The production of light(anti-)nuclei in high-energy collisions has long posed an apparent paradox:How can loosely bound systems such as the anti-deuteron with a binding energy of only 2.23 MeV be formed and survive in...The production of light(anti-)nuclei in high-energy collisions has long posed an apparent paradox:How can loosely bound systems such as the anti-deuteron with a binding energy of only 2.23 MeV be formed and survive in the extreme hot and dense hadronic environment emerging from proton–proton(pp)and heavy-ion collisions,where characteristic thermal energies exceed 100 MeV?A new femtoscopy analysis published on Nature[1]by the ALICE Collaboration at the Large Hadron Collider(LHC)delivers the clearest answer to date.展开更多
Despite advances in current anti-cancer therapies,challenges such as drug resistance,toxicity,and tumor heterogeneity persist.The limitations of traditional single-target drugs and simple combination therapies are bec...Despite advances in current anti-cancer therapies,challenges such as drug resistance,toxicity,and tumor heterogeneity persist.The limitations of traditional single-target drugs and simple combination therapies are becoming increasingly apparent1.To address these issues,a novel treatment strategy,the artificially intelligent synergistic engineered drug(AISED)paradigm,merits further exploration.This paradigm is based on the systematic engineered integration of multiple active ingredients into a unified single entity through artificial intelligence(AI).This strategy is aimed at developing new anti-cancer drug designs involving multiple ingredients,multiple molecular targets,and multiple biological effects,for multiple cancer types,thereby providing a novel theoretical paradigm for overcoming existing treatment bottlenecks.展开更多
Traditional Chinese medicine(TCM)has shown remarkable potential for treating liver fibrosis.In this study,to identify novel TCMs with antifibrotic properties,we used a technique called high-throughput sequencing-based...Traditional Chinese medicine(TCM)has shown remarkable potential for treating liver fibrosis.In this study,to identify novel TCMs with antifibrotic properties,we used a technique called high-throughput sequencing-based high-throughput screening(HTS2),which is based on RNA-mediated oligonucleotide annealing,selection,and ligation followed by sequencing.This technology achieved parallel and quantitative analysis of gene expression in response to thousands of drug treatments[1].展开更多
Primary biliary cirrhosis(PBC) is a chronic,progressive,cholestatic,organ-specific autoimmune disease of unknown etiology.It predominantly affects middle-aged women,and is characterized by autoimmune-mediated destruct...Primary biliary cirrhosis(PBC) is a chronic,progressive,cholestatic,organ-specific autoimmune disease of unknown etiology.It predominantly affects middle-aged women,and is characterized by autoimmune-mediated destruction of small-and medium-size intrahepatic bile ducts,portal inflammation and progressive scarring,which without proper treatment can ultimately lead to fibrosis and hepatic failure.Serum autoantibodies are crucial tools for differential diagnosis of PBC.While it is currently accepted that antimitochondrial antibodies are the most important serological markers of PBC,during the last five decades more than sixty autoantibodies have been explored in these patients,some of which had previously been thought to be specific for other autoimmune diseases.展开更多
AIM To analyze the clinical impact of preformed antiH LA-Cw vs antiH LA-A and/or-B donor-specific antibodies(DSA) in kidney transplantation.METHODS Retrospective study, comparing 12 patients transplanted with DSA excl...AIM To analyze the clinical impact of preformed antiH LA-Cw vs antiH LA-A and/or-B donor-specific antibodies(DSA) in kidney transplantation.METHODS Retrospective study, comparing 12 patients transplanted with DSA exclusively antiH LA-Cw with 23 patients with preformed DSA antiH LA-A and/or B.RESULTS One year after transplantation there were no differencesin terms of acute rejection between the two groups(3 and 6 cases, respectively in the DSA-Cw and the DSA-A-B groups; P = 1). At one year, eG FR was not significantly different between groups(median 59 mL /min in DSA-Cw group, compared to median 51 mL /min in DSA-A-B group, P = 0.192). Moreover, kidney graft survival was similar between groups at 5-years(100% in DSA-Cw group vs 91% in DSA-A-B group, P = 0.528). The sole independent predictor of antibody mediated rejection(AMR) incidence was DSA strength(HR = 1.07 per 1000 increase in MFI, P = 0.034). AMR was associated with shortened graft survival at 5-years, with 75% and 100% grafts surviving in patients with or without AMR, respectively(Log-rank P = 0.005).CONCLUSION Our data indicate that DSA-Cw are associated with an identical risk of AMR and impact on graft function in comparison with "classical" class I DSA.展开更多
AIM:To investigate possible associations of anti-nuclear envelope antibody(ANEA)with disease severity and survival in Greek primary biliary cirrhosis(PBC)patients.METHODS:Serum samples were collected at diagnosis from...AIM:To investigate possible associations of anti-nuclear envelope antibody(ANEA)with disease severity and survival in Greek primary biliary cirrhosis(PBC)patients.METHODS:Serum samples were collected at diagnosis from 147 PBC patients(85%female),who were followed-up for a median 89.5 mo(range 1-240).ANEA were detected with indirect immunofluorescence on 1% formaldehyde fixed Hep2 cells,and anti-gp210 antibodies were detected using an enzyme linked immunosorbent assay.Findings were correlated with clinical data,histology,and survival.RESULTS:ANEA were detected in 69/147(46.9%) patients and 31/147(21%)were also anti-gp210 positive.The ANEA positive patients were at a more advanced histological stage(Ⅰ-Ⅱ/Ⅲ-Ⅳ56.5%/43.5% vs 74.4%/25.6%,P=0.005)compared to the ANEA negative ones.They had a higher antimitochondrial antibodies(AMA)titer(≤1:160/>1:160 50.7%/49.3%vs 71.8%/28.2%,P=0.001)and a lower survival time(91.7 ±50.7 mo vs 101.8±55 mo,P=0.043).Moreover,they had more advanced fibrosis,portal inflammation,interface hepatitis,and proliferation of bile ductules(P =0.008,P=0.008,P=0.019,and P=0.027,respectively).They also died more frequently of hepatic failure and/or hepatocellular carcinoma(P=0.016).ANEA positive,anti-gp210 positive patients had a difference in stage(Ⅰ-Ⅱ/Ⅲ-Ⅳ54.8%/45.2%vs 74.4%/25.6%,P= 0.006),AMA titer(≤1:160/>1:160 51.6%/48.4%vs 71.8%/28.2%,P=0.009),survival(91.1±52.9 mo vs 101.8±55 mo,P=0.009),and Mayo risk score(5.5 ±1.9 vs 5.04±1.3,P=0.04)compared to the ANEA negative patients.ANEA positive,anti-gp210 negative patients had a difference in AMA titer(≤1:160/>1:160 50%/50%vs 71.8%/28.2%,P=0.002),stage(Ⅰ-Ⅱ/Ⅲ -Ⅳ57.9%/42.1%vs 74.4%/25.6%,P=0.033),fibrosis(P=0.009),portal inflammation(P=0.018),interface hepatitis(P=0.032),and proliferation of bile ductules(P=0.031).Anti-gp210 positive patients had a worse Mayo risk score(5.5±1.9 vs 4.9±1.7,P=0.038)than the anti-gp210 negative ones.CONCLUSION:The presence of ANEA and anti-gp210 identifies a subgroup of PBC patients with advanced disease severity and poor prognosis.展开更多
