BackgroundNecrotizing enterocolitis (NEC) is a severe inflammatory intestinal disease predominantly affecting premature infants and is characterized by immune dysregulation and epithelial barrier disruption. However, the cellular communication networks and key molecular regulators underlying NEC pathogenesis remain incompletely understood.MethodsSingle-cell RNA sequencing (scRNA-seq) and transcriptomic datasets of NEC were obtained from the Gene Expression Omnibus (GEO) database and analyzed using R-based bioinformatic workflows to characterize cellular composition, intercellular communication, immune infiltration, pathway activity, and candidate disease-associated genes. The expression of alpha kinase 2 (ALPK2) was validated in NEC intestinal tissues by quantitative real-time PCR, and its potential functional relevance was further investigated using lipopolysaccharide (LPS)-induced intestinal organoids.ResultsDendritic cells (DCs) occupied a central position in the NEC intercellular communication network and were enriched in antigen presentation and immune regulatory pathways. Machine learning identified ALPK2, ERICH1, and TMEM123 as candidate NEC-associated genes. Immune infiltration analysis revealed a disturbed immune microenvironment in NEC, with ALPK2 and ERICH1 negatively correlated with DC abundance. Functional enrichment analyses suggested that ALPK2 was predominantly associated with immune and inflammatory pathways, whereas ERICH1 was linked to metabolic and proliferative programs. ALPK2 expression was significantly elevated in ileal tissues from NEC patients and experimental NEC mice. In an inflammation model of LPS stimulation using mouse intestinal organoids, TGX221 suppressed inflammatory cytokine induction and partially restored tight junction protein expression.DiscussionThese findings highlight DCs as central mediators of NEC-associated immune communication and identify ALPK2 as a potential regulator of intestinal inflammation and epithelial barrier dysfunction, supporting ALPK2 as a candidate NEC-associated regulator with potential therapeutic implications.

Reexpansion pulmonary edema following pulmonary and mediastinal surgery presents a complex clinical challenge. Independent lung ventilation (ILV), which facilitates the application of distinct positive end-expiratory pressures (PEEP) and tidal volumes to each lung, may serve as an alternative therapeutic approach for managing reexpansion pulmonary edema. : A 58-year-old female patient presented with a giant space-occupying lesion measuring 17.1*11.2*19.2 cm in the left lung and underwent mediastinal tumor resection under general anesthesia. Intraoperatively, following the resection of the tumor and the invaded upper lobe of the left lung, the left lung was manually reopened, resulting in the development of reexpansion pulmonary edema (RPE). To prevent exudate from the left lung from infiltrating the right lung and to avoid barotrauma to the right lung due to excessive airway pressure, a dual ventilator mechanical ventilation strategy was employed. This approach utilized a double-lumen endotracheal tube, allowing for differential ventilation modes tailored to each lung. The mechanical ventilation treatment involving double-lumen bronchial intubation with various ventilation modes serves as an effective ventilatory support for managing reexpansion pulmonary edema.

Although the immunometabolite itaconate has long been considered an anti-inflammatory, we found that its profound accumulation paradoxically drives macrophage cell death and pro-inflammatory responses. However, the exact molecular mechanisms underlying itaconate-induced macrophage toxicity remain unclear. Here, we demonstrate that pathophysiologically relevant high concentrations of itaconate covalently alkylate the absent in melanoma 2 (AIM2) protein at the cysteine 113 (C113) residue. Itaconate-mediated C113 alkylation structurally stabilizes the AIM2 protein and triggers a conformational change, enabling it to drive ASC oligomerization, PANoptosome assembly, and subsequent macrophage PANoptosis. Utilizing in vitro lentiviral reconstitution in primary macrophages alongside plasmid-mediated expression in cell lines, we rigorously confirmed that the AIM2 C113A mutation completely abolishes itaconate-induced AIM2 stabilization and PANoptosis. In vivo models further corroborated the pathogenic contribution of this axis to systemic sepsis. Taken together, our findings reveal a novel pro-inflammatory mechanism of itaconate via the post-translational modification of AIM2. The itaconate-AIM2 alkylation axis provides crucial mechanistic insights into macrophage depletion and systemic inflammation, highlighting a potential therapeutic target for severe sepsis.

