Gastric cancer is one of the most common malignant tumors in the world.Its incidence ranks fifth among all malignant tumors worldwide and is the third leading cause of death among cancer patients.Surgery is currently ...Gastric cancer is one of the most common malignant tumors in the world.Its incidence ranks fifth among all malignant tumors worldwide and is the third leading cause of death among cancer patients.Surgery is currently considered to be the only radical treatment.However,the low rate of early diagnosis means that most patients have an advanced-stage disease at diagnosis which lost the chance of surgery.Therefore,the main treatment for advanced gastric cancer includes chemotherapy,targeted therapy,immunotherapy.The purpose of this study is to review the transition and current patterns of drug therapy for advanced gastric cancer and to provide assistance for subsequent clinical studies in advanced gastric cancer.展开更多
Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory ce...Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory cells and tissue damage in acute pancreatitis. A hallmark of the inflammatory response in pancreatitis is the induction of cytokine expression, which is regulated by a number of signaling molecules including oxidant-sensitive transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs). Cross-talk between ROS and pro-inflammatory cytokines is mediated by NF-κB, AP-1, STAT3, and MAPKs; this crosstalk amplifies the inflammatory cascade in acute pancreatitis. Therapeutic studies have shown that antioxidants and natural compounds can have beneficial effects for patients with pancreatitis and can also influence the expression of proinflammatory cytokines in cerulein-induced pancreatitis. Since oxidative stress may activate inflammatory signaling pathways and contribute to the development of pancreatitis, antioxidant therapy may alleviate the symptoms or prevent the development of pancreatitis. Since chronic administration of high doses of antioxidants may have deleterious effects, dosage levels and duration of antioxidant treatment should be carefully determined.展开更多
AIM: To test for the association between genome-wide methylation and myopia in human and mice. METHODS: Long interspersed nucleotide element 1(LINE-1) methylation levels were used to surrogate genome-wide methylation...AIM: To test for the association between genome-wide methylation and myopia in human and mice. METHODS: Long interspersed nucleotide element 1(LINE-1) methylation levels were used to surrogate genome-wide methylation level. We first tested for the association between high myopia(<-6 D) and LINE-1 methylation in leukocytes in 220 cases and 220 control subjects. Secondly, we validated the results of LINE-1 methylation in eyes from the form deprivation myopia(FDM) mice. Furthermore,we calculated the correlation of LINE-1 methylation levels between leukocyte DNA and ocular DNA in the mice. We also tested whether dopamine can alter LINE-1 methylation levels. RESULTS: The LINE-1 methylation level was significantly higher in the myopic human subjects than controls. The upper and middle tertiles of the methylation levels increased an approximately 2-fold(P≤0.002) risk for myopia than the lower tertile. Similarly, FDM mice had high LINE-1 methylation levels in the leukocyte, retina and sclera, and furthermore the methylation levels detected from these three tissues were significantly correlated. Immunohistochemical staining revealed higher levels of homocysteine and methionine in the rodent myopic eyes than normal eyes. Dopamine treatment to the cells reduced both LINE-1 methylation and DNA methyltransferase levels. CONCLUSION: LINE-1 hypermethylation may be associated with high myopia in human and mice. Homocysteine and methionine are accumulated in myopic eyes, which may provide excess methyl group for genome-wide methylation.展开更多
Plasmonic nanostructure-mediated photothermal therapy(PTT) has proven to be a promising approach for cancer treatment,and new approaches for its effective delivery to tumor lesions are currently being developed.This s...Plasmonic nanostructure-mediated photothermal therapy(PTT) has proven to be a promising approach for cancer treatment,and new approaches for its effective delivery to tumor lesions are currently being developed.This study aimed to assess macrophage-mediated delivery of PTT using radioiodine-124-labeled gold nanoparticles with crushed gold shells(124I-Au@AuCBs) as a theranostic nanoplatform.124I-Au@AuCBs exhibited effective photothermal conversion effects both in vitro and in vivo and were efficiently taken up by macrophages without cytotoxicity.After the administration of 124I-Au@AuCB-labeled macrophages to colon tumors,intensive signals were observed at tumor lesions,and subsequent in vivo PTT with laser irradiation yielded potent antitumor effects.The results indicate the considerable potential of 124I-Au@AuCBs as novel theranostic nanomaterials and the prominent advantages of macrophage-mediated cellular therapies in treating cancer and other diseases.展开更多
Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts.Recent studies have shown that...Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts.Recent studies have shown that histone demethylases are implicated in osteoblastogenesis;however,little is known about the role of histone demethylases in osteoclast formation.Here,we identified KDM4B as an epigenetic regulator of osteoclast differentiation.Knockdown of KDM4B significantly blocked the formation of tartrate-resistant acid phosphatase-positive multinucleated cells.Mice with myeloid-specific conditional knockout of KDM4B showed an osteopetrotic phenotype due to osteoclast deficiency.Biochemical analysis revealed that KDM4B physically and functionally associates with CCAR1 and MED1 in a complex.Using genome-wide chromatin immunoprecipitation(ChIP)-sequencing,we revealed that the KDM4B–CCAR1–MED1 complex is localized to the promoters of several osteoclast-related genes upon receptor activator of NF-κB ligand stimulation.We demonstrated that the KDM4B–CCAR1–MED1 signaling axis induces changes in chromatin structure(euchromatinization)near the promoters of osteoclast-related genes through H3K9 demethylation,leading to NF-κB p65 recruitment via a direct interaction between KDM4B and p65.Finally,small molecule inhibition of KDM4B activity impeded bone loss in an ovariectomized mouse model.Taken together,our findings establish KDM4B as a critical regulator of osteoclastogenesis,providing a potential therapeutic target for osteoporosis.展开更多
