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摘要： Low back pain is the leading cause of global disability with intervertebral disc (IVD) degeneration a major cause. However, no current treatments target the underlying pathophysiological causes. PCRX-201 presents a novel gene therapy approach that addresses this issue. PCRX-201 codes for interleukin-1 receptor antagonist, the signalling inhibitor of the pro-inflammatory cytokine interleukin-1, which orchestrates the catabolic degeneration of the IVD. Here, the ability of PCRX-201 to transduce human nucleus pulposus cells to increase IL-1Ra production was assessed together with effects on catabolic pathways. When transduced with PCRX-201, the production and release of IL-1Ra was increased in degenerate human nucleus pulposus cells and tissue. Whereas, the production of downstream proteins, including IL-1 beta, IL-6, MMP3, ADAMTS4 and VEGF were decreased in both cells and tissue, indicating a reduction in IL-1-induced catabolic signalling. Here, a novel gene therapy vector, PCRX-201, was shown to transduce degenerate NP cells and tissue, increasing the production of IL-1Ra. The increased IL-1Ra resulted in decreased production of catabolic cytokines, enzymes and angiogenic factors, whilst also increasing aggrecan expression. This demonstrates PCRX-201 enables the inhibition of IL-1-driven IVD degeneration. The ability of PCRX-201 to elicit anti-catabolic responses is promising and warrants further development to determine the efficacy of this exciting, novel gene therapy.

关键词： antibody engineering   bispecific antibody   cytokine mimetic   IL-12   NK cell   single-domain antibody   surrogate cytokine   T cell   VHH   yeast surface display  

摘要： In this work, we have generated bispecific interleukin (IL)-12 surrogate agonists based on camelid-derived single-domain antibodies (sdAbs) targeting the IL-12 receptor (IL-12R) subunits IL-12R beta 1 and IL-12R beta 2. Following immunization and antibody display-based paratope isolation, respective sdAbs were combinatorially reformatted into a monovalent bispecific architecture by grafting resulting paratopes onto the hinge region of a heterodimeric Fc region. Functional characterization using NK-92 cells enabled the identification of multiple different sdAb-based bispecifics displaying divergent IL-12R agonism capacities as analyzed by STAT4 phosphorylation. Further investigations by harnessing peripheral blood mononuclear cells (PBMCs) from healthy donors revealed attenuated pSTAT4 activation compared to recombinant human (rh) wild-type IL-12 regarding both natural killer (NK)-cell and T-cell activation but robust IL-12R agonism on stimulated T cells. While several sdAb-based IL-12 mimetics were nearly inactive on NK cells as well as T cells obtained from PBMCs, they elicited significant STAT4 phosphorylation and interferon (IFN)-gamma release on stimulated T cells as well as an IL-12-like transcriptional signature. Furthermore, we demonstrate that the activity of receptor agonism of generated bispecific IL-12 mimetics can also be biased towards stimulated T cells by changing the spatial orientation of the individual sdAbs within the molecular design architecture. Taken together, we present an alternative strategy to generate IL-12-like biologics with tailor-made characteristics.

关键词： ACR   Acute Cellular Rejection   AMR   Antibody-mediated Rejection   CMV   Cytomegalovirus   DSA   Donor-specific antibody   HLA   Human leukocyte antigen   IT   Intestinal Transplant   IVIG   Intravenous Immunoglobulin   MFI   Mean fluorescence intensity   mTOR inhibitors   Mammalian target of rapamycin inhibitors   PRA   Panel-reactive antibodies  

摘要： Background. Intestinal transplantation (IT) is a complex procedure that requires nuanced variability remains in immunosuppressive protocols across transplant centers due to a lack of consensus on the optimal approaches for induction, maintenance, and clinical testing. This variability complicates standardization and identification of best practices for IT recipients. Methods. A descriptive survey study was conducted to characterize immunosuppressive and testing strategies in IT at major transplant centers in the United States. Ten centers known to have performed over 10 ITs since 2015 were selected from the Scientific Registry of Transplant Recipients database. A 22-question survey was distributed to surgical directors, collecting data on pre-, peri-, and post-transplant immunological testing, desensitization strategies, immunosuppressive regimens, and management of antibody-mediated rejection (AMR) and acute cellular antigen (HLA) and donor-specific antibody (DSA) testing, with varying frequencies and methodologies. Desensitization was reported by 44% of centers for isolated IT and by 22% for multilevel targets across centers. Post-transplant DSA testing was performed by all centers, and protocol-driven endoscopic bowel biopsies were routine at 67% of centers. AMR was diagnosed at 89% of centers, with plasmapheresis and IVIG being the most common treatments. Variability was noted in desensitization practices and AMR management. Conclusion. This survey highlights considerable consistency in pre- and post-transplant test- ing and immunosuppressive regimens for IT recipients, while significant variability exists in desensitization strategies and AMR management. Further research is needed to standardize these practices to improve patient outcomes across transplant centers