AIM: To assess the prevalence and stability of different antiphospholipid antibodies(APLAs) and their association with disease phenotype and progression in inflammatory bowel diseases(IBD) patients.METHODS: About 458 ...AIM: To assess the prevalence and stability of different antiphospholipid antibodies(APLAs) and their association with disease phenotype and progression in inflammatory bowel diseases(IBD) patients.METHODS: About 458 consecutive patients [Crohn's disease(CD): 271 and ulcerative colitis(UC): 187] were enrolled into a follow-up cohort study in a tertiary IBD referral center in Hungary. Detailed clinical phenotypes were determined at enrollment by reviewing the patients' medical charts. Disease activity, medical treatment and data about evolvement of complications or surgical interventions were determined prospectively during the follow-up. Disease course(development f complicated disease phenotype and need for surgery),occurrence of thrombotic events, actual state of diseaseactivity according to clinical, laboratory and endoscopic scores and accurate treatment regime were recorded during the follow-up,(median, 57.4 and 61.6 mo for CD and UC). Sera of IBD patients and 103 healthy controls(HC) were tested on individual anti-β2-Glycoprotein-I(anti-β2-GPI IgA/M/G), anti-cardiolipin(ACA IgA/M/G)and anti-phosphatidylserine/prothrombin(anti-PS/PT IgA/M/G) antibodies and also anti-Saccharomyces cerevisiae antibodies(ASCA IgA/G) by enzyme-linked immunosorbent assay(ELISA). In a subgroup of CD(n = 198) and UC patients(n = 103), obtaining consecutive samples over various arbitrary timepoints during the disease course, we evaluated the intraindividual stability of the APLA status. Additionally,we provide an overview of studies, performed so far, in which significance of APLAs in IBD were assessed.RESULTS: Patients with CD had significantly higher prevalence of both ACA(23.4%) and anti-PS/PT(20.4%) antibodies than UC(4.8%, p < 0.0001 and10.2%, p = 0.004) and HC(2.9%, p < 0.0001 and15.5%, p = NS). No difference was found for the prevalence of anti-β2-GPI between different groups(7.2%-9.7%). In CD, no association was found between APLA and ASCA status of the patients.Occurrence of anti-β2-GPI, ACA and anti-PS/PT was not different between the group of patients with active vs inactive disease state according to appropriate clinical, laboratory and endoscopic scores in CD as well as in UC patients. All subtypes of anti-β2-GPI and ACA IgM status were found to be very stable over time, in contrast ACA IgG and even more ACA IgA status showed significant intraindividual changes.Changes in antibody status were more remarkable in CD than UC(ACA IgA: 49.9% vs 23.3% and ACA IgG:21.2% vs 5.8%). Interestingly, 59.1% and 30.1% of CD patients who received anti-TNF therapy showed significant negative to positive changes in ACA IgA and IgG antibody status respectively. APLA status was not associated with the clinical phenotype at diagnosis or during follow-up, medical therapy, or thrombotic events and it was not associated with the probability of developing complicated disease phenotype or surgery in a Kaplan-Meier analysis.CONCLUSION: The present study demonstrated enhanced formation of APLAs in CD patients. However,presence of different APLAs were not associated with the clinical phenotype or disease course.展开更多
The Editor-in-Chief has retracted this article.Following this publication,concerns were raised regarding the similarity of images presented in this article with previously published articles[1,2].The authors were unab...The Editor-in-Chief has retracted this article.Following this publication,concerns were raised regarding the similarity of images presented in this article with previously published articles[1,2].The authors were unable to provide a satisfactory explanation and raw data for the concerns upon request.展开更多
Celiac disease(CD)is a systemic autoimmune disorder triggered by gluten ingestion ingenetically predisposed individuals.It is characterized by intestinal histological damage and the production of specific autoantibodi...Celiac disease(CD)is a systemic autoimmune disorder triggered by gluten ingestion ingenetically predisposed individuals.It is characterized by intestinal histological damage and the production of specific autoantibodies.The latest European Society for Paediatric Gastroenterology,Hepatology,and Nutrition(ESPGHAN)2020 guidelines have excluded human leukocyte antigen(HLA)genotyping from the no-biopsy diagnostic approach due to its weak positive predictive value,limited availability,and high cost in some countries.However,HLA genetic testing remains valuable in certain clinical contexts.This study provided practical indications for when to request and how to interpret HLA genotyping,emphasizing its continued relevance for CD diagnosis in specific cases.We also proposed a strategy for monitoring the risk of developing type 1 diabetes(T1D)in patients with CD,based on the risk stratification carried by different HLA genotypes.A retrospective analysis of 746 patients with CD and 627 controls was conducted at our hospital starting in2012,when HLA genotyping became mandatory for the diagnosis of CD.We identified key clinical scenarios where HLA testing remains useful.Several high risk HLA-DQ genotypes strongly associated with CD were highlighted,including HLA-DQ2.5/HLA-DQ2.2and HLA-DQ2.5/HLA-DQ2.5.Notably,while the HLA-DQ2.5/HLA-DQ2.2 genotype is linked to CD,it appears to confer protection against T1D.To support clinical practice,we presented a table clarifying commonly used HLA terminology,and another summarized the main clinical situations in which HLAgenotyping should still be considered.These findings underscore the dual role of HLA testing:Not only can it help rule out CD in selected cases,but it also identifies patients with CD at risk for T1D,guiding personalized monitoring strategies.展开更多
DB-1310 and trastuzumab synergistically inhibit breast cancer(BC)cell proliferation in vitro.HER3 overexpression has been described in patients with HER2-positive BC1.We determined the levels of HER2 and HER3 expressi...DB-1310 and trastuzumab synergistically inhibit breast cancer(BC)cell proliferation in vitro.HER3 overexpression has been described in patients with HER2-positive BC1.We determined the levels of HER2 and HER3 expression in BC using RNA-seq data from 1,082 BC patient samples in the TCGA dataset and 67 BC cell lines in the CCLE database(Supplementary material 1).展开更多
Aim of Work: To investigate the value of the detection of antibodies against modified citrullinated vimentin antibodies (anti-MCV) in comparison with anti-CCP2-for the diagnosis of rheumatoid arthritis (RA). Patients ...Aim of Work: To investigate the value of the detection of antibodies against modified citrullinated vimentin antibodies (anti-MCV) in comparison with anti-CCP2-for the diagnosis of rheumatoid arthritis (RA). Patients and Methods: The study Included Forty patients with Rheumatoid arthritis (RA). They under went assessment by the disease activity score (DAS-28), visual analogue scale (VAS) and health assessment questionnaire (HAQ). Thirty healthy subjects matched for age and sex served as a control group. Blood samples were obtained from patients and controls for erythrocyte sedimentation rate (ESR), C reactive protein (CRP), rheumatoid factor (RF). Anti-CCP2 and anti-MCV were determined using ELISA technique. Results: Estimated serum levels of anti-CCP2 and anti-MCV were significantly higher in patients compared to controls (p 0.001). There were no significant correlations between anti-MCV levels and age, dis- ease duration, duration of morning stiffness, number of swollen and tender joints, HAQ or ESR in patients with RA, while serum levels correlates significantly with DAS28, VAS and CRP (p 0.05). Anti-CCP2 correlates significantly with DAS28, VAS and CRP and ANA (p 0.05). Serum anti-MCV and anti-CCP2 were significantly correlated with each other (r = 0.483;p The receiver operating characteristic (ROC) curve was drawn and it showed that anti-MCV had diagnostic specificity, sensitivity of 93.3%, 75.5%, respectively, while anti-CCP2 specificity, sensitivity of 98.1%, 85%, respectively. Conclusion: Serum anti-MCV as well as the anti-CCP-2 assay perform comparably well in the diagnosis of RA. In the high-specificity range, however, the anti-CCP2 assay appears to be superior to the anti-MCV test.展开更多