Nineteen diterpenoids, including saldigitin A(1) bearing an unprecedented 10-methylated 6/7/6 carbon ring system, two new icetexanes(2, 3), and two new nor-abietanes(5, 6) were characterized from the roots of Salvia d...Nineteen diterpenoids, including saldigitin A(1) bearing an unprecedented 10-methylated 6/7/6 carbon ring system, two new icetexanes(2, 3), and two new nor-abietanes(5, 6) were characterized from the roots of Salvia digitaloides. Their structures were elucidated by the analysis of the spectroscopic data,X-ray crystallography, and TDDFT calculations of ECD spectra. The novel architecture of 1 should be biogenetically derived through the cleavage and re-cyclization of the B/C rings from the normal abietane skeleton. Biologically, 1–5 exhibited noticeable inhibitions on Ca_(v)3.1 low voltage-gated Ca2+channel(LVGCC), with IC50values in the range of 3.43–11.70 μmol/L. They are the first example of diterpenoids with 6/7/6 carbon rings system as Ca_(v)3.1 antagonists.展开更多
BACKGROUND Irritable bowel syndrome(IBS)is a highly prevalent gastrointestinal disorder with poor response to treatment.IBS with predominant diarrhea(IBS-D)is accompanied by abdominal pain as well as high stool freque...BACKGROUND Irritable bowel syndrome(IBS)is a highly prevalent gastrointestinal disorder with poor response to treatment.IBS with predominant diarrhea(IBS-D)is accompanied by abdominal pain as well as high stool frequency and urgency.Purified clinoptilolite-tuff(PCT),which is approved by the Food and Drug Administration for use as a dietary supplement with the brand name G-PUR®,has previously shown therapeutic potential in other indications based on its physical adsorption capacity.AIM To assess whether symptoms of IBS-D can be ameliorated by oral treatment with PCT.METHODS In this randomized,placebo-controlled,double-blind pilot study,30 patients with IBS-D diagnosis based on Rome IV criteria were enrolled.Following a 4-wk run-in phase,14 patients were randomized to receive a 12-wk treatment with G-PUR®(2 g three times daily),and 16 patients received placebo.The relief from IBS-D symptoms as measured by the proportion of responders according to the Subject’s Global Assessment(SGA)of Relief was assessed as the primary outcome.For the secondary outcomes,validated IBS-D associated symptom questionnaires,exploratory biomarkers and microbiome data were collected.RESULTS The proportions of SGA of Relief responders after 12 wk were comparable in both groups,namely 21%in the G-PUR®group and 25%in the placebo group.After 4 wk of treatment,36%of patients in the G-PUR®group vs 0%in the placebo group reported complete or considerable relief.An improvement in daily abdominal pain was noted in 94%vs 83%(P=0.0353),and the median number of days with diarrhea per week decreased by 2.4 d vs 0.3 d in the G-PUR®and placebo groups,respectively.Positive trends were observed for 50%of responders in the Bristol Stool Form Scale.Positive trends were also noted for combined abdominal pain and stool consistency response and the Perceived Stress Questionnaire score.Only 64%in the G-PUR®group compared to 86%in the placebo group required rescue medication intake during the study.Stool microbiome studies showed a minor increase in diversity in the G-PUR®group but not in the placebo group.No PCT-related serious adverse events were reported.CONCLUSION In this randomized,double-blind,placebo-controlled study,the PCT product,G-PUR®,demonstrated safety and clinical benefit towards some symptoms of IBS-D,representing a promising novel treatment option for these patients.展开更多
Alpha-fetoprotein-producing gastric or gastro-esophageal junction(AFP-G/GEJ)cancer,a rare gastric cancer subtype,exhibits increased angiogenesis and more immunosuppression than non-AFP-G/GEJ cancer.The potential benef...Alpha-fetoprotein-producing gastric or gastro-esophageal junction(AFP-G/GEJ)cancer,a rare gastric cancer subtype,exhibits increased angiogenesis and more immunosuppression than non-AFP-G/GEJ cancer.The potential benefits of anti-angiogenic agents and immunotherapy for this specific subtype remain unknown.This multi-center,single-arm,phase 2 trial(ClinicalTrials.gov NCT04609176)evaluated the antitumor activity,safety,and biomarkers of camrelizumab plus apatinib and S-1 and oxaliplatin(SOX),followed by maintenance treatment with camrelizumab plus apatinib,as a first-line treatment in patients with AFP-G/GEJ adenocarcinoma.Primary endpoint was the confirmed objective response rate(ORR)per RECIST v1.1 in the full analysis set.Secondary endpoints were disease control rate(DCR),progression-free survival(PFS),overall survival(OS),duration of response,time to response,and safety.Between December 4,2020,and August 4,2023,36 patients were enrolled and treated.The trial met its primary endpoint with a confirmed ORR of 66.7%(95%Cl:49.0-81.4).The DCR was 88.9%(95%Cl:73.9-96.9).With a median follow-up of 11.7 months(range:3.2-37.9),the median PFS reached 7.8 months(95%Cl:4.9-12.3)and the median OS reached 18.0 months(95%Cl:10.5-NR).No new safety concerns were identified.In exploratory analysis,patients with durable clinical benefit exhibited higher pre-treatment(PD-1+)CD8+T cell densities and effective scores.First-line treatment with camrelizumab plus apatinib and SOX,followed by maintenance treatment with camrelizumab plus apatinib,is effective and safe in AFP-G/GEJ adenocarcinoma.Further studies are necessary to validate these findings.展开更多