关键词： cytokines   interleukin-6   luminal A   macrophages   non-responder   T cells  

摘要： Drug non-responsiveness is the major reason for the poor prognosis of hormonal receptor-positive breast cancer (ER+/PR+ BCa), particularly the luminal A subtype. However, the underlying mechanism of drug non-responsiveness remains unknown. Flow cytometry and t-SNE analysis followed by ELISA validation of responder and non-responder unveiled lower secretion of IFN-gamma, IL-12, and higher levels of IL-6 and TGF-beta in CD4(+) T cells (P < 0.001), CD8(+) T cells (P < 0.001), FOXP3(+) Tregs (P < 0.001) and CD206(+) TAMs (P < 0.001) in non-responders. Treatment of isolated CD206(+) TAMs with recombinant IL-6 upregulated the expression of ARG-1 (arginase-1) and subsequent increase of TGF-beta(+) Tregs (P < 0.001) and IL-6(+) Tregs (P < 0.001) in luminal A BCa. Our findings showed IL-6 mediated ARG-1(+)CD206(+) TAMs polarization induced FOXP3(+) Tregs infiltration in TME of non-responder in luminal A BCa.

关键词： CCL2   degeneration   dog   human explant   intervertebral disc  

摘要： BackgroundCell-free regenerative strategies, such as notochordal cell (NC)-derived extracellular vesicles (EVs), are an attractive alternative in developing new therapies for intervertebral disc (IVD) degeneration. NC-EVs have been reported to elicit matrix anabolic effects on nucleus pulposus cells from degenerated IVDs cultured under basal conditions. However, the degenerative process is exacerbated by pro-inflammatory cytokines contributing to the vicious degenerative cycle. Therefore, this study explores whether NC-EVs modulate interleukin (IL)-1 beta-mediated pro-inflammatory responses in the degenerating *** study utilized two IL-1 beta induced pro-catabolic culture models;a dog 3D nucleus pulposus (NP) cell pellet culture and a human patient-derived, ex vivo NP tissue culture system. Porcine NC-EVs were generated from NC-conditioned medium by differential centrifugation followed by size exclusion chromatography. Donor matched EV-depleted media were generated by overnight ultracentrifugation, whereafter the EV-depleted NCCM supernatant was subjected to size exclusion chromatography. To investigate whether observed effects were EV-associated, NC-EVs conditions were compared to EV-depleted controls in the absence and presence of IL-1 *** size and concentration of NC-EVs were quantified by nanoparticle tracking analysis, which showed minimal donor variation and confirmed depletion of EVs in the EV-depleted media. In the IL-1 beta-induced catabolic cascade, the NC-EVs did not elicit anabolic effects at the matrix level nor did they rescue the pro-catabolic phenotype within dog pellets. Modification of the CCL2 secretion seemed to be context dependent in the human explants: where EVs treatment stimulated CCL2 secretion but in the presence of IL-1 beta this effect was counteracted. Secretion of IL-6 and C-X-C motif chemokine ligand 1 was significantly decreased in NC-EV + IL-1 beta vs. control+IL-1 beta but not compared to EV-depleted human