IntroductionAcute graft-versus-host disease (aGVHD) is a major cause of mortality following hematopoietic stem cell transplantation (HSCT). Its pathogenesis is primarily driven by alloimmune T cells, which recognize host tissues as foreign. A deeper characterization of the T cell receptor (TCR) repertoires in patients with aGVHD could provide critical insights into the disease's mechanisms and identify potential predictive biomarkers.MethodsWe employed next-generation sequencing to comprehensively profile the T cell receptor alpha (TRA) and beta (TRB) chains in HSCT recipients, comparing those with and without aGVHD. Our analysis focused on defining the functional kinetics of TCR clones, monitoring changes in overall T-cell diversity through the identification of complementarity-determining region 3 (CDR3) sequences, and quantifying the extent of clonal expansion within the T-cell population.ResultsOur analysis revealed that TCR repertoires exhibited significantly increased diversity in patients with active aGVHD compared to those without. Notably, this elevated diversity was dynamic and decreased as the symptoms of aGVHD improved clinically. Furthermore, TCR clustering analysis identified the presence of common TCR repertoire signatures among different patients who developed aGVHD, suggesting shared antigen-driven T cell responses.DiscussionThe dynamic changes and shared signatures within the TCR repertoire are closely associated with the development and resolution of aGVHD. These findings indicate that monitoring the TCR repertoire could serve as a valuable tool for predicting the onset of aGVHD. This approach holds promise for facilitating more personalized diagnostic and treatment strategies for aGVHD, and potentially for other T-cell-mediated pathologies.

Acquired pure red cell aplasia (aPRCA) is rare and challenging to treat. We investigated the efficacy and safety of sirolimus plus roxadustat in patients with aPRCA (Chinese Clinical Trial Register number, ChiCTR2200065107). We enrolled 82 patients with aPRCA in this prospective single-arm, open-label, multicenter trial between October 2022 and January 2024. Treatment response and safety files were evaluated. The median age was 63 years. Seven patients withdrew during the trial period. Sirolimus plus roxadustat produced an overall response (OR) in 65 patients (90.3%) 3 months after initiation, which included a complete response (CR) in 39 (54.2%) and a partial response in 26 (36.1%). The 3-month CR rate was significantly higher in the newly diagnosed group (65.9% vs. 38.7%; P = 0.022). The 6-month OR rate in the entire cohort was 93.0% (CR, 77.5%; PR, 15.5%). The mean hemoglobin concentration increased from 5.5 ± 1.6 g/dL at baseline to 11.6 ± 2.5 g/dL after 6 months of treatment. The proportions of patients who achieved transfusion independence within 1, 2, and 3 months of treatment were 57.4%, 76.6%, and 89.5%, respectively. The Functional Assessment of Chronic Illness Therapy-Fatigue Scale score and SF-36 survey score significantly improved after treatment. Treatment-related adverse events occurred in 24 patients (29.2%), and four events (4.9%) were grade ≥3. Sirolimus plus roxadustat is a promising treatment for aPRCA and has an acceptable safety profile, which warrants further investigation in a randomized setting.