Using plants to produce heterologous proteins makes it very attractive due to the potentially low costs. Using this procedure it is possible to produce medicinal protein for clinical applications with the plants biore...Using plants to produce heterologous proteins makes it very attractive due to the potentially low costs. Using this procedure it is possible to produce medicinal protein for clinical applications with the plants bioreactors increasing gradually. The paper proposes the five major systems of the plant bioreactor as well as their advantage and disadvantage and the development of each system. Focuses on the five major systems of the plant bioreactor to produce vaccines, antibodies and medical protein and the research achievement at the present stage and the research on my laboratory. The key technology research of plant bioreactor such as new genes, new biological components, new technologies and new research methods related with plant bioreactor offer a work foundation for a long-term development in future.展开更多
Cells orchestrate their processes through complex interactions,precisely organizing biomolecules in space and time.Recent discoveries have highlighted the crucial role of biomolecular condensates—membrane-less assemb...Cells orchestrate their processes through complex interactions,precisely organizing biomolecules in space and time.Recent discoveries have highlighted the crucial role of biomolecular condensates—membrane-less assemblies formed through the condensation of proteins,nucleic acids,and other molecules—in driving efficient and dynamic cellular processes.These condensates are integral to various physiological functions,such as gene expression and intracellular signal transduction,enabling rapid and finely tuned cellular responses.Their ability to regulate cellular signaling pathways is particularly significant,as it requires a careful balance between flexibility and precision.Disruption of this balance can lead to pathological conditions,including neurodegenerative diseases,cancer,and viral infections.Consequently,biomolecular condensates have emerged as promising therapeutic targets,with the potential to offer novel approaches to disease treatment.In this review,we present the recent insights into the regulatory mechanisms by which biomolecular condensates influence intracellular signaling pathways,their roles in health and disease,and potential strategies for modulating condensate dynamics as a therapeutic approach.Understanding these emerging principles may provide valuable directions for developing effective treatments targeting the aberrant behavior of biomolecular condensates in various diseases.展开更多
The demand for safe vaccines that ensure long-term and broad protection against multiple viral variants has dramatically increased after the emergence of catastrophic infectious diseases such as COVID-19.To ensure lon...The demand for safe vaccines that ensure long-term and broad protection against multiple viral variants has dramatically increased after the emergence of catastrophic infectious diseases such as COVID-19.To ensure long-term and broad protection against heterologous virus variants,antigen-specific polyfunctional T cells should be orchestrated with the activation of follicular helper T(TFH)cells and germinal center(GC)B cells.Herein,we suggest a novel engineered nanoadjuvant(SE(Trojan-TLR7/8a))that enhances the migration of nonexhausted antigen-presenting cells(APCs)into lymph nodes and elicits the activation of TFH cells,the generation of GC B cells,and polyfunctional T cells via multiscale dynamic immunomodulation through squalene nanoemulsion(SE)-mediated macroscopic control of vaccine delivery and Trojan-TLR7/8a-enabled dynamic and sustained activation of APCs at the cellular level.SE(Trojan-TLR7/8a)can be lyophilized,reduce systemic toxicity,and outperform current commercial vaccine adjuvants(Alum or AS03)and mRNA vaccines.SE(Trojan-TLR7/8a)ensures cross-protection against diverse influenza and SARS-CoV-2 variants,providing 100%protection while maintaining a healthy state.SE(Trojan-TLR7/8a)also sustains a potent T-cell response in an aged ferret model of SFTSV infection.SE(Trojan-TLR7/8a)suggested herein provides a novel vaccine design principle for dynamic modulation at the multiscale level and demonstrates long-term and broad protective immunity against emerging pandemic and endemic infectious viruses.展开更多
To evaluate the efficacy and safety of KN026,a novel bispecific HER2(ECD2 and ECD4)antibody,plus KN046,a PD-L1,and CTLA4 bispecific antibody,in patients with advanced HER2-positive solid tumors.We conducted two sequen...To evaluate the efficacy and safety of KN026,a novel bispecific HER2(ECD2 and ECD4)antibody,plus KN046,a PD-L1,and CTLA4 bispecific antibody,in patients with advanced HER2-positive solid tumors.We conducted two sequentially designed phase Ib and Il studies with similar target populations and evaluation schedules.The primary endpoints included safety,maximum tolerated dose(MTD),the recommended phase Il dose(RP2D)for the phase Ib study,and the objective response rate(ORR)and duration of response(DoR)for the phase llstudy.Hereby,we solely report the results from 113 nonbreast cancer patients.In phase Ib,MTD was not reached.Dose 3 was confirmed to be acceptable for the phase lIl study.An objective response has been exclusively observed in HER2-positive patients.Any grade treatment-related adverse events(TRAEs)were reported in 108(95.6%)patients.The most common TRAEs were infusion reactions(38.9%),anemia(37.2%),elevated AST(31.0%),and diarrhea(30.1%).Among the 108 patients evaluated for efficacy,the overall ORR was 55.6%(95%Cl,45.7%,65.1%).In the HER2-positive GC subgroup,38 patients received this regimen as the 1st-line treatment and 30 patients achieved an objective response,with an ORR of 78.9%(95%Cl,62.7%,90.4%).Among 27 pretreated patients,the ORR was 44.4%(95%Cl,25.5%,64.7%).In the other HER2-positive solid tumor subgroup(n=34),the ORR was 52.9%(95%CI 35.1%,70.2%).Thus,KN026 plus KN04 exhibits promising efficacy and acceptable safety profiles in HER2-positive nonbreast cancer,as does the 1st-line treatment for GC.展开更多