Primary biliary cirrhosis(PBC)is a chronic progressive cholestatic liver disease characterized by immunemediated destruction of the small-and medium-sized intrahepatic bile ducts and the presence of antimitochondrial ...Primary biliary cirrhosis(PBC)is a chronic progressive cholestatic liver disease characterized by immunemediated destruction of the small-and medium-sized intrahepatic bile ducts and the presence of antimitochondrial antibodies(AMA)in the serum.AMA are detected in over 90%of patients with PBC,whereas their prevalence in the general population is extremely low,varying from 0.16%to 1%.Previous studies have shown that the unique characteristics of biliary epithelial cells undergoing apoptosis may result in a highly direct and very specific immune response to mitochondrial autoantigens.Moreover,recent studies have demonstrated that serum from AMA-positive PBC patients is reactive with a number of xenobiotic modified E2 subunits of the pyruvate dehydrogenase complex,which is not observed in the serum of normal individuals.These findings indicate that chemicals originating from the environment may be associated with a breakdown in the tolerance to mitochondrial autoantigens.While it is currently generally accepted that AMA are the most specific serological markers of PBC,more than 60 au-toantibodies have been investigated in patients with PBC,and some have previously been considered specific to other autoimmune diseases.This review covers the recent progress in research on the pathogenetic and clinical significance of important autoantibodies in PBC.Determining the pathogenic role of those autoantibodies in PBC remains a priority of basic and clinical research.展开更多
OBJECTIVE： Carica papaya is an important fruit with its seeds used in the treatment of ulcer in Nigeria This study investigated the anti-ulcerogenic and antioxidant activities of aqueous extract of Carica papaya seed...OBJECTIVE： Carica papaya is an important fruit with its seeds used in the treatment of ulcer in Nigeria This study investigated the anti-ulcerogenic and antioxidant activities of aqueous extract of Carica papaya seed against indomethacin-induced peptic ulcer in male rats. METHODS： Thirty male rats were separated into 6 groups （A-F） of five rats each. For 14 d before ulcer induction with indomethacin, groups received once daily oral doses of vehicle （distilled water）, cimetidine 200 mg/kg body weight （BW）, or aqueous extract of C. papaya seed at doses of 100, 150 or 200 mg/kg BW （groups A, B, C, D, E and F, respectively）. Twenty-four hours after the last treatment, groups B, C, D, E and F were treated with 100 mg/kg BW of indomethacin to induce ulcer formation. RESULTS： Carica papaya seed extract significantly （P〈0.05） increased gastric pH and percentage of ulcer inhibition relative to indomethacin-induced ulcer rats. The extract significantly （P〈0.05） decreased gastric acidity, gastric acid output, gastric pepsin secretion, ulcer index and gastric secretion volume relative to group B. These results were similar to that achieved by pretreatment with cimetidine. Specific activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase in the extract-treated groups （D, E and F） were increased significantly over the group B （P〈0.05）. Pretreatment with the seed extract protected rats from the indomethacin-mediated decrease in enzyme function experienced by the group B. Similarly, indomethacin-mediated decrease in reduced glutathione level and indomethacin-mediated increase in malondialdehyde were reversed by Carica papaya extract. CONCLUSION： In this study, pretreatment with aqueous extract of Carica papaya seed exhibited anti- ulcerogenic and antioxidant effects, which may be due to the enhanced antioxidant enzymes.展开更多
Flat, straight sheets of paper, standing vertically on edge cannot support any load placed upon their top edge, but once formed into fractal tube conic sections, they have been measured to support up to 97.52 (± ...Flat, straight sheets of paper, standing vertically on edge cannot support any load placed upon their top edge, but once formed into fractal tube conic sections, they have been measured to support up to 97.52 (± 2.27) kilograms (215 (± 5) pounds) of weight with strength-per-weight ratio up to 10,336 (± 240). So, strength has been discovered to be an emergent characteristic arising solely from addition of intelligent order. It is proposed to impose such intelligent order upon, preferably, at least 6 laser beams by focusing each of them to form cones of light, arranging the cones to form a wall of a larger fractal cone, and converging all of them to a common focal point inside a vacuum chamber to give them sufficient strength near this focal point to attract, hold, and move neutral antimatter, preferably anti-lithium. This opens the new field of structural engineering of light and re-defines the concept of strength. Means of cancelling out radiation pressure by reflection of laser beams back to the common focal point are proposed to enable laser confinement of particles having low polarizability, such as anti-hydrogen. Counter-circulation of light by reflection at grazing incidence is proposed as a means of returning escaping antimatter back to the common focal point containment area. Means are proposed to inject a stream of matter into the contained antimatter to create a matter-antimatter reactor and propulsion engine. Since anti-lithium is not available, yet, means are proposed to test these structures by confining ordinary lithium, instead, and by hitting it with anti-protons and/or positrons. Means are proposed to modulate the matter-antimatter reaction with information to create modulated gravitational waves for communication. The proposed structures would enable efficient, stable, safe confinement of antimatter, which would allow better study of antimatter, and make possible renewable, clean, safe, matter-antimatter reactor generators and propulsion engines, antimatter-assisted fusion reactors, and modulated gravitational wave generators.展开更多
AIM To investigate the prevalence and clinical significance of autoimmune liver disease(ALD)-related autoantibodies in patients with biliary atresia(BA).METHODS Sera of 124 BA patients and 140 age-matched non-BA contr...AIM To investigate the prevalence and clinical significance of autoimmune liver disease(ALD)-related autoantibodies in patients with biliary atresia(BA).METHODS Sera of 124 BA patients and 140 age-matched non-BA controls were assayed for detection of the following autoantibodies: ALD profile and specific anti-nuclear antibodies(ANAs), by line-blot assay; ANA and antineutrophil cytoplasmic antibody(ANCA), by indirect immunofluorescence assay; specific ANCAs and antiM2-3 E, by enzyme linked immunosorbent assay. Associations of these autoantibodies with the clinical features of BA(i.e., cytomegalovirus infection, degree of liver fibrosis, and short-term prognosis of Kasai procedure) were evaluated by Spearman's correlation coefficient.RESULTS The overall positive rate of serum autoantibodies in preoperative BA patients was 56.5%. ALD profile assay showed that the positive reaction to primary biliary cholangitis-related autoantibodies in BA patients was higher than that to autoimmune hepatitis-related autoantibodies. Among these autoantibodies, anti-BPO was detected more frequently in the BA patients than in the controls(14.8% vs 2.2%, P < 0.05). Accordingly, 32(25.8%) of the 124 BA patients also showed a high positive reaction for anti-M2-3 E. By comparison, the controls had a remarkably lower frequency of anti-M2-3 E(P < 0.05), with 6/92(8.6%) of patients with other liver diseases and 2/48(4.2%) of healthy controls. The prevalence of ANA in BA patients was 11.3%, which was higher than that in disease controls(3.3%, P < 0.05), but the reactivity to specific ANAs was only 8.2%. The prevalence of ANCAs(ANCA or specific ANCAs) in BA patients was also remarkably higher than that in the healthy controls(37.9% vs 6.3%, P < 0.05), but showed no difference from that in patients with other cholestasis. ANCA positivity was closely associated with the occurrence of postoperative cholangitis(r = 0.61, P < 0.05), whereas none of the autoantibodies showed a correlation to cytomegalovirus infection or the stages of liver fibrosis.CONCLUSION High prevalence of autoantibodies in the BA developmental process strongly reveals the autoimmunemediated pathogenesis. Serological ANCA positivity may be a useful predictive biomarker of postoperative cholangitis.展开更多