Colon cancer remains a therapeutic challenge due to limited efficacy of current treatments. This study investigates the synergistic antitumor effects of cordycepin combined with CTLA-4 inhibitors, focusing on their ability to reshape the gut microbiome. By integrating multi-omics approaches, we elucidate the mechanisms underlying the enhanced efficacy of this triple therapy. Our findings reveal that cordycepin combined with CTLA-4 inhibitors significantly improves antitumor efficacy in the MC38 colon cancer mouse model. This enhancement is mediated by the critical role of the Eubacterium brachy group in modulating the tumor immune microenvironment. Based on these results, we propose a "microbiome-immune" triple therapy strategy involving cordycepin, CTLA-4 inhibitors, and Eubacterium rectale. Non-targeted metabolomics analysis using LC-MS identified specific activation of the histidine metabolism pathway, with elevated levels of the key metabolite Cetirizine N-Oxide potentially contributing to enhanced immune activity. Single-cell transcriptomic analysis demonstrated that the triple therapy significantly increased the responsiveness of tumor antigen-specific CD8+ T cells to CTLA-4 inhibitors, thereby boosting their antitumor activity. Moreover, the triple therapy not only enhanced the antitumor functionality of conventional effector CD4+ T cells but also effectively prevented their exhaustion. Mechanistic studies further revealed that the triple therapy suppresses the activity of the Bcl6 regulatory network, thereby reducing the immunosuppressive function of Tregs and destroying the immunosuppressive interplay between myeloid immune cells and Tregs. These results demonstrate a promising "microbiome-immune" dual-targeting strategy for colon cancer with clinical translational potential.

ABSTRACT Objectives Studies on the efficacy and safety of haploidentical hematopoietic stem cell transplantation (haplo‐SCT) with anti‐thymocyte globulin (ATG) in patients aged ≥ 60 years remain limited. Methods We performed a study presenting data from 54 patients aged ≥ 60 years with hematologic malignancies who underwent haplo‐SCT with ATG. Results The median follow‐up was 15 months. The median overall survival (OS) at 1‐, 2‐, and 3‐year was 68.4%, 51.2%, and 47.6%, respectively. The cumulative incidence of non‐relapse mortality (NRM) at 1 and 3 years post haplo‐SCT was 22.9% and 34.8%, respectively. The cumulative incidence of 1‐ and 3‐years relapse rate was 11.3% and 25.6%. The 100‐day cumulative incidence of Grade II–IV acute graft‐versus‐host disease (aGvHD) was 23.1%, while the 3‐year cumulative incidence of extensive chronic graft‐versus‐host disease (cGvHD) was 10.4%. The absence of complete remission at the time of haplo‐SCT was identified as a risk factor for OS, relapse, and NRM. Conclusions Our study suggests that haplo‐SCT with ATG is a safe and effective treatment option for patients aged ≥ 60 years. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.

Epstein-Barr virus (EBV) reactivation is a common complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly in patients receiving high-dose anti-thymocyte globulin (ATG)-containing conditioning regimens. If left untreated, EBV reactivation may progress to post-transplant lymphoproliferative disorder (PTLD), a life-threatening condition. While preemptive therapy with the standard dose of rituximab (RTX), 375 mg/m², is recommended for EBV-related complications, such a high dose may be unnecessary in post-transplant settings where the total lymphocyte mass is significantly reduced compared to lymphoma conditions. This retrospective study assessed the efficacy and safety of fixed low-dose RTX (100-200 mg per dose) as an exploratory dose de-escalation preemptive therapy for low-load EBV DNA-emia (<10,000 copies/mL) occurring within four months post-transplantation. Among 83 high-risk patients, RTX achieved a high EBV clearance rate of 93.9% (95% CI: 88.6%-99.2%), with comparable effectiveness observed between the 100 mg and 200 mg dosage groups. Viral clearance was rapid, with most patients becoming EBV-DNA negative after 1 to 2 doses. RTX was well tolerated, with no treatment discontinuations due to adverse events. Despite preemptive RTX, four patients (5%) developed PTLD, which aligns with previously reported rates in similar populations. At a median follow-up of 41.6 months, the 3-year overall survival (OS) rate was 67.7%, with no significant differences in OS, relapse, or nonrelapse mortality between the two dosage cohorts. These findings suggest that a fixed low-dose RTX regimen, as an exploratory dose de-escalation strategy, is safe, effective, and well-tolerated for the preemptive management of low-load EBV DNA-emia in allo-HSCT recipients. While these results are hypothesis-generating, they indicate rapid viral clearance and favorable long-term outcomes, warranting further validation in comparative studies.

