A Phase 2b/3, Multi-Center, Randomized, Double-Blind, Placebo Controlled Trial to Evaluate the Safety and Efficacy of Pagibaximab Injection in Very Low Birth Weight (VLBW) Neonates for the Prevention of Staphylococcal Sepsis

开始日期2009-12-22

申办/合作机构

Biosynexus, Inc.

NCT00646399 / Completed临床2/3期

Evaluate the safety, PK and efficacy comparing Pagibaximab Injection to placebo in preventing staphylococcal sepsis in very low birth weight infants. 1550 infants will be enrolled prior to 48 hours of life and will be randomized 1:1 to receive active drug or placebo on study days 0, 1, 2, 9, 16, and 23.

开始日期2009-03-01

申办/合作机构

Biosynexus, Inc.

NCT00631800 / Completed临床2期

Phase II Randomized, Double Blind, Placebo Controlled, Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity Study in VLBW Neonates of BSYX-A110, for the Prevention of Staphylococcal Infection

The purpose of this study is to evaluate the safety (including tolerability), pharmacokinetics, pharmacodynamics and clinical activity of BSYX-A110 administered in a 3-dose regimen on Study Days 0, 7, and 14.

开始日期2003-05-01

申办/合作机构

Biosynexus, Inc.

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100 项与 LTA 相关的临床结果

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100 项与 LTA 相关的转化医学

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0 项与 LTA 相关的专利（医药）

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2,095

项与 LTA 相关的文献（医药）

2024-12-31·European Journal of Psychotraumatology

DNA methylation changes in association with trauma-focused psychotherapy efficacy in treatment-resistant depression patients: a prospective longitudinal study

Article

作者: Mattevi, Stefania ; Menesello, Valentina ; Hohoff, Christa ; Martini, Paolo ; Minelli, Alessandra ; Bortolomasi, Marco ; Baune, Bernhard T ; Carvalho Silva, Rosana ; Gennarelli, Massimo

Background: Stressful events increase the risk for treatment-resistant depression (TRD), and trauma-focused psychotherapy can be useful for TRD patients exposed to early life stress (ELS). Epigenetic processes are known to be related to depression and ELS, but there is no evidence of the effects of trauma-focused psychotherapy on methylation alterations.Objective: We performed the first epigenome-wide association study to investigate methylation changes related to trauma-focused psychotherapies effects in TRD patients.Method: Thirty TRD patients assessed for ELS underwent trauma-focused psychotherapy, of those, 12 received trauma-focused cognitive behavioural therapy, and 18 Eye Movement Desensitization and Reprocessing (EMDR). DNA methylation was profiled with Illumina Infinium EPIC array at T0 (baseline), after 8 weeks (T8, end of psychotherapy) and after 12 weeks (T12 - follow-up). We examined differentially methylated CpG sites and regions, as well as pathways analysis in association with the treatment.Results: Main results obtained have shown 110 differentially methylated regions (DMRs) with a significant adjusted p-value area associated with the effects of trauma-focused psychotherapies in the entire cohort. Several annotated genes are related to inflammatory processes and psychiatric disorders, such as LTA, GFI1, ARID5B, TNFSF13, and LST1. Gene enrichment analyses revealed statistically significant processes related to tumour necrosis factor (TNF) receptor and TNF signalling pathway. Stratified analyses by type of trauma-focused psychotherapy showed statistically significant adjusted p-value area in 141 DMRs only for the group of patients receiving EMDR, with annotated genes related to inflammation and psychiatric disorders, including LTA, GFI1, and S100A8. Gene set enrichment analyses in the EMDR group indicated biological processes related to inflammatory response, particularly the TNF signalling pathway.Conclusion: We provide preliminary valuable insights into global DNA methylation changes associated with trauma-focused psychotherapies effects, in particular with EMDR treatment.

2024-11-01·Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy

Precision classification and quantitative analysis of bacteria biomarkers via surface-enhanced Raman spectroscopy and machine learning

Article

作者: Kumar, Amit ; Chen, Xianyan ; Zughaier, Susu M ; Zhao, Yiping ; Islam, Md Redwan

The SERS spectra of six bacterial biomarkers, 2,3-DHBA, 2,5-DHBA, Pyocyanin, lipoteichoic acid (LTA), Enterobactin, and β-carotene, of various concentrations, were obtained from silver nanorod array substrates, and the spectral peaks and the corresponding vibrational modes were identified to classify different spectra. The spectral variations in three different concentration regions due to various reasons have imposed a challenge to use classic calibration curve methods to quantify the concentration of biomarkers. Depending on baseline removal strategy, i.e., local or global baseline removal, the calibration curve differed significantly. With the aid of convolutional neural network (CNN), a two-step process was established to classify and quantify biomarker solutions based on SERS spectra: using a specific CNN model, a remarkable differentiation and classification accuracy of 99.99 % for all six biomarkers regardless of the concentration can be achieved. After classification, six regression CNN models were established to predict the concentration of biomarkers, with coefficient of determination R² > 0.97 and mean absolute error (MAE) < 0.27. The feature of important calculations indicates the high classification and quantification accuracies were due to the intrinsic spectral features in SERS spectra. This study showcases the synergistic potential of SERS and advanced machine learning algorithms and holds significant promise for bacterial infection diagnostics.