Microwave thermochemotherapy(MTC)has been applied to treat lip squamous cell carcinoma(LSCC),but a deeper understanding of its therapeutic mechanisms and molecular biology is needed.To address this,we used single-cell...Microwave thermochemotherapy(MTC)has been applied to treat lip squamous cell carcinoma(LSCC),but a deeper understanding of its therapeutic mechanisms and molecular biology is needed.To address this,we used single-cell transcriptomics(scRNA-seq)and spatial transcriptomics(ST)to highlight the pivotal role of tumor-associated neutrophils(TANs)among tumor-infiltrating immune cells and their therapeutic response to MTC.MNDA+TANs with anti-tumor activity(N1-phenotype)are found to be abundantly infiltrated by MTC with benefit of increased blood perfusion,and these TANs are characterized by enhanced cytotoxicity,ameliorated hypoxia,and upregulated IL1B,activating T&NK cells and fibroblasts via IL1B-IL1R.In this highly anti-tumor immunogenic and hypoxia-reversed microenvironment under MTC,fibroblasts accumulated in the tumor front(TF)can recruit N1-TANs via CXCL2-CXCR2 and clear N2-TANs(pro-tumor phenotype)via CXCL12-CXCR4,which results in the aggregation of N1-TANs and extracellular matrix(ECM)deposition.In addition,we construct an N1-TANs marker,MX2,which positively correlates with better prognosis in LSCC patients,and employ deep learning techniques to predict expression of MX2 from hematoxylin-eosin(H&E)-stained images so as to conveniently guide decision making in clinical practice.Collectively,our findings demonstrate that the N1-TANs/fibroblasts defense wall formed in response to MTC effectively combat LSCC.展开更多
The anti-metabolite chemotherapeutic, gemcitabine is relatively effective for a spectrum of neoplastic conditions that include various forms of leukemia and adenocarcinoma/carcinoma. Rapid systemic deamination of gemc...The anti-metabolite chemotherapeutic, gemcitabine is relatively effective for a spectrum of neoplastic conditions that include various forms of leukemia and adenocarcinoma/carcinoma. Rapid systemic deamination of gemcitabine accounts for a brief plasma half-life but its sustained administration is often curtailed by sequelae and chemotherapeutic-resistance. A molecular strategy that diminishes these limitations is the molecular design and synthetic production of covalent gemcitabine immunoche-motherapeutics that possess properties of selective “targeted” delivery. The simultaneous dual selective “targeted” delivery of gemcitabine at two separate sites on the external surface membrane of a single cancer cell types represents a therapeutic approach that can increase cytosol chemotherapeutic deposition;prolong chemotherapeutic plasma half-life (reduces administration frequency);minimize innocent exposure of normal tissues and healthy organ systems;and ultimately enhance more rapid and thorough resolution of neoplastic cell populations. Materials and Methods: A light-reactive gemcitabine intermediate synthesized utilizing succinimidyl 4,4-azipentanoate was covalently bound to anti-EGFR or anti-HER2/neu IgG by exposure to UV light (354-nm) resulting in the synthesis of covalent immunoche-motherapeutics, gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu]. Cytotoxic anti-neoplastic potency of gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] between?gemcitabine-equivalent concentrations of 10-12 M and 10-6 M was determined utilizing chemotherapeutic-resistant mammary adenocarcinoma (SKRr-3). The organoselenium compound, [Se]-methylselenocysteine was evaluated to determine if it complemented the anti-neoplastic potency of the covalent gemcitabine immunoche-motherapeutics. Results: Gemcitabine-(C4-amide)-[anti-EGFR], gemcitabine-(C4-amide)-[anti-HER2/neu] and the dual simultaneous combination of gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu] all had anti-neoplastic cytotoxic potency against mammary adenocarcinoma. Gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] produced progressive increases in anti-neoplastic cytotoxicity that were greatest between gemcitabine-equivalent concentrations of 10-9 M and 10-6 M. Dual simultaneous combinations of gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu] produced levels of anti-neoplastic cytotoxicity intermediate between each of the individual covalent gemcitabine immunochemotherapeutics. Total anti-neoplastic cytotoxicity of the dual simultaneous combination of gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] against chemothe-rapeutic-resistant mammary adenocarcinoma (SKBr-3) was substantially higher when formulated with [Se]-methylsele-no-cysteine.展开更多
Objective:To evaluate the predictive value of the neutrophil⁃to⁃lymphocyte ratio(NLR)and the systemic immune⁃inflammation index(SII)in predicting patients with anti⁃melanoma differentiation⁃associated gene 5⁃positive(...Objective:To evaluate the predictive value of the neutrophil⁃to⁃lymphocyte ratio(NLR)and the systemic immune⁃inflammation index(SII)in predicting patients with anti⁃melanoma differentiation⁃associated gene 5⁃positive(anti⁃MDA5+)dermatomyositis(DM)develop into the rapidly progressive interstitial lung disease(RPILD).Methods:We retrospectively analyzed the clinical and laboratory data of 124 anti⁃MDA5+DM patients from the First Affiliated Hospital of Nanjing Medical University between March 2019 and September 2023.We identified independent risk factors associated with the development and mortality of RPILD with the Cox regression analysis,and determined the optimal cut⁃off values for predicting adverse outcomes with the receiver operating characteristic(ROC)curve analysis.Results:Among the 124 patients,36 patients(29.03%)developed RPILD,and 39 patients(31.45%)died during the follow⁃up period.The results of multivariate Cox regression analysis showed that the elevated NLR was an independent risk factor for RPILD development,while the elevated SII expression was independently associated with the increased mortality of RPILD.Based on the ROC curve analysis,NLR>6.12 was a predictor for RPILD,and SII>875.79 was associated with increased mortality risk of RPILD.Conclusion:Both NLR and SII are accessible,cost⁃effective,and reliable prognostic indicators for the prognosis of patients with anti⁃MDA5^(+)DM,providing a valuable guidance for clinical management and risk stratification of the disease.展开更多
基金supported in part by the National Key Research and Development Project of China(No.2024YFA1612500)the National Natural Science Foundation of China(Nos.12422509,12375121,12547102)。
文摘The production of light(anti-)nuclei in high-energy collisions has long posed an apparent paradox:How can loosely bound systems such as the anti-deuteron with a binding energy of only 2.23 MeV be formed and survive in the extreme hot and dense hadronic environment emerging from proton–proton(pp)and heavy-ion collisions,where characteristic thermal energies exceed 100 MeV?A new femtoscopy analysis published on Nature[1]by the ALICE Collaboration at the Large Hadron Collider(LHC)delivers the clearest answer to date.