Voltage-gated calcium channels(VGCCs) play critical roles in cardiac and skeletal muscle contractions,hormone and neurotransmitter release,as well as slower processes such as cell proliferation,differentiation,migrati...Voltage-gated calcium channels(VGCCs) play critical roles in cardiac and skeletal muscle contractions,hormone and neurotransmitter release,as well as slower processes such as cell proliferation,differentiation,migration and death.Mutations in VGCCs lead to numerous cardiac,muscle and neurological disease,and their physiological function is tightly regulated by kinases,phosphatases,G-proteins,calmodulin and many other proteins.Fifteen years ago,RGK proteins were discovered as the most potent endogenous regulators of VGCCs.They are a family of monomeric GTPases(Rad,Rem,Rem2,and Gem/Kir),in the superfamily of Ras GTPases,and they have two known functions: regulation of cytoskeletal dynamics including dendritic arborization and inhibition of VGCCs.Here we review the mechanisms and molecular determinants of RGK-mediated VGCC inhibition,the physiological impact of this inhibition,and recent evidence linking the two known RGK functions.展开更多
Background and Aims:It remains difficult to forecast the 180-day prognosis of patients with hepatitis B virus-acuteon-chronic liver failure(HBV-ACLF)using existing prognostic models.The present study aimed to derive n...Background and Aims:It remains difficult to forecast the 180-day prognosis of patients with hepatitis B virus-acuteon-chronic liver failure(HBV-ACLF)using existing prognostic models.The present study aimed to derive novel-innovative models to enhance the predictive effectiveness of the 180-day mortality in HBV-ACLF.Methods:The present cohort study examined 171 HBV-ACLF patients(non-survivors,n=62;survivors,n=109).The 27 retrospectively collected parameters included the basic demographic characteristics,clinical comorbidities,and laboratory values.Backward stepwise logistic regression(LR)and the classification and regression tree(CART)analysis were used to derive two predictive models.Meanwhile,a nomogram was created based on the LR analysis.The accuracy of the LR and CART model was detected through the area under the receiver operating characteristic curve(AUROC),compared with model of end-stage liver disease(MELD)scores.Results:Among 171 HBV-ACLF patients,the mean age was 45.17 years-old,and 11.7%of the patients were female.The LR model was constructed with six independent factors,which included age,total bilirubin,prothrombin activity,lymphocytes,monocytes and hepatic encephalopathy.The following seven variables were the prognostic factors for HBV-ACLF in the CART model:age,total bilirubin,prothrombin time,lymphocytes,neutrophils,monocytes,and blood urea nitrogen.The AUROC for the CART model(0.878)was similar to that for the LR model(0.878,p=0.898),and this exceeded that for the MELD scores(0.728,p<0.0001).Conclusions:The LR and CART model are both superior to the MELD scores in predicting the 180-day mortality of patients with HBV-ACLF.Both the LR and CART model can be used as medical decision-making tools by clinicians.展开更多
Neuroendocrine neoplasm of the pancreas is a rare tumor with limited treatment options.Among such tumors,treatment for pancreatic neuroendocrine tumor(PanNET)G3 is the most difficult.Temozolomide(TMZ)is commonly used ...Neuroendocrine neoplasm of the pancreas is a rare tumor with limited treatment options.Among such tumors,treatment for pancreatic neuroendocrine tumor(PanNET)G3 is the most difficult.Temozolomide(TMZ)is commonly used to treat PanNET.However,TMZ may cause tumor gene alkylation,which induces drug resistance and rapid disease progression.Herein,we present a case of a female who was diagnosed with PanNET G3 and achieved a partial response to toripalimab,an anti-programmed cell death-ligand 1(anti-PD-L1)monoclonal antibody,after multiple cycles of TMZ treatment.Genomic profiling revealed that compared with the patient’s samples collected at baseline,the postTMZ-treatment samples had markedly higher levels of tumor mutational burden(TMB)associated with characteristic alkylating mutational signature representing a positive correlation with favorable response to anti-PD-1 treatment.In addition,we observed a germline truncating mutation of MUTYH(W156*)that was considered to be pathogenic and potentially conferred to genomic instability.This case suggests that anti-PD-1 therapy could be a treatment option for PanNET patients with increased TMB after TMZ-based treatment.展开更多
Biliary tract cancers(BTCs)comprise a group of heterogeneous poor prognosis cancers with increasing incidence recent years.The combination chemotherapy with cisplatin and gemcitabine is the first-line therapy for adva...Biliary tract cancers(BTCs)comprise a group of heterogeneous poor prognosis cancers with increasing incidence recent years.The combination chemotherapy with cisplatin and gemcitabine is the first-line therapy for advanced BTC.There remains no accepted standard treatment in the second-line setting.Nowadays,more and more novel treatment strategies have entered development,with some encouraging results being seen.Here,we review the current treatment status and clinical characteristics of BTC,the role of immunotherapy in BTC as well as the design of clinical trials for oncology drugs for BTC which aim to focus on the future profiles of clinical care and resolution of BTC.展开更多
文摘Gastric cancer is one of the most common malignant tumors in the world.Its incidence ranks fifth among all malignant tumors worldwide and is the third leading cause of death among cancer patients.Surgery is currently considered to be the only radical treatment.However,the low rate of early diagnosis means that most patients have an advanced-stage disease at diagnosis which lost the chance of surgery.Therefore,the main treatment for advanced gastric cancer includes chemotherapy,targeted therapy,immunotherapy.The purpose of this study is to review the transition and current patterns of drug therapy for advanced gastric cancer and to provide assistance for subsequent clinical studies in advanced gastric cancer.
