been used in hospital settings but are also appropriate therapies for gastrointestinal disorders in outpatient medical practice.Oral serum-derived bovine immunoglobulin/protein isolate(SBI) has been shown in clinical studies to reduce loose stools and improve stool consistency as well as other symptoms(i.e.,abdominal pain,bloating,and urgency) in patients with irritable bowel syndrome with diarrhea(IBS-D) and human immunodeficiency virus-associated enteropathy.This case series reports the outcomes of 14 IBS patients who received SBI as an addition to standard of care at an individual physician's clinical practice.The patients:2 IBS with constipation(IBS-C),7 IBS-D,2 mixed diarrhea and constipation IBS(IBS-M) and 3 undefined IBS(IBS-U; also described by some physicians as IBS-Bloating),ranged in age from 22-87 years.SBI(5 g or 10 g daily dose) was added to the patient's current standard care and followed for several weeks to determine if symptoms were improved with the addition of SBI.Overall,12 of the 14 patients indicated some level of improvement through direct questioning of the patients regarding changes from the prior visit.One IBS-Bloating patient had a resolution of symptoms and two patients(1 IBS-Bloating and 1 IBS-C) discontinued therapy because of insufficient relief.The 12 patients who continued on therapy reported an overall improvement in symptoms with better stool consistency,decreased frequency as well as reductions in abdominal pain,bloating,distention,and incontinence.In most cases,therapeutic effects of SBI were seen within the first four weeks of therapy with continued improvements at subsequent visits.SBI has a multifaceted mechanism of action and may help to manage IBS by providing a distinct protein source required to normalize bowel function,gastrointestinal microbiota,and nutritionally enhance tight junction protein expression between intestinal epithelial cells.SBI as a medical food provides a safe option for patients with IBS-D but may have application in other forms of IBS.
基金supported by grants from the"BioGreen21 Agri-Tech Inovation Program(project no.PJ015824 to S.Y.L.and PJ0159992021 to M.G.K.)",Rural Development Administration(RDA),South Koreaby the Basic Science Research Program through the National Research Foundation(NRF)of South Korea funded by the Ministry of Education(NRF-2018R1A6A3A11049525 to H.B.C.).
文摘Reactive oxygen signaling regulates numerous biological processes,including stress responses in plants.Redox sensors transduce reactive oxygen signals into cellular responses.Here,we present biochemical evidence that a plant quiescin sulfhydryl oxidase homolog(QSOX1)is a redox sensor that negatively regulates plant immunity against a bacterial pathogen.The expression level of QSOX1 is inversely correlated with pathogen-induced reactive oxygen species(ROS)accumulation.Interestingly,QSOX1 both senses and regulates ROS levels by interactingn with and mediating redox regulation of S-nitrosoglutathione reductase,which,consistent with previous findings,influences reactive nitrogen-mediated regulation of ROS generation.Collectively,our data indicate that QSOX1 is a redox sensorthat negatively regulates plant immunity by linking reactive oxygen and reactive nitrogen signaling to limit ROS production.
文摘Objective To investigate the prevalence of antiendothelial cell antib odies and its possible role in the pathogenesis in lupus nephritis Methods Sera from 58 patients with lupus nephritis were studied Cellu l ar enzyme linked immunoabsaborbent assay was used to detect antiendothelia l cell a ntibodies, and immunoblotting technique was performed to determine its specific endothelial target antigens Results 362% of the patients with lupus nephritis had elevated IgG is o type antiendothelial cell antibodies The association was revealed between th e presence of antiendothelial cell antibodies (AECA) and some laboratory and re nal biopsy features, such as thrombocytopenia, higher serum IgG level, lower ser um C3 level, higher erythrocyte sedimentation rate (ESR), presence of antin uc lear antibody (ANA), antidsDNA antibodies and glomerular thrombosis Antien d othelial cell antibodies were consisted of a group of heterogeneous antibodies, and reacted with different endothelial cell antigens which ranged from 12-90?kD in molecular size in immunoblot A correlation was demonstrated between heavy p roteinuria (>35?g/24?hr) and the existence of antibodies against both 27 and 29 ?kD endothelial cell antigens, an association between the presence of glomerula r capillary thrombi and antibody against the 29?kD endothelial cell antigen was also found Conclusions Lupus nephritis patients with antiendothelial cell antibo dies showed a complex autoimmune disorder and clinical disease activity, and the results also provided an indirect evidence that antiendothelial cell antibodi es might contribute to the pathogenesis of lupus nephritis