文摘Despite advances in current anti-cancer therapies,challenges such as drug resistance,toxicity,and tumor heterogeneity persist.The limitations of traditional single-target drugs and simple combination therapies are becoming increasingly apparent1.To address these issues,a novel treatment strategy,the artificially intelligent synergistic engineered drug(AISED)paradigm,merits further exploration.This paradigm is based on the systematic engineered integration of multiple active ingredients into a unified single entity through artificial intelligence(AI).This strategy is aimed at developing new anti-cancer drug designs involving multiple ingredients,multiple molecular targets,and multiple biological effects,for multiple cancer types,thereby providing a novel theoretical paradigm for overcoming existing treatment bottlenecks.
基金supported by the National Key R&D Program of China(2023YFA1406200)the National Natural Science Foundation of China(T2521005,12174144,12474009,12174146,and 124B2059)the Special Construction Project Fund for Shan-dong Province Taishan Scholars.
文摘Multifunctional optical responsive materials have grown increasingly pivotal in addressingthe escalating demands of sensing,detection,and anti-counterfeiting applications[1,2].These materials exhibit distinct visible optical variations upon exposure to external stimuli,such as pressure,temperature,light,solvents,pH fluctuations,or mechanical force.Fluorescent sensing and anti-counterfeiting technologies leveraging these optical responses have emerged as highly promising solutions.
文摘Traditional Chinese medicine(TCM)has shown remarkable potential for treating liver fibrosis.In this study,to identify novel TCMs with antifibrotic properties,we used a technique called high-throughput sequencing-based high-throughput screening(HTS2),which is based on RNA-mediated oligonucleotide annealing,selection,and ligation followed by sequencing.This technology achieved parallel and quantitative analysis of gene expression in response to thousands of drug treatments[1].
文摘Primary biliary cirrhosis(PBC) is a chronic,progressive,cholestatic,organ-specific autoimmune disease of unknown etiology.It predominantly affects middle-aged women,and is characterized by autoimmune-mediated destruction of small-and medium-size intrahepatic bile ducts,portal inflammation and progressive scarring,which without proper treatment can ultimately lead to fibrosis and hepatic failure.Serum autoantibodies are crucial tools for differential diagnosis of PBC.While it is currently accepted that antimitochondrial antibodies are the most important serological markers of PBC,during the last five decades more than sixty autoantibodies have been explored in these patients,some of which had previously been thought to be specific for other autoimmune diseases.
文摘AIM To analyze the clinical impact of preformed antiH LA-Cw vs antiH LA-A and/or-B donor-specific antibodies(DSA) in kidney transplantation.METHODS Retrospective study, comparing 12 patients transplanted with DSA exclusively antiH LA-Cw with 23 patients with preformed DSA antiH LA-A and/or B.RESULTS One year after transplantation there were no differencesin terms of acute rejection between the two groups(3 and 6 cases, respectively in the DSA-Cw and the DSA-A-B groups; P = 1). At one year, eG FR was not significantly different between groups(median 59 mL /min in DSA-Cw group, compared to median 51 mL /min in DSA-A-B group, P = 0.192). Moreover, kidney graft survival was similar between groups at 5-years(100% in DSA-Cw group vs 91% in DSA-A-B group, P = 0.528). The sole independent predictor of antibody mediated rejection(AMR) incidence was DSA strength(HR = 1.07 per 1000 increase in MFI, P = 0.034). AMR was associated with shortened graft survival at 5-years, with 75% and 100% grafts surviving in patients with or without AMR, respectively(Log-rank P = 0.005).CONCLUSION Our data indicate that DSA-Cw are associated with an identical risk of AMR and impact on graft function in comparison with "classical" class I DSA.
基金Supported by PENED 2003(03E_66)from the Greek Secretariat of Research and Technology to Theodoropoulos PA
文摘AIM:To investigate possible associations of anti-nuclear envelope antibody(ANEA)with disease severity and survival in Greek primary biliary cirrhosis(PBC)patients.METHODS:Serum samples were collected at diagnosis from 147 PBC patients(85%female),who were followed-up for a median 89.5 mo(range 1-240).ANEA were detected with indirect immunofluorescence on 1% formaldehyde fixed Hep2 cells,and anti-gp210 antibodies were detected using an enzyme linked immunosorbent assay.Findings were correlated with clinical data,histology,and survival.RESULTS:ANEA were detected in 69/147(46.9%) patients and 31/147(21%)were also anti-gp210 positive.The ANEA positive patients were at a more advanced histological stage(Ⅰ-Ⅱ/Ⅲ-Ⅳ56.5%/43.5% vs 74.4%/25.6%,P=0.005)compared to the ANEA negative ones.They had a higher antimitochondrial antibodies(AMA)titer(≤1:160/>1:160 50.7%/49.3%vs 71.8%/28.2%,P=0.001)and a lower survival time(91.7 ±50.7 mo vs 101.8±55 mo,P=0.043).Moreover,they had more advanced fibrosis,portal inflammation,interface hepatitis,and proliferation of bile ductules(P =0.008,P=0.008,P=0.019,and P=0.027,respectively).They also died more frequently of hepatic failure and/or hepatocellular carcinoma(P=0.016).ANEA positive,anti-gp210 positive patients had a difference in stage(Ⅰ-Ⅱ/Ⅲ-Ⅳ54.8%/45.2%vs 74.4%/25.6%,P= 0.006),AMA titer(≤1:160/>1:160 51.6%/48.4%vs 71.8%/28.2%,P=0.009),survival(91.1±52.9 mo vs 101.8±55 mo,P=0.009),and Mayo risk score(5.5 ±1.9 vs 5.04±1.3,P=0.04)compared to the ANEA negative patients.ANEA positive,anti-gp210 negative patients had a difference in AMA titer(≤1:160/>1:160 50%/50%vs 71.8%/28.2%,P=0.002),stage(Ⅰ-Ⅱ/Ⅲ -Ⅳ57.9%/42.1%vs 74.4%/25.6%,P=0.033),fibrosis(P=0.009),portal inflammation(P=0.018),interface hepatitis(P=0.032),and proliferation of bile ductules(P=0.031).Anti-gp210 positive patients had a worse Mayo risk score(5.5±1.9 vs 4.9±1.7,P=0.038)than the anti-gp210 negative ones.CONCLUSION:The presence of ANEA and anti-gp210 identifies a subgroup of PBC patients with advanced disease severity and poor prognosis.