基金Supported by National Research Foundation of Korea grant funded by the Korea government No.2007-0056092
文摘Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory cells and tissue damage in acute pancreatitis. A hallmark of the inflammatory response in pancreatitis is the induction of cytokine expression, which is regulated by a number of signaling molecules including oxidant-sensitive transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs). Cross-talk between ROS and pro-inflammatory cytokines is mediated by NF-κB, AP-1, STAT3, and MAPKs; this crosstalk amplifies the inflammatory cascade in acute pancreatitis. Therapeutic studies have shown that antioxidants and natural compounds can have beneficial effects for patients with pancreatitis and can also influence the expression of proinflammatory cytokines in cerulein-induced pancreatitis. Since oxidative stress may activate inflammatory signaling pathways and contribute to the development of pancreatitis, antioxidant therapy may alleviate the symptoms or prevent the development of pancreatitis. Since chronic administration of high doses of antioxidants may have deleterious effects, dosage levels and duration of antioxidant treatment should be carefully determined.
基金Supported by the grants from the Taiwan Ministry of Science and Technology(MOST 104-2622-B-037-005)Taiwan Ministry of Health and Welfare Clinical Trial Centre(MOHW107-TDU-B-212-123004)Drug Development Center,China Medical University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education(MOE)in Taiwan
文摘AIM: To test for the association between genome-wide methylation and myopia in human and mice. METHODS: Long interspersed nucleotide element 1(LINE-1) methylation levels were used to surrogate genome-wide methylation level. We first tested for the association between high myopia(<-6 D) and LINE-1 methylation in leukocytes in 220 cases and 220 control subjects. Secondly, we validated the results of LINE-1 methylation in eyes from the form deprivation myopia(FDM) mice. Furthermore,we calculated the correlation of LINE-1 methylation levels between leukocyte DNA and ocular DNA in the mice. We also tested whether dopamine can alter LINE-1 methylation levels. RESULTS: The LINE-1 methylation level was significantly higher in the myopic human subjects than controls. The upper and middle tertiles of the methylation levels increased an approximately 2-fold(P≤0.002) risk for myopia than the lower tertile. Similarly, FDM mice had high LINE-1 methylation levels in the leukocyte, retina and sclera, and furthermore the methylation levels detected from these three tissues were significantly correlated. Immunohistochemical staining revealed higher levels of homocysteine and methionine in the rodent myopic eyes than normal eyes. Dopamine treatment to the cells reduced both LINE-1 methylation and DNA methyltransferase levels. CONCLUSION: LINE-1 hypermethylation may be associated with high myopia in human and mice. Homocysteine and methionine are accumulated in myopic eyes, which may provide excess methyl group for genome-wide methylation.
基金supported by National Research Foundation of Korea(NRF) grants funded by the Korea Government(MSIP)a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI) funded by the Ministry of Health&Welfare,Republic of Korea(HI16C1501)+1 种基金a grant from the Medical Cluster R&D Support Project through the Daegu-Gyeongbuk Medical Innovation Foundation(DGMIF) funded by the Ministry of Health and Welfare(HT16C0001,HT16C0002,HT17C0009)a National Research Foundation of Korea(NRF) Grant funded by the Korea Government(MSIP)(2014R1A1A1003323,2017R1D1A1B03028340,2018R1D1AB07047417)
文摘Plasmonic nanostructure-mediated photothermal therapy(PTT) has proven to be a promising approach for cancer treatment,and new approaches for its effective delivery to tumor lesions are currently being developed.This study aimed to assess macrophage-mediated delivery of PTT using radioiodine-124-labeled gold nanoparticles with crushed gold shells(124I-Au@AuCBs) as a theranostic nanoplatform.124I-Au@AuCBs exhibited effective photothermal conversion effects both in vitro and in vivo and were efficiently taken up by macrophages without cytotoxicity.After the administration of 124I-Au@AuCB-labeled macrophages to colon tumors,intensive signals were observed at tumor lesions,and subsequent in vivo PTT with laser irradiation yielded potent antitumor effects.The results indicate the considerable potential of 124I-Au@AuCBs as novel theranostic nanomaterials and the prominent advantages of macrophage-mediated cellular therapies in treating cancer and other diseases.
基金support of the National Research Foundation of Korea(2017R1C1B2008017,2020R1A6A1A06046235,and 2020R1A2C1008179 to K.K.,2019R1I1A1A01061125 to S.J.Y.).
文摘Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts.Recent studies have shown that histone demethylases are implicated in osteoblastogenesis;however,little is known about the role of histone demethylases in osteoclast formation.Here,we identified KDM4B as an epigenetic regulator of osteoclast differentiation.Knockdown of KDM4B significantly blocked the formation of tartrate-resistant acid phosphatase-positive multinucleated cells.Mice with myeloid-specific conditional knockout of KDM4B showed an osteopetrotic phenotype due to osteoclast deficiency.Biochemical analysis revealed that KDM4B physically and functionally associates with CCAR1 and MED1 in a complex.Using genome-wide chromatin immunoprecipitation(ChIP)-sequencing,we revealed that the KDM4B–CCAR1–MED1 complex is localized to the promoters of several osteoclast-related genes upon receptor activator of NF-κB ligand stimulation.We demonstrated that the KDM4B–CCAR1–MED1 signaling axis induces changes in chromatin structure(euchromatinization)near the promoters of osteoclast-related genes through H3K9 demethylation,leading to NF-κB p65 recruitment via a direct interaction between KDM4B and p65.Finally,small molecule inhibition of KDM4B activity impeded bone loss in an ovariectomized mouse model.Taken together,our findings establish KDM4B as a critical regulator of osteoclastogenesis,providing a potential therapeutic target for osteoporosis.