2024-11-01·Fish & Shellfish Immunology

A newly identified secretory phospholipase A2 group XIIA homolog (LcPLA2XIIA) in Larimichthys crocea exhibits antimicrobial and antitumor activities

Article

作者: Shi, Jian-Gao ; Li, Shouhu ; Peng, Shi-Ming ; Wang, Yuan ; Wang, Ya-Bing ; Qin, Chuang ; Wang, Xiao-Shan ; Li, Xin-Cang

The phospholipase A2 (PLA2) superfamily has attracted increasing attention in recent years due to the multiple physiological and pathological functions exerted by its members. Up to date, the knowledge about the biological role of PLA2XIIA subfamily members remains limited. In this study, a new member of PLA2XIIA subfamily, LcPLA2XIIA, was characterized in large yellow croaker. Different from most members of the PLA2 superfamily with positive charge, LcPLA2XIIA encodes an anionic protein, which is similar to other members of PLA2XIIA subfamily. LcPLA2XIIA is highly expressed in the intestine, and afterwards, it is up-regulated after with Pseudomonas plecoglossicida or Staphylococcus aureus. LcPLA2XIIA exhibits strong inhibitory activity against these two bacteria. The results indicate that LcPLA2XIIA plays an important role in the antimicrobial immune responses of large yellow croaker. LcPLA2XIIA displays strong binding activity to all the tested bacteria. It specifically interacts with LTA, a unique component on the surface of Gram-positive bacteria. It also significantly promotes bacterial agglutination in the presence of Ca²⁺. These findings reveal that the binding and agglutinating abilities of LcPLA2XIIA to bacteria contribute greatly to its antibacterial activity. In addition, LcPLA2XIIA significantly inhibits the proliferation of infectious hematopoietic necrosis virus instead of recombinant human adenovirus type 5. It also suppresses the growth of human colorectal adenocarcinoma cells by inducing apoptosis, but it has no obvious inhibitory effect on the growth of epithelioma papulosum cyprinid cells. This study provides new insights into the antibacterial activity, and the mechanism of LcPLA2XIIA in large yellow croaker, and antiviral and antitumor functions of PLA2XIIA subfamily members.