基金Supported by Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences,Internal Research Grant of University of Debrecen and the IOIBD Research Grant
文摘AIM: To assess the prevalence and stability of different antiphospholipid antibodies(APLAs) and their association with disease phenotype and progression in inflammatory bowel diseases(IBD) patients.METHODS: About 458 consecutive patients [Crohn's disease(CD): 271 and ulcerative colitis(UC): 187] were enrolled into a follow-up cohort study in a tertiary IBD referral center in Hungary. Detailed clinical phenotypes were determined at enrollment by reviewing the patients' medical charts. Disease activity, medical treatment and data about evolvement of complications or surgical interventions were determined prospectively during the follow-up. Disease course(development f complicated disease phenotype and need for surgery),occurrence of thrombotic events, actual state of diseaseactivity according to clinical, laboratory and endoscopic scores and accurate treatment regime were recorded during the follow-up,(median, 57.4 and 61.6 mo for CD and UC). Sera of IBD patients and 103 healthy controls(HC) were tested on individual anti-β2-Glycoprotein-I(anti-β2-GPI IgA/M/G), anti-cardiolipin(ACA IgA/M/G)and anti-phosphatidylserine/prothrombin(anti-PS/PT IgA/M/G) antibodies and also anti-Saccharomyces cerevisiae antibodies(ASCA IgA/G) by enzyme-linked immunosorbent assay(ELISA). In a subgroup of CD(n = 198) and UC patients(n = 103), obtaining consecutive samples over various arbitrary timepoints during the disease course, we evaluated the intraindividual stability of the APLA status. Additionally,we provide an overview of studies, performed so far, in which significance of APLAs in IBD were assessed.RESULTS: Patients with CD had significantly higher prevalence of both ACA(23.4%) and anti-PS/PT(20.4%) antibodies than UC(4.8%, p < 0.0001 and10.2%, p = 0.004) and HC(2.9%, p < 0.0001 and15.5%, p = NS). No difference was found for the prevalence of anti-β2-GPI between different groups(7.2%-9.7%). In CD, no association was found between APLA and ASCA status of the patients.Occurrence of anti-β2-GPI, ACA and anti-PS/PT was not different between the group of patients with active vs inactive disease state according to appropriate clinical, laboratory and endoscopic scores in CD as well as in UC patients. All subtypes of anti-β2-GPI and ACA IgM status were found to be very stable over time, in contrast ACA IgG and even more ACA IgA status showed significant intraindividual changes.Changes in antibody status were more remarkable in CD than UC(ACA IgA: 49.9% vs 23.3% and ACA IgG:21.2% vs 5.8%). Interestingly, 59.1% and 30.1% of CD patients who received anti-TNF therapy showed significant negative to positive changes in ACA IgA and IgG antibody status respectively. APLA status was not associated with the clinical phenotype at diagnosis or during follow-up, medical therapy, or thrombotic events and it was not associated with the probability of developing complicated disease phenotype or surgery in a Kaplan-Meier analysis.CONCLUSION: The present study demonstrated enhanced formation of APLAs in CD patients. However,presence of different APLAs were not associated with the clinical phenotype or disease course.
文摘The Editor-in-Chief has retracted this article.Following this publication,concerns were raised regarding the similarity of images presented in this article with previously published articles[1,2].The authors were unable to provide a satisfactory explanation and raw data for the concerns upon request.
基金Supported by Fondazione di Sardegna,No.2020.2284.
文摘Celiac disease(CD)is a systemic autoimmune disorder triggered by gluten ingestion ingenetically predisposed individuals.It is characterized by intestinal histological damage and the production of specific autoantibodies.The latest European Society for Paediatric Gastroenterology,Hepatology,and Nutrition(ESPGHAN)2020 guidelines have excluded human leukocyte antigen(HLA)genotyping from the no-biopsy diagnostic approach due to its weak positive predictive value,limited availability,and high cost in some countries.However,HLA genetic testing remains valuable in certain clinical contexts.This study provided practical indications for when to request and how to interpret HLA genotyping,emphasizing its continued relevance for CD diagnosis in specific cases.We also proposed a strategy for monitoring the risk of developing type 1 diabetes(T1D)in patients with CD,based on the risk stratification carried by different HLA genotypes.A retrospective analysis of 746 patients with CD and 627 controls was conducted at our hospital starting in2012,when HLA genotyping became mandatory for the diagnosis of CD.We identified key clinical scenarios where HLA testing remains useful.Several high risk HLA-DQ genotypes strongly associated with CD were highlighted,including HLA-DQ2.5/HLA-DQ2.2and HLA-DQ2.5/HLA-DQ2.5.Notably,while the HLA-DQ2.5/HLA-DQ2.2 genotype is linked to CD,it appears to confer protection against T1D.To support clinical practice,we presented a table clarifying commonly used HLA terminology,and another summarized the main clinical situations in which HLAgenotyping should still be considered.These findings underscore the dual role of HLA testing:Not only can it help rule out CD in selected cases,but it also identifies patients with CD at risk for T1D,guiding personalized monitoring strategies.
文摘DB-1310 and trastuzumab synergistically inhibit breast cancer(BC)cell proliferation in vitro.HER3 overexpression has been described in patients with HER2-positive BC1.We determined the levels of HER2 and HER3 expression in BC using RNA-seq data from 1,082 BC patient samples in the TCGA dataset and 67 BC cell lines in the CCLE database(Supplementary material 1).