基金financially supported by the National Natural Science Foundation of China (Nos. 32070392 and 32070393)the Second Tibetan Plateau Scientific Expedition and Research(STEP) Program (Nos. 2019QZKK0502-0303 and 2019QZKK0502-0304)+2 种基金Natural Science Foundation of Yunnan Province (Nos.202001AS070040 and 202101AV070010)Yunnan Young&Elite Talents Project (No. YNWR-QNBJ-2020-277)CAS “Light of West China” Program (2021)。
文摘Nineteen diterpenoids, including saldigitin A(1) bearing an unprecedented 10-methylated 6/7/6 carbon ring system, two new icetexanes(2, 3), and two new nor-abietanes(5, 6) were characterized from the roots of Salvia digitaloides. Their structures were elucidated by the analysis of the spectroscopic data,X-ray crystallography, and TDDFT calculations of ECD spectra. The novel architecture of 1 should be biogenetically derived through the cleavage and re-cyclization of the B/C rings from the normal abietane skeleton. Biologically, 1–5 exhibited noticeable inhibitions on Ca_(v)3.1 low voltage-gated Ca2+channel(LVGCC), with IC50values in the range of 3.43–11.70 μmol/L. They are the first example of diterpenoids with 6/7/6 carbon rings system as Ca_(v)3.1 antagonists.
基金We thank myBioma GmbH for the microbiome analyses and designing the corresponding figures for the manuscript.
文摘BACKGROUND Irritable bowel syndrome(IBS)is a highly prevalent gastrointestinal disorder with poor response to treatment.IBS with predominant diarrhea(IBS-D)is accompanied by abdominal pain as well as high stool frequency and urgency.Purified clinoptilolite-tuff(PCT),which is approved by the Food and Drug Administration for use as a dietary supplement with the brand name G-PUR®,has previously shown therapeutic potential in other indications based on its physical adsorption capacity.AIM To assess whether symptoms of IBS-D can be ameliorated by oral treatment with PCT.METHODS In this randomized,placebo-controlled,double-blind pilot study,30 patients with IBS-D diagnosis based on Rome IV criteria were enrolled.Following a 4-wk run-in phase,14 patients were randomized to receive a 12-wk treatment with G-PUR®(2 g three times daily),and 16 patients received placebo.The relief from IBS-D symptoms as measured by the proportion of responders according to the Subject’s Global Assessment(SGA)of Relief was assessed as the primary outcome.For the secondary outcomes,validated IBS-D associated symptom questionnaires,exploratory biomarkers and microbiome data were collected.RESULTS The proportions of SGA of Relief responders after 12 wk were comparable in both groups,namely 21%in the G-PUR®group and 25%in the placebo group.After 4 wk of treatment,36%of patients in the G-PUR®group vs 0%in the placebo group reported complete or considerable relief.An improvement in daily abdominal pain was noted in 94%vs 83%(P=0.0353),and the median number of days with diarrhea per week decreased by 2.4 d vs 0.3 d in the G-PUR®and placebo groups,respectively.Positive trends were observed for 50%of responders in the Bristol Stool Form Scale.Positive trends were also noted for combined abdominal pain and stool consistency response and the Perceived Stress Questionnaire score.Only 64%in the G-PUR®group compared to 86%in the placebo group required rescue medication intake during the study.Stool microbiome studies showed a minor increase in diversity in the G-PUR®group but not in the placebo group.No PCT-related serious adverse events were reported.CONCLUSION In this randomized,double-blind,placebo-controlled study,the PCT product,G-PUR®,demonstrated safety and clinical benefit towards some symptoms of IBS-D,representing a promising novel treatment option for these patients.
基金Capital's Funds for Health Improvement and Research(2024-1-1021)Beijing Natural Science Foundation(Z20J00105)+2 种基金National Natural Science Foundation of China(82272627)Beijing Natural Science Foundation(L234003)the Beijing Xisike Clinical Oncology Research Foundation(Y-HR2020ZD-0773)。
文摘Alpha-fetoprotein-producing gastric or gastro-esophageal junction(AFP-G/GEJ)cancer,a rare gastric cancer subtype,exhibits increased angiogenesis and more immunosuppression than non-AFP-G/GEJ cancer.The potential benefits of anti-angiogenic agents and immunotherapy for this specific subtype remain unknown.This multi-center,single-arm,phase 2 trial(ClinicalTrials.gov NCT04609176)evaluated the antitumor activity,safety,and biomarkers of camrelizumab plus apatinib and S-1 and oxaliplatin(SOX),followed by maintenance treatment with camrelizumab plus apatinib,as a first-line treatment in patients with AFP-G/GEJ adenocarcinoma.Primary endpoint was the confirmed objective response rate(ORR)per RECIST v1.1 in the full analysis set.Secondary endpoints were disease control rate(DCR),progression-free survival(PFS),overall survival(OS),duration of response,time to response,and safety.Between December 4,2020,and August 4,2023,36 patients were enrolled and treated.The trial met its primary endpoint with a confirmed ORR of 66.7%(95%Cl:49.0-81.4).The DCR was 88.9%(95%Cl:73.9-96.9).With a median follow-up of 11.7 months(range:3.2-37.9),the median PFS reached 7.8 months(95%Cl:4.9-12.3)and the median OS reached 18.0 months(95%Cl:10.5-NR).No new safety concerns were identified.In exploratory analysis,patients with durable clinical benefit exhibited higher pre-treatment(PD-1+)CD8+T cell densities and effective scores.First-line treatment with camrelizumab plus apatinib and SOX,followed by maintenance treatment with camrelizumab plus apatinib,is effective and safe in AFP-G/GEJ adenocarcinoma.Further studies are necessary to validate these findings.