This study aimed to develop a predictive nomogram model and to validate the value of tear interleukin-6 (IL-6) detection using the i-ImmunDx™ platform combined with ocular surface signs for the early diagnosis of ocular graft-versus-host disease (oGVHD). A total of 79 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at the Fourth Affiliated Hospital of Soochow University from November 2021 to July 2024 were enrolled. They were randomly divided into a training set (49 cases) and a validation set (30 cases). Tear inflammatory factors in the training set were detected using flow cytometric bead array (CBA), while the validation set was analyzed with the i-ImmunDx™ system. Ocular surface signs, including lid margin hyperemia, lid margin irregularity, meibomian gland obstruction, meibum quality and conjunctival lesion were recorded for all patients. Stepwise logistic regression identified ln(IL-6), lid margin hyperemia, lid margin irregularity, and meibomian gland obstruction as significant predictors associated with oGVHD. A nomogram model was constructed based on these factors. The model’s performance was evaluated using receiver operating characteristic (ROC) curves, Hosmer-Lemeshow tests, and decision curve analysis (DCA). The area under the curve (AUC) values for the training and validation sets were 0.93 (95

PurposeTo investigate the outcome of single amniotic membrane transplantation (AMT) in the treatment of corneal melting associated with ocular graft-versus-host disease (oGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT), and to explore the correlative risk factors.MethodsA retrospective case series study. Data of 303 patients with oGVHD were reviewed, and cases of corneal melting undergoing AMT were collected. Patients were divided into the single-AMT success group and the single-AMT failure group according to the recurrence of corneal melting within 6 months after receiving the initial AMT. The preoperative ocular assessments (including corneal fluorescence staining, conjunctival congestion, lid margin lesion score, and corneal optical coherence tomography) and characteristics related to HSCT were compared between the two groups.ResultsA total of 31 patients were enrolled in this retrospective study, comprising 21 males (67.74%). At 6 months after the initial AMT, 21 cases achieved corneal healing, while corneal melting recurred in 10 cases. There were no differences in the primary disease and donor sources between the single-AMT success group and the failure group. The incidence of lung GVHD in the failure group was higher than that in the success group (OR = 8.021, 95% CI: 1.379 to 64.902, p = 0.020).ConclusionAmniotic membrane transplantation can be used as a treatment for oGVHD-related corneal melting. Lung GVHD may be associated with the failure of single AMT surgery. It is recommended to strengthen postoperative immune regulation and follow-up management.

Bronchiolitis obliterans syndrome (BOS) is a severe pulmonary complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), with early prediction being crucial. While pulmonary function tests (PFTs) are fundamental for BOS assessment, the predictive value of pretransplant PFT results remains uncertain. In this study involving allo-HSCT recipients with hematologic malignancies who survived over 100 days post-HSCT, we aimed to determine the predictive significance of pretransplant PFTs for BOS. Data from 742 eligible patients were randomly divided into training and validation cohorts, and machine learning algorithms were employed for feature engineering, feature selection, and modeling. Principal component analysis (PCA) was utilized to reduce the dimensionality of PFT parameters. Over a median follow-up of 573.5 days, 57 patients developed BOS, with a median interval of 269 days from transplantation to BOS onset. Our multivariate logistic regression (MLR) model, incorporating the first principal components of PCA-treated PFT results along with age, sex, and previous nonpulmonary chronic graft-versus-host disease (GvHD), demonstrated discriminant AUC values of 0.671 (95 % CI, 0.522-0.820) and 0.669 (95 % CI, 0.588-0.751) in the validation and training sets, respectively. Pretransplant PFT results emerged as pivotal in predicting BOS risk post-allo-HSCT. The MLR model, developed through data-driven machine learning, effectively identifies high-risk BOS populations at an early stage.

