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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： 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.

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： 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...

摘要： In contrast to chimeric antigen receptor T cells, T cell receptor (TCR)-engineered T cells can target intracellular tumor-associated antigens crucial for treating solid tumors. However, most trials published so far show limited clinical activity. Here we report interim data from a first-in-human, multicenter, open-label, 3 + 3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME)-directed TCR T cell therapy in HLA-A*02+ patients with PRAME+ recurrent and/or refractory solid tumors, including melanoma and sarcoma. Primary objectives include the evaluation of safety and tolerability and the determination of the maximum tolerated dose (MTD) and/or recommended dose for extension. Secondary objectives include the evaluation of IMA203 TCR-engineered T cell persistence in peripheral blood, tumor response as well as duration of response. A total of 27 patients were enrolled in the phase 1a dose escalation and 13 patients in the phase 1b dose extension. IMA203 T cells were safe, and the MTD was not reached. Of the 41 patients receiving treatment (that is, who started lymphodepletion), severe cytokine release syndrome was observed in 4.9% (2/41), and severe neurotoxicity did not occur. In the 40 patients treated with IMA203, an overall response rate consisting of patients with unconfirmed or confirmed response (u/cORR) of 52.5% (21/40) and a cORR of 28.9% (11/38) was observed with a median duration of response of 4.4 months (range, 2.4-23.0, 95% confidence interval: 2.6-not reached) across multiple indications. Rapid T cell engraftment and long-term persistence of IMA203 T cells were observed. IMA203 T cells trafficked to all organs, and confirmed responses were more frequent in patients with higher dose. T cell exhaustion was not observed in the periphery;deep responses were enriched at higher PRAME expression;and higher T cell infiltration resulted in longer progression-free survival. Overall, IMA203

摘要： In 1969, the British band Pink Floyd released a landmark record entitled Ummagumma. The album included a mysterious song “Careful with that Axe Eugene” highlighted by electronic sound effects that created an aural landscape not appreciated before ...

关键词： 2DG   2-deoxy-D-glucose   ACC1   acetyl-coenzyme A carboxylase 1   AMPK   AMP-activated protein kinase   ATMs   adipose tissue macrophages   BHB   β-hydroxybutyrate   CNS   central nervous system   CPZ   cuprizone   CR   calorie restriction   CRMs   CR mimetics   CRP   C-reactive protein   DCs   dendritic cells   DSS   dextran sodium sulfate   EAE   experimental autoimmune encephalomyelitis   ESR   erythrocyte sedimentation rate   FMD   fasting-mimicking diet   FOXO   forkhead box O   HPA   hypothalamic–pituitary–adrenal   IBD   inflammatory bowel disease   IF   intermittent fasting   IFN-γ   interferon-gamma   IL   interleukin   IMQ   imiquimod   LPS   lipopolysaccharide   MS   multiple sclerosis   mTOR   mammalian target of rapamycin   NF-κB   necrosis factor-κB   NK   natural killer   RA   rheumatoid arthritis   RRMS   relapsing–remitting MS   S1P   sphingosine-1-phosphate   SIRT   sirtuins   SLE   systemic lupus erythematosus   Th   T helper   TLR   toll-like receptor   TNF-α   tumor necrosis factor-α   Treg(s)   regulatory T cell(s)   TRF   time-restricted feeding  

摘要： Calorie restriction (CR) is a well known intervention associated with multifaceted anti-aging and pro-longevity health benefits. It induces complex physiological cellular and molecular adaptations, resulting in the fine-tuning of metabolic and immune responses in both homeostatic and diseased states. It has thus been extensively studied both preclinically and clinically, uncovering its therapeutic potential against inflammatory conditions, particularly autoimmune diseases. CR mimetics (CRMs), that is, molecules that mimic CR's effects, have also been widely investigated to counteract inflammatory states associated with numerous diseases, including autoimmunity. However, a comprehensive overview of how CR and CRMs modulate different aspects of immune responses, thereby potentially modifying autoimmunity, is still lacking. Here, we reviewed the latest progress on the impacts of CR and CRMs on the immune system and the current evidence on their potential translation in the clinical management of people with autoimmune diseases. First, we summarized different types of CR and CRMs and their main mechanisms of action. We next reviewed comprehensively how CR and CRMs modulate immune cells and discussed up-to-date preclinical and clinical advances in using CR and CRMs in the context of some of the most common autoimmune diseases. Finally, challenges faced in CR-related research and its translation into the clinic are discussed. Significance Statement: Calorie restriction (CR) encompasses various approaches for daily or intermittent reduction in calorie intake while maintaining adequate nutrient intake. It acts through cell-intrinsic and-extrinsic pathways to modulate immune cell functions. CR is emerging as a strategy for autoimmune disease management. CR's effects could be partially mimicked by molecules called CR mimetics, which are proposed to achieve CR's effects without reducing food intake. CR and CR mimetics have been tested as promising potential therapeutics in pre

关键词： Neuroinflammation   Aging   Type-I interferons   Parkinson's disease   Microglia  

摘要： Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by motor dysfunction. Pathological hallmarks of the disease include selective dopaminergic neuronal death, intraneuronal deposits known as Lewy bodies and extensive neuroinflammation within the central nervous system (CNS). Microglia are the key cellular players in mediating this neuroinflammatory response, propagating this neuropathology to exacerbate the neuronal cell death. Growing evidence suggests a role for the type-I interferons (IFN) in driving the neuroinflammatory response in PD, with increased type-I IFN signatures reported in both PD patients and in animal models of the disease. This review will discuss 1) the key players that modulate the neuroinflammatory response in PD and their implications in the CNS 2) the contribution of the type-I IFNs in driving the neuroinflammatory response in PD, and 3) evidence for therapeutically targeting type-I IFN signalling to slow disease progression. A greater understanding of the underlying mechanisms that lead to the elevated neuroinflammatory response in PD could lead to new advances in therapeutic targets that effectively slow the disease progression.