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关键词： HLA   italic>HLA-DPA1*02:112   new allele   next-generation sequencing  

摘要： The HLA-DPA1*02:112 allele differs from the HLA-DPA1*02:02:02:01 allele by a single nucleotide at codon 29 in exon 2.

关键词： HLA   sensitization   plasma exchange   serum dilutions   antibody-mediated rejection  

摘要： Therapeutic plasma exchange (TPE) remains a primary therapy for addressing circulating donor-specific antibodies against mismatched human leukocyte antigens, which pose a significant challenge to successful transplantation of solid organs and hematopoietic cells. In this study, we aimed to evaluate the response to 5 TPE sessions in patients undergoing desensitization, as well as in patients who developed antibody-mediated rejection posttransplant. Sera collected before and after each TPE session was treated with EDTA and tested using the single-antigen bead assay as undiluted or 1:4, 1:16, 1:64, and 1:256 diluted. The reduction in human leukocyte antigen antibodies correlated with previously established total immunoglobulin G reduction levels. However, we observed that class I antibody levels were reduced by 85% to 90% while class II antibodies were reduced by only 75% to 80% after 5 TPE sessions. We also found that dilutions performed on pretreatment serum were predictive of the response to TPE. This approach was used to design TPE based desensitization protocols for highly sensitized patients across various organ , tissue types, as well as for treating patients with antibody-mediated rejection. Our data suggest that serum dilution may be an effective method for assessing the likelihood of response to TPE, thereby aiding in the guidance of treatment strategies.

关键词： biologics   monoclonal antibody   reactive therapeutic drug monitoring   clinical-decision support tool   model-informed precision dosing  

摘要： Background Proactive therapeutic drug monitoring (TDM) for tumor necrosis factor alpha antagonist (anti-TNF) therapy in adult inflammatory bowel disease (IBD) remains controversial, with inconsistent findings from clinical trials and meta-analyses. Pediatric societal guidelines endorse the implementation of proactive TDM. However, the integration of TDM into clinical practice by pediatric gastroenterologists has not been characterized. This study was undertaken to delineate the practice patterns, attitudes, and barriers associated with anti-TNF TDM among pediatric gastroenterologists across the United *** A 28-item questionnaire was developed based on prior adult surveys and current pediatric literature, undergoing 3 rounds of iteration. The survey was comprised of physician demographics, center demographics, TDM practice behavior questions and case-scenarios. The survey was deployed through the ImproveCareNow Learning Health System Network between February and June *** Among 380 invitees, 256 (77%) completed the questionnaire. Among respondents, 67% (171) were academic-affiliates, and 55% (140) were female. There was notable variability in the number of patients with IBD seen per practice. All respondents reported using TDM for infliximab, and the majority for adalimumab, and the vast majority utilizing a proactive TDM approach. The principal barriers to TDM implementation were insurance denials, cost, and logistical challenges. More respondents indicated they would initiate TDM during infliximab induction for severe ulcerative colitis than for Crohn's *** In contrast to the adult literature, most pediatric gastroenterologists report undertaking proactive TDM for anti-TNF agents in IBD management. Precision dosing tools reflective of an individual's pharmacokinetics are desired and need to be further studied. Therapeutic drug monitoring (TDM), monitoring of anti-tumor necrosis factor (TNF) drug blood levels, is recommended for th