BACKGROUD:Neonatal necrotizing enterocolitis (NEC) is a severe intestinal disease potentially linked to gut microbiota dysbiosis. This prospective observational study aimed to evaluate the role of dysbiosis in NEC development. METHOD:We included preterm infants with a birth weight <1500 g or gestational age <32 weeks, admitted to Shanghai Children's Hospital from April 9, 2019, to March 30, 2023. Stool samples were prospectively collected and preserved. Cases were infants meeting Bell's stages 2 or 3 criteria for NEC, while controls were matched by gestational age, birth weight, delivery mode, and birth date. Fecal DNA was amplified and pyrosequenced using 16S rRNA gene primers. RESULTS:We analyzed 370 stool samples from 74 infants (37 NEC cases and 37 controls). Microbial composition in NEC cases differed significantly from controls. Firmicutes abundance began to decline in the case group from the third week of life. At NEC onset, Proteobacteria abundance (p = 0.0001) and the Bacteroidetes/Firmicutes (B/F) ratio (p = 0.006) were significantly higher in cases. A significant increase in the B/F ratio was noted one week before NEC onset (p = 0.02). ROC curve analysis showed an AUC of 0.77; a B/F ratio >0.0439 yielded 81 % specificity and 82 % sensitivity. CONCLUSION:An elevated B/F ratio was observed before NEC onset, suggesting it may serve as a predictive biomarker and potential target for NEC prevention.

Pathogen-induced septic death presents a substantial public health challenge, with its neuroimmune mechanisms largely unexplored. Our study investigates neurotransmitter modulation of ACOD1 expression, a regulator of immunometabolism activated by bacterial lipopolysaccharide (LPS). Screening neurotransmitters identifies dopamine as a potent inhibitor of LPS-induced ACOD1 expression in innate immune cells. Mechanistically, DRD2 forms a complex with TLR4, initiating MAPK3-dependent CREB1 phosphorylation and subsequent ACOD1 transcription. Conversely, dopamine disrupts TLR4-MYD88 interaction via DRD2 without affecting the formation of the LPS-induced TLR4-MD2-CD14 complex. Enhanced ACOD1 expression induces CD274/PD-L1 production independently of itaconate, precipitating inflammation-associated immunosuppression in sepsis. Delayed administration of pramipexole, a dopamine agonist, mitigates lethality in bacterial sepsis mouse models. Conversely, the dopamine antagonist aripiprazole exacerbates sepsis mortality. Dysregulation of the dopamine-ACOD1 axis correlates with sepsis severity in patients, indicating a potential therapeutic target for modulating this neuroimmune pathway.

Chronic graft-versus-host disease (cGVHD) is a major complication for long-term survivors after hematopoietic cell transplantation (HCT). Bronchiolitis obliterans syndrome (BOS) is the crucial manifestation of lung cGVHD. Ruxolitinib has been approved by the Food and Drug Administration (FDA) for cGVHD treatment, but the response for BOS has not been sufficiently evaluated. We conducted a multicenter study involving 125 patients diagnosed with BOS post-HCT who received second-line therapies, including 77 patients treated with ruxolitinib (ruxolitinib group) and 48 patients with non-ruxolitinib therapies (control group). The primary endpoint was progression of BOS. By the third month, 18.2