摘要： Background: Chronic inflammation is a well-recognized contributor to hypertension pathogenesis. However, the role of targeting inflammation in hypertension treatment, particularly through modulation of inflammatory markers like interleukin-6 (IL-6), remains less understood. We investigated the effects of antihypertensive medications with and without IL-6-lowering properties on long-term blood pressure (BP) control in a multiethnic cohort in the Netherlands. Methods: Participants from HELIUS cohort receiving hypertension treatment were followed over six years. BP control at follow-up was determined using WHO criteria. Due to unavailability of IL-6 data, a literature review was conducted to classify antihypertensives based on their IL-6-lowering properties - a proxy approach. Logistic regression models were used to assess associations between the IL-6-lowering potential of antihypertensives and BP control, both within and between antihypertensive classes. Effect modification by ethnicity was explored. Results: A total of 1510 participants were included (mean age 57 years, 62 % women). Within the calcium channel blocker (CCB) class, medications with IL-6-lowering properties (amlodipine and barnidipine) were associated with superior BP control (aOR 1.41, 95 % confidence interval 1.05-1.90) compared to other CCBs (lercanidipine, nifedipine, verapamil, clevidipine, diltiazem). No significant associations were observed within angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs), between different antihypertensive drug classes, nor across ethnic groups. Conclusion: Amlodipine and barnidipine were associated with better BP control compared to other CCBs. Our findings provide an important starting point for understanding the role of IL-6 in hypertension management. Further studies are warranted to confirm these observations by directly measuring IL-6 levels and investigating underlying mechanisms.

关键词： HLA-A*31:01:58   novel allele   sequence-based typing  

摘要： The HLA-A*31:01:58 allele differs from HLA-A*31:01:02:01 by one nucleotide substitution in codon 130 in exon 3.

关键词： HLA-B*51:385   novel allele   sequencing-based typing  

摘要： The HLA-B*51:385 allele differs from HLA-B*51:285 by a single non-synonymous nucleotide change in exon 3.

关键词： IL23R   IL-23-signalling   Ancient genomics   Crohn's disease   Ulcerative colitis   Inflammatory bowel diseases  

摘要： Background The hypomorphic variant rs11209026-A in the IL23R gene provides significant protection against immune-related diseases in Europeans, notably inflammatory bowel diseases (IBD). Today, the A-allele occurs with an average frequency of 5% in Europe. Methods This study comprised 251 ancient genomes from Europe spanning over 14,000 years. In these samples, the investigation focused on admixture-informed analyses and selection scans of rs11209026-A and its haplotypes. Findings rs11209026-A was found at high frequencies in Anatolian Farmers (AF, 18%). AF later introduced the allele into the ancient European gene-pool. Subsequent admixture caused its frequency to decrease and formed the current southwest-to-northeast allele frequency cline in Europe. The geographic distribution of rs11209026-A may influence the gradient in IBD incidence rates that are highest in northern and eastern Europe. Interpretation Given the dramatic changes from hunting and gathering to agriculture during the Neolithic, AF might have been exposed to selective pressures from a pro-inflammatory lifestyle and diet. Therefore, the protective A-allele may have increased survival by reducing intestinal inflammation and microbiome dysbiosis. The adaptively evolved function of the variant likely contributes to the high efficacy and low side-effects of modern IL-23 neutralisation therapies for chronic inflammatory diseases. Copyright (c) 2025 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://***/licenses/by/4.0/).

关键词： Interleukin 17 (IL-17)   invasive breast cancer (IBC)   immune microenvironment   prognostic biomarkers  

摘要： Background: Recently, interleukin 17 (IL-17) has been found to play a critical role in the development of breast cancer. However, its prognostic significance in invasive breast cancer (IBC) remains unclear. This study aims to determine the role of IL-17-related signatures in IBC to identify novel therapeutic options. Methods: IBC data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used to identify IL- 17-related prognostic genes. A predictive model was developed using TCGA data and validated using METABRIC data. The relationship between IL-17 scores and immune landscape, chemotherapy drug sensitivity [half maximal inhibitory concentration (IC50)], and immune checkpoint gene expression was analyzed. The quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to validate key gene expression in breast tumor and normal tissue samples. Results: The predictive model identified core IL-17-related prognostic genes and successfully estimated the prognosis of IBC patients. The model's validity was confirmed using METABRIC data. Patients with high IL-17 scores had worse overall survival (OS) compared to those with low IL-17 scores. Low IL-17 scores were associated with higher immune checkpoint gene expression and predicted enhanced responses to cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1) therapies. Patients with low IL-17 scores exhibited a higher abundance of immune microenvironment components. Furthermore, qRT-PCR confirmed the lower expression of OR51E1, NDRG2, RGS2, and TSPAN7 in breast tumors compared to normal tissue. Conclusions: IL-17-related signatures are promising biomarkers for predicting the prognosis of IBC patients. These findings suggest that IL-17-related markers could be used to guide individualized therapeutic strategies, potentially improving outcomes for IBC patients.