关键词： AMPK   AMP kinase   AT2   alveolar type 2   ATM   ataxia-telangiectasia mutated   Bach   BTB and CNC homology-1   Bcl   B-cell lymphoma   BET   bromodomain and extra-terminal domain   CAR   chimeric antigen receptor   CDK   cyclin-dependent kinase   CDKN   cyclin-dependent kinase inhibitor   CF   cystic fibrosis   CFTR   CF transmembrane conductance regulator   COPD   chronic obstructive pulmonary disease   D+Q   dasitinib plus quercetin   DDR   DNA damage response   DR   death receptor   DRI   D-retro-inverso   EV   extracellular vesicle   FEV1   forced expiratory volume in 1 second   GLS-1   glutaminase 1   HSP90   heat shock protein 90   IL   interleukin   IPF   idiopathic pulmonary fibrosis   JAK   Janus-activated kinase   KEAP1   Kelch-like ECH-associated protein 1   MAPK   mitogen-activated protein kinase   Mcl-1   myeloid cell leukemia-1   MDM   mouse double minute   MMP   matrix metalloproteinase   mROS   mitochondrial reactive oxygen species   MSC   mesenchymal stem cell   mTOR   mechanistic target of rapamycin   mTORC   mTOR complex   NF-κB   nuclear factor-κB   Nox   NADPH oxidase   Nrf2   nuclear factor erythroid 2-related factor 2   PAH   pulmonary arterial hypertension   PAI-1   plasminogen activator inhibitor-1   PI3K   phosphoinositide-3-kinase   PPAR   peroxisome proliferator activated receptor   PROTAC   proteolysis targeting chimera   PTEN   phosphatase tensin homolog   S6K1   S6 kinase-1   SA-β-gal   senescence-associated β-galactosidase   SASP   senescence-associated secretory phenotype   SIRT   sirtuin   STAC   sirtuin-activating compound   TFEB   transcription factor EB   TGF   transforming growth factor   TNF   tumor necrosis factor  

摘要： Chronic respiratory diseases are an enormous burden on healthcare and the third ranked cause of death globally. There is now compelling evidence that acceleration of lung aging and associated cellular senescence is a key driving mechanism of several chronic lung diseases, particularly chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Senescent cells, arising from oxidative stress and unrepaired damage, can accumulate in the lung and develop a senescence-associated secretory phenotype, spreading senescence and resulting in disease progression. In addition, there is a reduction in normally protective antiaging molecules, such as sirtuins, in the lungs. The role of cellular senescence in chronic lung disease has driven interest in senotherapy that targets senescent cells as a novel approach to treating respiratory diseases, and includes repurposing of existing drugs or developing new therapies. Senomorphics, which prevent the development of senescence and inhibit senescence-associated secretory phenotype mediators, include inhibitors of phosphoinositide-3-kinase-mechanistic target of rapamycin signaling, novel antioxidants, and sirtuin activators. Senolytics remove senescent cells by inducing apoptosis and include inhibitors of antiapoptotic proteins, such as B-cell lymphoma-extra large, inhibitors of forkhead box O-4-p53 interaction, heat shock protein 90 inhibitors, and cardiac glycosides. Senotherapies have been effective in animal models of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, and several clinical trials are currently underway. The safety of these treatments after long-term administration requires further study, but this could potentially to be a promising approach to treating chronic lung diseases.

关键词： HLA-DPB1*1772:01   novel allele   sequencing-based typing  

摘要： The HLA-DPB1*1772:01 allele differs from HLA-DPB1*05:01:01:01 by a single non-synonymous nucleotide change in exon 2.

关键词： nephrotic syndrome   idiopathic nephrotic syndrome   minimal change disease   focal segmental glomerulosclerosis   pediatric   children   pathogenesis   immune mechanisms   FSGS   Focal segmental glomerulosclerosis   GWAS   Genome-wide association studies   HLA   Human leukocyte antigen   IL   Interleukin   INS   Idiopathic nephrotic syndrome   MCD   Minimal change disease   NS   Nephrotic syndrome   PSMA1   Proteasome subunit alpha type 1   SSNS   Steroid sensitive nephrotic syndrome   suPAR   Soluble urokinase plasminogen activator receptor   Th   T-helper   TNF   Tumor necrosis factor alpha   Treg   T-regulatory   UCHL1   Ubiquitin C-terminal hydrolase L1  

摘要： Autoantibodies and Circulating Factors Described in Idiopathic Nephrotic Syndrome Circulating factor Population studied Biomarker positive, n (%) Reference Autoantibodies Annexin A2 Children with nephrotic syndrome 106/596 (18%) Ye et al (2021) Ne...