项与 LTA 相关的新闻（医药）

2024-09-24

·生物探索

Nature｜NKp46活化ILC1放大自身免疫组织损伤

引言自身免疫病（autoimmune diseases）是机体免疫系统对自身组织器官攻击导致的炎症性疾病。自身免疫病的发病具有隐匿性、遗传倾向、难治性和复发性。常见的自身免疫病包括系统性红斑狼疮、I型糖尿病、类风湿性关节炎等。自身免疫病的发生与自身免疫耐受的打破进而引起自身反应抗体和细胞毒细胞的产生有关。然而，有意思的是，部分健康人群即使存在自身抗体，但并没有进一步发展为疾病状态，表明自身耐受的打破本身并不足以引起全面的炎症和组织损伤【1】。因此，一个关键的问题是炎症信号在自身免疫病中如何启动以及进一步放大，最终导致疾病的启始和恶化，这对于自身免疫病的治疗具有重要意义。近日，德国柏林夏里特医学院Antigoni Triantafyllopoulou研究团队在Nature上发表了文章Amplification of autoimmune organ damage by NKp46-activated ILC1的研究文章。这项研究揭示NKp46调节ILC1-巨噬细胞-肾实质细胞轴，在不影响自身免疫条件下促进肾脏炎性级联反应放大导致组织损伤，为自身免疫宿主易感的分子机制提供深层次理解以及对慢性炎症性疾病的免疫治疗有重要意义。作者首先在雌性NZB/W F1代小鼠中监测免疫细胞浸润情况。使用静脉注射CD45荧光抗体标记血管相关CD45+免疫细胞（CD45i.v.+）以区分组织浸润CD45+免疫细胞（CD45i.v.-）。NKp46作为激活型免疫受体常表达在ILC1、NK和部分黏膜ILC3（NCR+ILC3），这里统称为NKp46+ILC。流式分析发现组织NKp46+ILC在狼疮肾炎肾组织中显著增加。NK细胞表达而CD49b-ILC1和ILC3细胞并不表达CD49b和Eomes。在狼疮肾炎（lupus nephritis，LN）中，血管相关免疫细胞表型为Eomes+CD49b+，表明NK细胞；而组织浸润细胞为Eomes-CD49b-，表明CD49b-ILC1和ILC3细胞。鉴于NK细胞依赖于Eomes，而ILC1和NKp46+ILC3依赖于GATA3。作者分别在Ncr1cre/+;Eomesfl/fl小鼠观察到CD49b+细胞显著降低，而CD49b+CD45i.v.-细胞不受影响，在Ncr1cre/+;GATA3fl/fl小鼠观察到CD49b+NK细胞比例不变，而CD49b+CD45i.v.-细胞显著降低。与此同时,作者在人肾炎组织中同样观察到NKp46+ILC1和ILC3样细胞。总之，上述数据表明CD49b+NKp46+ILC是NK细胞，而组织CD49b-NKp46+ILC是ILC1或NKp46+ILC3。随后，作者探索NKp46+ILC在狼疮肾炎中的作用。虽然短期anti-asialoGM1注射有效删除组织和血管相关NKp46+ILC，但长期anti-asialoGM1注射显著降低组织而非血管相关NKp46+ILC。体内结果显示，长期anti-asialoGM1注射有效改善狼疮肾炎症状，如降低蛋白尿和血尿素氮但并不影响anti-dsDNA滴度。另外，作者发现使用NKp46封闭抗体（mNCR1.15）虽然不能清除NKp46+ILC，但杀伤和结合实验表明其可以有效阻断NKp46功能。体内结果同样显示mNCR1.15在不影响anti-dsDNA滴度条件下有效改善狼疮肾炎症状。scRNA-seq分析表明阻断NKp46逆转肾炎中足细胞的丢失和毛细血管内皮损伤。总之，上述数据表明自身免疫性组织损伤需要NKp46+ILC和NKp46信号。随后，作者分析肾组织内NKp46+ILC，包括tILC（ILC1和NKp46+ILC3）和tNK。tILC高表达ILC1基因（Thy1、Cxcr6、Cd226和Tbx21）而低表达NK相关基因（Eomes、granzymes和Klra）。肾炎中两种NK细胞富集，包括Tcf7+NK和Tigit+NK，分别代表早期分化和失能状态。tILC则主要包括Zfp683+tILC、Il7r+tILC和Il2+tILC，分别代表成熟、未成熟ILC1以及活化增殖ILC状态。值得注意的是，作者发现一种Tnfrsf9+tILC，高表达Il2ra和TNF超家族基因（例如Tnfrsf1b、Tnfrsf9、Lta和Tnfsf14）、黏附分子Icam1、趋化因子Ccl1和生长因子Csf1以及Csf2。Tnfrsf9+tILC而非其他NKp46+ILC，富集NKp46激活相关基因且在肾炎中以NKp46依赖方式增加浸润。为了确定Tnfrsf9+tILC是ILC1还是ILC3，作者分析RORγt-fate map（FM）小鼠发现Tnfrsf9+tILC大部分来源于RORγt-FM-细胞，表明NKp46刺激调控的主要是ILC1，但也会NKp46+ILC1短暂激活RORγt表达。由于NKp46+tILC低细胞毒性和前述其可以产生Csf2以及肾炎单核巨噬细胞的显著改变，作者推测NKp46+tILC的组织损伤能力可能依赖于Csf2介导的单核巨噬调节作用。首先，作者发现Tnfrsf9+tILC是肾组织唯一产生Csf2的tILC和tNK细胞，且Csf2的产生依赖于NKp46信号。其次，Csf2-tdTomato报告小鼠发现在肾小球附近，NKp46+ILC是最主要的CSF2表达细胞。另外，CSF2封闭抗体显著减轻肾炎相关的蛋白尿、尿素氮和近端肾小管上皮损伤。最后，疾病相关的巨噬细胞大部分来源于外周血单核细胞，且CSF1R封闭删除巨噬细胞抑制肾损伤。因此，上述数据表明NKp46+tILC来源的CSF2募集外周单核细胞来源的巨噬细胞介导自身免疫组织损伤。正常肾组织巨噬细胞为CD11blowMHC-IIhigh，而肾炎肾组织巨噬细胞为CD11bhighMHC-IIhigh/low。那么NKp46信号阻断如何影响疾病相关巨噬细胞呢？作者发现NKp46阻断虽然减轻肾炎症状，但没有再次恢复CD11blowMHC-IIhigh的巨噬细胞稳态表型，而只是大量减少疾病相关巨噬细胞浸润，表明NKp46+ILC通过CSF2调节疾病相关巨噬细胞扩增。随后，转录组测序分析发现狼疮肾炎相关一群TREM2+巨噬细胞，TREM2与巨噬细胞胞葬正相关，而与促炎基因负相关，表明TREM2+巨噬细胞是组织损伤的反应细胞。后续实验发现TREM2缺失导致肾小球毛细血管结构紊乱，表明TREM2在促进巨噬细胞向抗炎分化发挥作用。综上所述，这项研究通过肾脏免疫细胞和实质细胞scRNA-seq结合抗体阻断和基因敲除实验，揭示NKp46+ILC1细胞通过Csf2介导单核巨噬细胞调节放大自身免疫组织损伤，对炎症性病理损伤及其治疗具有重要意义。参考文献 1. Mahasish, Shome., Yunro, Chung., Ramani, Chavan., Jin G, Park., Ji, Qiu., Joshua, LaBaer.(2022). Serum autoantibodyome reveals that healthy individuals share common autoantibodies. Cell Rep, 39(9), 0. doi:10.1016/j.celrep.2022.110873 https://doi.org/10.1038/s41586-024-07907-x 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

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