Although significant progressions in antiviral studies of IFNβ have been demonstrated, the role of the proteasome in modulating cross-talk between TBK1-IFNβ signaling and viral replication during viral infection is not fully elucidated. Here, we discover that deficiency of REGγ, a proteasome activator, significantly reduces IFNβ production and increases viral replications in mice, leading to increased mortality in virus infection models. Our mechanistic study indicates that REGγ interacts with and degrades the protein phosphatase subunit Protein Phosphatase 2 Catalytic Subunit Beta (PPP2CB). This degradation disrupts the dephosphorylation of TBK1 and its interaction with IRF3, resulting in the activation of IFNβ-mediated antiviral signaling. In response to viral infection, up-regulation of REGγ in macrophages accelerates the degradation of PPP2CB, which increases the activation of TBK1-IRF3-IFNβ axis and thereby restricts viral replications and pathology. Interestingly, IFNβ enhances REGγ expression in viral infection, forming a positive feedback regulatory loop. In conclusion, our work demonstrates that REGγ is a positive modulator of IFNβ signaling during antiviral response, highlighting that this procedure is regulated via REGγ degradation of PPP2CB and provides a new insight into the coordination between antiviral response and proteasome activity. Thus, REGγ-proteasome activity and phosphatase PPP2CB may be potential targets in host defense against viruses.

BACKGROUND:It has been revealed that carbapenem-resistant Klebsiella pneumoniae (CRKP) colonization is closely associated with subsequent clinical infections. This study aimed to investigate the resistance and epidemiology of CRKP isolated from anal swabs and subsequent clinical infection specimens in two pediatric intensive care unit (ICU) departments. Clinical characteristics were analyzed to identify the risk factors of CRKP infection. METHODS:A 3-year retrospective study was carried out in pediatric intensive care units (PICU) and neonatal intensive care units (NICU). CRKP isolates from colonization and infection samples were characterized by testing resistance genes and multilocus sequence typing (MLST). The results of MLST were analyzed to derive CCs by Bionumeric 8.0. Clinical variables such as gestational age, birth weight, mode of delivery, underlying diseases, exposure of antimicrobial agents, history of surgery, length of hospital stay, and prognosis were collected through the electronic medical record system and analyzed by SPSS 22.0. RESULTS:Of the 2225 patients who were screened for CRE colonization, 7.42% of patients were detected positive. The incidence of subsequent infection was 18.18%. Carbapenemase genes blaKPC-2 and blaNDM-1 were the most prevalent in the colonization and infection of CRKP. The majority of CRKP isolated from anal swabs and infection samples belonged to CC11/ST11. The distribution of CC11 in the PICU was significantly higher than in NICU. ST11/blaKPC-2 was significantly higher in infection CRKP isolates. Age older than one year and usage of carbapenems within 3 months prior to detection of CRKP colonization were independent risk factors for CRKP clinical infection. CONCLUSION:The main prevalence of CRKP varies in different departments. Colonization of ST11/blaKPC-2 CRKP may increase the incidence of subsequent infections in pediatric ICU patients. Age and usage of carbapenems could increase the risk of CRKP infection in this study.

Objective This study was to investigate the clinical features of hematological disorders complicated by invasive pulmonary fungal infections and identify factors affecting treatment outcomes, with the aim of developing a predictive model. Methods Clinical data were collected from patients with hematological disorders and invasive pulmonary fungal infections between January 2020 and June 2023. Based on metagenomics next generation sequencing (mNGS) of bronchoalveolar lavage fluid (BALF), patients were categorized into three groups: Candida, Mucor, and Aspergillus. General conditions, clinical features, treatments, and outcomes were compared. Treatment outcomes were assessed two months after therapy and classified as either improved or not improved. Factors influencing outcomes were analyzed, and a risk prediction model for treatment failure was developed. Results A total of 89 patients with hematological diseases and invasive pulmonary fungal infections were included: 26 with Candida, 25 with Mucor, and 38 with Aspergillus. Significant differences were observed between groups in long-term corticosteroid use, hematological disease outcomes, neutropenia duration, treatment duration, central venous catheter placement, galactomannan (GM) test results, CD4+ T-cell count, and clinical manifestations. After two months of antifungal therapy, improvement rates were 96.15 % for Candida, 76.00 % for Mucor, and 63.16 % for Aspergillus. Logistic regression analysis identified elevated platelet count (OR = 0.9823, 95%CI: 0.9663–0.9945), D-dimer (OR = 1.2130, 95%CI: 1.0544–1.4934), C-reactive protein (OR = 1.0066, 95%CI: 1.0026–1.0111) and medication adjustments based on mNGS results (OR = 0.0495, 95%CI: 0.0108–0.1624) as significant prognostic factors. A nomogram prediction model based on these factors demonstrated good discrimination with a C-index of 0.86. Conclusion The clinical features and treatment outcomes differ among fungal types in patients with hematological disorders and invasive pulmonary fungal infections. The nomogram prediction model, incorporating platelet count, D-dimer, C-reactive protein and mNGS-guided therapy adjustments, offers robust predictive performance for two-month treatment outcomes.