关键词： atopic dermatitis   JAK/STAT   MC903   reconstructed human skin   ruxolitinib   skin explants  

摘要： Atopic dermatitis (AD) is a prevalent inflammatory skin disorder characterized by an impaired skin barrier, dysregulated immune system and pruritis. Emerging pharmaceutical therapies for AD include selective Janus kinase (JAK) inhibitors such as ruxolitinib, the first dual JAK1/JAK2 inhibitor approved by the US Food and Drug Administration. This study aimed to evaluate the effects of ruxolitinib on AD-related symptoms using mouse and human skin models. AD-related symptoms were assessed in MC903/ruxolitinib-treated mice, including ear swelling, histological analysis, pruritus, serum biomarker quantification and immune cell analysis. Additionally, immunohistochemistry and transcriptome analysis were conducted on AD-related cytokine-treated reconstructed human skin (RHS) and ruxolitinib-treated human skin explants with and without tape-stripping. Ruxolitinib-treated mice exhibited reduced inflammation, including decreased ear swelling and diminished pruritus. Furthermore, reductions in immune cell populations, including T cells and serum biomarker IL-13, were observed in ruxolitinib-treated mice. Transcriptome analysis revealed increased STAT3 expression and decreased skin barrier gene FLG in AD-related cytokine-treated RHS. Regardless of tape stripping, ruxolitinib-treated skin explants exhibited decreased IL13RA1 expression and increased expression of skin barrier genes FLG, FLG2 and LOR. Ruxolitinib treatment in mice resulted in decreased inflammation and pruritus, along with increased expression of skin barrier proteins through downregulation of IL-13. Consistently, ruxolitinib-treated human skin explants demonstrated enhanced expression of skin barrier proteins, while IL-13 treatment of RHS led to downregulation of these proteins. These findings support data from human clinical trials indicating reduced SCORAD, pruritus and inflammatory phenotypes in AD patients treated with ruxolitinib.

关键词： Severe asthma   Biologics   Clinical remission   Exacerbation  

摘要： Background: The optimal selection of biologics is critical for achieving clinical remission (CR) in patients with severe asthma. This real-world study examined baseline prebiologic factors associated with CR in patients with severe asthma receiving anti-IL-4R alpha, anti-IL-5/5R, or anti-IgE treatment. Methods: This Japanese multicenter retrospective observational study included consecutive patients with severe asthma whose spirometry and asthma control test (ACT) data were available after at least 1 year of anti-IL-4R alpha, anti-IL-5/5R, or anti-IgE treatment. The 3-domain CR was defined based on no maintenance oral corticosteroid (OCS) use, no exacerbation in the previous year, and ACT >= 23. The 4-domain CR was defined based on no OCS, no exacerbation, ACT >= 20, and percentage-predicted forced expiratory volume in 1 s >= 80 %. Results: A total of 236 patients with severe asthma were included (n = 81, 104, and 51 for the anti-IL-4R alpha, anti-IL-5/5R, and anti-IgE treatment groups, respectively). The rates of 3-and 4-domain CR were 28-47 % and 22-36 %, respectively. In the multivariate models, the presence of chronic rhinosinusitis and higher FeNO levels were associated with 3-domain CR in patients receiving anti-IL-4R alpha treatment but not in those receiving anti-IL-5/5R or anti-IgE treatment after adjusting for baseline OCS use, past-year exacerbation history, body mass index, sex, and disease duration. Moreover, higher FeNO levels were associated with 4-domain CR in patients receiving anti-IL-4R alpha treatment after adjustment for the same variables. Conclusion: Anti-IL-4R alpha treatment may be effective for patients with severe asthma who have chronic rhinosinusitis or high FeNO levels at baseline.