基金National Ministry of Science and Technology "836" Project grant number:2007AA100503
文摘Using plants to produce heterologous proteins makes it very attractive due to the potentially low costs. Using this procedure it is possible to produce medicinal protein for clinical applications with the plants bioreactors increasing gradually. The paper proposes the five major systems of the plant bioreactor as well as their advantage and disadvantage and the development of each system. Focuses on the five major systems of the plant bioreactor to produce vaccines, antibodies and medical protein and the research achievement at the present stage and the research on my laboratory. The key technology research of plant bioreactor such as new genes, new biological components, new technologies and new research methods related with plant bioreactor offer a work foundation for a long-term development in future.
基金supported by the National Research Foundation of Korea(NRF)grants NRF-2022R1A4A3024551 and RS-2024-00457141(to W.K.)the Bio&Medical Technology Development Program grant NRF-2022M3A9J3073020(to B.C.)funded by the Ministry of Science,ICT&Future Planning.Figures 1,3,4,5,6,7,8,9,10,and 11 were created using BioRender(http://biorender.com/).
文摘Cells orchestrate their processes through complex interactions,precisely organizing biomolecules in space and time.Recent discoveries have highlighted the crucial role of biomolecular condensates—membrane-less assemblies formed through the condensation of proteins,nucleic acids,and other molecules—in driving efficient and dynamic cellular processes.These condensates are integral to various physiological functions,such as gene expression and intracellular signal transduction,enabling rapid and finely tuned cellular responses.Their ability to regulate cellular signaling pathways is particularly significant,as it requires a careful balance between flexibility and precision.Disruption of this balance can lead to pathological conditions,including neurodegenerative diseases,cancer,and viral infections.Consequently,biomolecular condensates have emerged as promising therapeutic targets,with the potential to offer novel approaches to disease treatment.In this review,we present the recent insights into the regulatory mechanisms by which biomolecular condensates influence intracellular signaling pathways,their roles in health and disease,and potential strategies for modulating condensate dynamics as a therapeutic approach.Understanding these emerging principles may provide valuable directions for developing effective treatments targeting the aberrant behavior of biomolecular condensates in various diseases.
基金supported by National Research Foundation(NRF)grants funded by the Korean government(grant numbers RS-2025-00513566 and RS-2023-00218648),Republic of Korea(Prof.Yong Taik Lim)supported by NRF grants funded by Korean government(grant number 2021R1A6A1A03045495),Republic of Korea(Prof.Jong-Soo Lee)supported by the Institute for Basic Science(grant number IBS-R801-D1),Republic of Korea(Director Young Ki Choi).
文摘The demand for safe vaccines that ensure long-term and broad protection against multiple viral variants has dramatically increased after the emergence of catastrophic infectious diseases such as COVID-19.To ensure long-term and broad protection against heterologous virus variants,antigen-specific polyfunctional T cells should be orchestrated with the activation of follicular helper T(TFH)cells and germinal center(GC)B cells.Herein,we suggest a novel engineered nanoadjuvant(SE(Trojan-TLR7/8a))that enhances the migration of nonexhausted antigen-presenting cells(APCs)into lymph nodes and elicits the activation of TFH cells,the generation of GC B cells,and polyfunctional T cells via multiscale dynamic immunomodulation through squalene nanoemulsion(SE)-mediated macroscopic control of vaccine delivery and Trojan-TLR7/8a-enabled dynamic and sustained activation of APCs at the cellular level.SE(Trojan-TLR7/8a)can be lyophilized,reduce systemic toxicity,and outperform current commercial vaccine adjuvants(Alum or AS03)and mRNA vaccines.SE(Trojan-TLR7/8a)ensures cross-protection against diverse influenza and SARS-CoV-2 variants,providing 100%protection while maintaining a healthy state.SE(Trojan-TLR7/8a)also sustains a potent T-cell response in an aged ferret model of SFTSV infection.SE(Trojan-TLR7/8a)suggested herein provides a novel vaccine design principle for dynamic modulation at the multiscale level and demonstrates long-term and broad protective immunity against emerging pandemic and endemic infectious viruses.
基金supported by the National Natural Science Foundation of China(91959205 to L.S.)the Natural Science Foundation of Beijing Municipality(Z200015 to X.T.Z).
文摘To evaluate the efficacy and safety of KN026,a novel bispecific HER2(ECD2 and ECD4)antibody,plus KN046,a PD-L1,and CTLA4 bispecific antibody,in patients with advanced HER2-positive solid tumors.We conducted two sequentially designed phase Ib and Il studies with similar target populations and evaluation schedules.The primary endpoints included safety,maximum tolerated dose(MTD),the recommended phase Il dose(RP2D)for the phase Ib study,and the objective response rate(ORR)and duration of response(DoR)for the phase llstudy.Hereby,we solely report the results from 113 nonbreast cancer patients.In phase Ib,MTD was not reached.Dose 3 was confirmed to be acceptable for the phase lIl study.An objective response has been exclusively observed in HER2-positive patients.Any grade treatment-related adverse events(TRAEs)were reported in 108(95.6%)patients.The most common TRAEs were infusion reactions(38.9%),anemia(37.2%),elevated AST(31.0%),and diarrhea(30.1%).Among the 108 patients evaluated for efficacy,the overall ORR was 55.6%(95%Cl,45.7%,65.1%).In the HER2-positive GC subgroup,38 patients received this regimen as the 1st-line treatment and 30 patients achieved an objective response,with an ORR of 78.9%(95%Cl,62.7%,90.4%).Among 27 pretreated patients,the ORR was 44.4%(95%Cl,25.5%,64.7%).In the other HER2-positive solid tumor subgroup(n=34),the ORR was 52.9%(95%CI 35.1%,70.2%).Thus,KN026 plus KN04 exhibits promising efficacy and acceptable safety profiles in HER2-positive nonbreast cancer,as does the 1st-line treatment for GC.