Patients with seasonal allergic rhinitis (SAR) usually seek treatment when symptoms become unbearable during the pollen season. It remains unclear whether initiating sublingual immunotherapy (SLIT) during the pollen season affects patients’ safety. This study aims to compare the tolerability of initiating Artemisia annua SLIT during the pollen season versus before the season. Ninety patients with Artemisia-induced SAR were recruited and equally randomized into the coseasonal initiation treatment (COS-SLIT) group and the preseasonal initiation treatment (PRE-SLIT) group. The COS-SLIT group started SLIT when allergic symptoms occurred during the 2022 pollen season, while the PRE-SLIT group began SLIT four months before the expected season in 2022. Patients were categorized as mild symptoms or moderate-severe symptoms group based on the level of visual analog scale (VAS) scores evaluated during the 2021 pollen season. The incidence, frequency, performance, and alleviating measures of adverse events (AEs) were analyzed after the up-dosing phase (5 weeks), at three months (13 weeks), six months (26 weeks), and twelve months (52 weeks). A total of 72 patients (32 patients in the COS-SLIT group and 40 patients in the PRE-SLIT) were included in the analysis. Among these patients, 33 reported a total of 78 AEs. No significant difference was found in the frequency and number of patients experiencing AEs between the COS-SLIT and PRE-SLIT groups during the four follow-up periods (all p > 0.05). There were no significant differences in the symptoms or alleviating measures of AEs between the two groups in general (all p > 0.05). Furthermore, the most common AEs in the COS-SLIT group were nasal symptoms (n = 14), lip edema (n = 10), and cough (n = 4), while in the PRE-SLIT group were nasal symptoms (n = 12), lip edema (n = 8), and ocular pruritus (n = 6). Symptomatic drugs were the most common alleviating measures in both groups (61.29

Sepsis is a life-threatening condition characterized by a dysregulated host innate immune response to pathogen infection. Here, we identify a pathological role for bromodomain-containing 3 (BRD3) in driving septic shock by upregulating aconitate decarboxylase 1 (ACOD1) in monocytes and macrophages via a non-canonical pathway. Mechanistically, lipopolysaccharide triggers an interaction between BRD3 and tripartite motif containing 21 (TRIM21), which activates CREB binding lysine acetyltransferase (CREBBP) via its E3 ligase activity, facilitating CREBBP's binding to and acetylation of cyclic adenosine monophophate (cAMP)-response-element-binding protein 1 (CREB1). BRD3 then recognizes and phosphorylates acetylated CREB1 at the transcription-activating site, thereby upregulating ACOD1 transcription. In four murine models of infection, myeloid-specific Brd3 deletion (Brd3Mye-/-) or pharmacological intervention using small-molecule inhibitor OTX015 confers significant protection, reducing systemic inflammation and organ injury, similar to the effects observed in Acod1Mye-/- mice. In patients with sepsis, elevated BRD3 levels correlate with accelerated inflammation, increased disease severity, and a greater risk of in-hospital death. These findings establish BRD3 as a potential therapeutic target for managing infection-associated immune dysregulation.