文摘Aim of Work: To investigate the value of the detection of antibodies against modified citrullinated vimentin antibodies (anti-MCV) in comparison with anti-CCP2-for the diagnosis of rheumatoid arthritis (RA). Patients and Methods: The study Included Forty patients with Rheumatoid arthritis (RA). They under went assessment by the disease activity score (DAS-28), visual analogue scale (VAS) and health assessment questionnaire (HAQ). Thirty healthy subjects matched for age and sex served as a control group. Blood samples were obtained from patients and controls for erythrocyte sedimentation rate (ESR), C reactive protein (CRP), rheumatoid factor (RF). Anti-CCP2 and anti-MCV were determined using ELISA technique. Results: Estimated serum levels of anti-CCP2 and anti-MCV were significantly higher in patients compared to controls (p 0.001). There were no significant correlations between anti-MCV levels and age, dis- ease duration, duration of morning stiffness, number of swollen and tender joints, HAQ or ESR in patients with RA, while serum levels correlates significantly with DAS28, VAS and CRP (p 0.05). Anti-CCP2 correlates significantly with DAS28, VAS and CRP and ANA (p 0.05). Serum anti-MCV and anti-CCP2 were significantly correlated with each other (r = 0.483;p The receiver operating characteristic (ROC) curve was drawn and it showed that anti-MCV had diagnostic specificity, sensitivity of 93.3%, 75.5%, respectively, while anti-CCP2 specificity, sensitivity of 98.1%, 85%, respectively. Conclusion: Serum anti-MCV as well as the anti-CCP-2 assay perform comparably well in the diagnosis of RA. In the high-specificity range, however, the anti-CCP2 assay appears to be superior to the anti-MCV test.
文摘Primary biliary cirrhosis(PBC)is a chronic progressive cholestatic liver disease characterized by immunemediated destruction of the small-and medium-sized intrahepatic bile ducts and the presence of antimitochondrial antibodies(AMA)in the serum.AMA are detected in over 90%of patients with PBC,whereas their prevalence in the general population is extremely low,varying from 0.16%to 1%.Previous studies have shown that the unique characteristics of biliary epithelial cells undergoing apoptosis may result in a highly direct and very specific immune response to mitochondrial autoantigens.Moreover,recent studies have demonstrated that serum from AMA-positive PBC patients is reactive with a number of xenobiotic modified E2 subunits of the pyruvate dehydrogenase complex,which is not observed in the serum of normal individuals.These findings indicate that chemicals originating from the environment may be associated with a breakdown in the tolerance to mitochondrial autoantigens.While it is currently generally accepted that AMA are the most specific serological markers of PBC,more than 60 au-toantibodies have been investigated in patients with PBC,and some have previously been considered specific to other autoimmune diseases.This review covers the recent progress in research on the pathogenetic and clinical significance of important autoantibodies in PBC.Determining the pathogenic role of those autoantibodies in PBC remains a priority of basic and clinical research.
文摘OBJECTIVE： Carica papaya is an important fruit with its seeds used in the treatment of ulcer in Nigeria This study investigated the anti-ulcerogenic and antioxidant activities of aqueous extract of Carica papaya seed against indomethacin-induced peptic ulcer in male rats. METHODS： Thirty male rats were separated into 6 groups （A-F） of five rats each. For 14 d before ulcer induction with indomethacin, groups received once daily oral doses of vehicle （distilled water）, cimetidine 200 mg/kg body weight （BW）, or aqueous extract of C. papaya seed at doses of 100, 150 or 200 mg/kg BW （groups A, B, C, D, E and F, respectively）. Twenty-four hours after the last treatment, groups B, C, D, E and F were treated with 100 mg/kg BW of indomethacin to induce ulcer formation. RESULTS： Carica papaya seed extract significantly （P〈0.05） increased gastric pH and percentage of ulcer inhibition relative to indomethacin-induced ulcer rats. The extract significantly （P〈0.05） decreased gastric acidity, gastric acid output, gastric pepsin secretion, ulcer index and gastric secretion volume relative to group B. These results were similar to that achieved by pretreatment with cimetidine. Specific activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase in the extract-treated groups （D, E and F） were increased significantly over the group B （P〈0.05）. Pretreatment with the seed extract protected rats from the indomethacin-mediated decrease in enzyme function experienced by the group B. Similarly, indomethacin-mediated decrease in reduced glutathione level and indomethacin-mediated increase in malondialdehyde were reversed by Carica papaya extract. CONCLUSION： In this study, pretreatment with aqueous extract of Carica papaya seed exhibited anti- ulcerogenic and antioxidant effects, which may be due to the enhanced antioxidant enzymes.
文摘Flat, straight sheets of paper, standing vertically on edge cannot support any load placed upon their top edge, but once formed into fractal tube conic sections, they have been measured to support up to 97.52 (± 2.27) kilograms (215 (± 5) pounds) of weight with strength-per-weight ratio up to 10,336 (± 240). So, strength has been discovered to be an emergent characteristic arising solely from addition of intelligent order. It is proposed to impose such intelligent order upon, preferably, at least 6 laser beams by focusing each of them to form cones of light, arranging the cones to form a wall of a larger fractal cone, and converging all of them to a common focal point inside a vacuum chamber to give them sufficient strength near this focal point to attract, hold, and move neutral antimatter, preferably anti-lithium. This opens the new field of structural engineering of light and re-defines the concept of strength. Means of cancelling out radiation pressure by reflection of laser beams back to the common focal point are proposed to enable laser confinement of particles having low polarizability, such as anti-hydrogen. Counter-circulation of light by reflection at grazing incidence is proposed as a means of returning escaping antimatter back to the common focal point containment area. Means are proposed to inject a stream of matter into the contained antimatter to create a matter-antimatter reactor and propulsion engine. Since anti-lithium is not available, yet, means are proposed to test these structures by confining ordinary lithium, instead, and by hitting it with anti-protons and/or positrons. Means are proposed to modulate the matter-antimatter reaction with information to create modulated gravitational waves for communication. The proposed structures would enable efficient, stable, safe confinement of antimatter, which would allow better study of antimatter, and make possible renewable, clean, safe, matter-antimatter reactor generators and propulsion engines, antimatter-assisted fusion reactors, and modulated gravitational wave generators.