基金supported by the Dyson College 2014 Faculty Summer Research Grant Program (Zafir Buraei)Dyson College 2014 Summer Undergraduate Student-Faculty Research Award (Zafir Buraei and Sukhjinder Kaur)+2 种基金the National Key Basic Research Program of China (2014CB910301 to Yang Jian)the Top Talents Program of Yunnan Province, China (Yang Jian)the US National Institutes of Health (NS053494 to Yang Jian)
文摘Voltage-gated calcium channels(VGCCs) play critical roles in cardiac and skeletal muscle contractions,hormone and neurotransmitter release,as well as slower processes such as cell proliferation,differentiation,migration and death.Mutations in VGCCs lead to numerous cardiac,muscle and neurological disease,and their physiological function is tightly regulated by kinases,phosphatases,G-proteins,calmodulin and many other proteins.Fifteen years ago,RGK proteins were discovered as the most potent endogenous regulators of VGCCs.They are a family of monomeric GTPases(Rad,Rem,Rem2,and Gem/Kir),in the superfamily of Ras GTPases,and they have two known functions: regulation of cytoskeletal dynamics including dendritic arborization and inhibition of VGCCs.Here we review the mechanisms and molecular determinants of RGK-mediated VGCC inhibition,the physiological impact of this inhibition,and recent evidence linking the two known RGK functions.
基金The study was supported by the National Natural Science Foundation of China(No.81470888)and(No.82002461)the Medjaden Academy and Research Foundation for Young Scientists(No.MJR20211110)the Fund for Fostering Young Scholars of Peking University Health Science Center(No.BMU2021PY010).
文摘Background and Aims:It remains difficult to forecast the 180-day prognosis of patients with hepatitis B virus-acuteon-chronic liver failure(HBV-ACLF)using existing prognostic models.The present study aimed to derive novel-innovative models to enhance the predictive effectiveness of the 180-day mortality in HBV-ACLF.Methods:The present cohort study examined 171 HBV-ACLF patients(non-survivors,n=62;survivors,n=109).The 27 retrospectively collected parameters included the basic demographic characteristics,clinical comorbidities,and laboratory values.Backward stepwise logistic regression(LR)and the classification and regression tree(CART)analysis were used to derive two predictive models.Meanwhile,a nomogram was created based on the LR analysis.The accuracy of the LR and CART model was detected through the area under the receiver operating characteristic curve(AUROC),compared with model of end-stage liver disease(MELD)scores.Results:Among 171 HBV-ACLF patients,the mean age was 45.17 years-old,and 11.7%of the patients were female.The LR model was constructed with six independent factors,which included age,total bilirubin,prothrombin activity,lymphocytes,monocytes and hepatic encephalopathy.The following seven variables were the prognostic factors for HBV-ACLF in the CART model:age,total bilirubin,prothrombin time,lymphocytes,neutrophils,monocytes,and blood urea nitrogen.The AUROC for the CART model(0.878)was similar to that for the LR model(0.878,p=0.898),and this exceeded that for the MELD scores(0.728,p<0.0001).Conclusions:The LR and CART model are both superior to the MELD scores in predicting the 180-day mortality of patients with HBV-ACLF.Both the LR and CART model can be used as medical decision-making tools by clinicians.
文摘Neuroendocrine neoplasm of the pancreas is a rare tumor with limited treatment options.Among such tumors,treatment for pancreatic neuroendocrine tumor(PanNET)G3 is the most difficult.Temozolomide(TMZ)is commonly used to treat PanNET.However,TMZ may cause tumor gene alkylation,which induces drug resistance and rapid disease progression.Herein,we present a case of a female who was diagnosed with PanNET G3 and achieved a partial response to toripalimab,an anti-programmed cell death-ligand 1(anti-PD-L1)monoclonal antibody,after multiple cycles of TMZ treatment.Genomic profiling revealed that compared with the patient’s samples collected at baseline,the postTMZ-treatment samples had markedly higher levels of tumor mutational burden(TMB)associated with characteristic alkylating mutational signature representing a positive correlation with favorable response to anti-PD-1 treatment.In addition,we observed a germline truncating mutation of MUTYH(W156*)that was considered to be pathogenic and potentially conferred to genomic instability.This case suggests that anti-PD-1 therapy could be a treatment option for PanNET patients with increased TMB after TMZ-based treatment.
基金The study was supported by the National Natural Science Foundation of China(No.82002461)Medjaden Academy and Research Foundation for Young Scientists(MJR20211110)as well as the Fund for Fostering Young Scholars of Peking University Health Science Center(BMU2021PY010)。
文摘Biliary tract cancers(BTCs)comprise a group of heterogeneous poor prognosis cancers with increasing incidence recent years.The combination chemotherapy with cisplatin and gemcitabine is the first-line therapy for advanced BTC.There remains no accepted standard treatment in the second-line setting.Nowadays,more and more novel treatment strategies have entered development,with some encouraging results being seen.Here,we review the current treatment status and clinical characteristics of BTC,the role of immunotherapy in BTC as well as the design of clinical trials for oncology drugs for BTC which aim to focus on the future profiles of clinical care and resolution of BTC.