基金the Guangdong Provincial Science and Technology Planning Project,No.2014A020212520the Guangzhou Science and Technology Project,No.201707010014
文摘AIM To investigate the prevalence and clinical significance of autoimmune liver disease(ALD)-related autoantibodies in patients with biliary atresia(BA).METHODS Sera of 124 BA patients and 140 age-matched non-BA controls were assayed for detection of the following autoantibodies: ALD profile and specific anti-nuclear antibodies(ANAs), by line-blot assay; ANA and antineutrophil cytoplasmic antibody(ANCA), by indirect immunofluorescence assay; specific ANCAs and antiM2-3 E, by enzyme linked immunosorbent assay. Associations of these autoantibodies with the clinical features of BA(i.e., cytomegalovirus infection, degree of liver fibrosis, and short-term prognosis of Kasai procedure) were evaluated by Spearman's correlation coefficient.RESULTS The overall positive rate of serum autoantibodies in preoperative BA patients was 56.5%. ALD profile assay showed that the positive reaction to primary biliary cholangitis-related autoantibodies in BA patients was higher than that to autoimmune hepatitis-related autoantibodies. Among these autoantibodies, anti-BPO was detected more frequently in the BA patients than in the controls(14.8% vs 2.2%, P < 0.05). Accordingly, 32(25.8%) of the 124 BA patients also showed a high positive reaction for anti-M2-3 E. By comparison, the controls had a remarkably lower frequency of anti-M2-3 E(P < 0.05), with 6/92(8.6%) of patients with other liver diseases and 2/48(4.2%) of healthy controls. The prevalence of ANA in BA patients was 11.3%, which was higher than that in disease controls(3.3%, P < 0.05), but the reactivity to specific ANAs was only 8.2%. The prevalence of ANCAs(ANCA or specific ANCAs) in BA patients was also remarkably higher than that in the healthy controls(37.9% vs 6.3%, P < 0.05), but showed no difference from that in patients with other cholestasis. ANCA positivity was closely associated with the occurrence of postoperative cholangitis(r = 0.61, P < 0.05), whereas none of the autoantibodies showed a correlation to cytomegalovirus infection or the stages of liver fibrosis.CONCLUSION High prevalence of autoantibodies in the BA developmental process strongly reveals the autoimmunemediated pathogenesis. Serological ANCA positivity may be a useful predictive biomarker of postoperative cholangitis.
基金supported by National Natural Science Foundation of China grants(Nos.82173326 and 82473058)Key Research and Development Project of Sichuan Province(Nos.2024YFFK0374 and 2024YFFK0198)Interdisciplinary Innovation Project of West China College of Stomatology,Sichuan University(RD-03-202004).
文摘Microwave thermochemotherapy(MTC)has been applied to treat lip squamous cell carcinoma(LSCC),but a deeper understanding of its therapeutic mechanisms and molecular biology is needed.To address this,we used single-cell transcriptomics(scRNA-seq)and spatial transcriptomics(ST)to highlight the pivotal role of tumor-associated neutrophils(TANs)among tumor-infiltrating immune cells and their therapeutic response to MTC.MNDA+TANs with anti-tumor activity(N1-phenotype)are found to be abundantly infiltrated by MTC with benefit of increased blood perfusion,and these TANs are characterized by enhanced cytotoxicity,ameliorated hypoxia,and upregulated IL1B,activating T&NK cells and fibroblasts via IL1B-IL1R.In this highly anti-tumor immunogenic and hypoxia-reversed microenvironment under MTC,fibroblasts accumulated in the tumor front(TF)can recruit N1-TANs via CXCL2-CXCR2 and clear N2-TANs(pro-tumor phenotype)via CXCL12-CXCR4,which results in the aggregation of N1-TANs and extracellular matrix(ECM)deposition.In addition,we construct an N1-TANs marker,MX2,which positively correlates with better prognosis in LSCC patients,and employ deep learning techniques to predict expression of MX2 from hematoxylin-eosin(H&E)-stained images so as to conveniently guide decision making in clinical practice.Collectively,our findings demonstrate that the N1-TANs/fibroblasts defense wall formed in response to MTC effectively combat LSCC.
文摘The anti-metabolite chemotherapeutic, gemcitabine is relatively effective for a spectrum of neoplastic conditions that include various forms of leukemia and adenocarcinoma/carcinoma. Rapid systemic deamination of gemcitabine accounts for a brief plasma half-life but its sustained administration is often curtailed by sequelae and chemotherapeutic-resistance. A molecular strategy that diminishes these limitations is the molecular design and synthetic production of covalent gemcitabine immunoche-motherapeutics that possess properties of selective “targeted” delivery. The simultaneous dual selective “targeted” delivery of gemcitabine at two separate sites on the external surface membrane of a single cancer cell types represents a therapeutic approach that can increase cytosol chemotherapeutic deposition;prolong chemotherapeutic plasma half-life (reduces administration frequency);minimize innocent exposure of normal tissues and healthy organ systems;and ultimately enhance more rapid and thorough resolution of neoplastic cell populations. Materials and Methods: A light-reactive gemcitabine intermediate synthesized utilizing succinimidyl 4,4-azipentanoate was covalently bound to anti-EGFR or anti-HER2/neu IgG by exposure to UV light (354-nm) resulting in the synthesis of covalent immunoche-motherapeutics, gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu]. Cytotoxic anti-neoplastic potency of gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] between?gemcitabine-equivalent concentrations of 10-12 M and 10-6 M was determined utilizing chemotherapeutic-resistant mammary adenocarcinoma (SKRr-3). The organoselenium compound, [Se]-methylselenocysteine was evaluated to determine if it complemented the anti-neoplastic potency of the covalent gemcitabine immunoche-motherapeutics. Results: Gemcitabine-(C4-amide)-[anti-EGFR], gemcitabine-(C4-amide)-[anti-HER2/neu] and the dual simultaneous combination of gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu] all had anti-neoplastic cytotoxic potency against mammary adenocarcinoma. Gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] produced progressive increases in anti-neoplastic cytotoxicity that were greatest between gemcitabine-equivalent concentrations of 10-9 M and 10-6 M. Dual simultaneous combinations of gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu] produced levels of anti-neoplastic cytotoxicity intermediate between each of the individual covalent gemcitabine immunochemotherapeutics. Total anti-neoplastic cytotoxicity of the dual simultaneous combination of gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] against chemothe-rapeutic-resistant mammary adenocarcinoma (SKBr-3) was substantially higher when formulated with [Se]-methylsele-no-cysteine.
文摘Objective:To evaluate the predictive value of the neutrophil⁃to⁃lymphocyte ratio(NLR)and the systemic immune⁃inflammation index(SII)in predicting patients with anti⁃melanoma differentiation⁃associated gene 5⁃positive(anti⁃MDA5+)dermatomyositis(DM)develop into the rapidly progressive interstitial lung disease(RPILD).Methods:We retrospectively analyzed the clinical and laboratory data of 124 anti⁃MDA5+DM patients from the First Affiliated Hospital of Nanjing Medical University between March 2019 and September 2023.We identified independent risk factors associated with the development and mortality of RPILD with the Cox regression analysis,and determined the optimal cut⁃off values for predicting adverse outcomes with the receiver operating characteristic(ROC)curve analysis.Results:Among the 124 patients,36 patients(29.03%)developed RPILD,and 39 patients(31.45%)died during the follow⁃up period.The results of multivariate Cox regression analysis showed that the elevated NLR was an independent risk factor for RPILD development,while the elevated SII expression was independently associated with the increased mortality of RPILD.Based on the ROC curve analysis,NLR>6.12 was a predictor for RPILD,and SII>875.79 was associated with increased mortality risk of RPILD.Conclusion:Both NLR and SII are accessible,cost⁃effective,and reliable prognostic indicators for the prognosis of patients with anti⁃MDA5^(+)DM,providing a valuable guidance for clinical management and risk stratification of the disease.
