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关键词： Actinobacillus pleuropneumoniae   Amyloid precursor protein   CpxAR   IL-1β   Lipopolysaccharide   Porcine alveolar macrophage   β-Amyloid  

摘要： Actinobacillus pleuropneumoniae (A. pleuropneumoniae), a porcine respiratory tract pathogen, causes porcine pleuropneumonia. Porcine alveolar macrophages (PAMs) play a crucial role during A. pleuropneumoniae infection. Amyloid precursor protein (APP) can be cleaved by β- and γ-secretase to produce β-amyloid (Aβ). APP and Aβ are associated with the inflammatory response. They activate microglia and astrocytes to secrete IL-1β, IL-6, and other cytokines. In this study, we found that during the interaction between A. pleuropneumoniae and PAMs, the two-component system CpxAR upregulates wecA expression, increasing lipopolysaccharide (LPS) production. LPS promotes APP production and cleavage to generate Aβ. The Aβ activates NF-κB, leading to increased IL-1β expression. We hypothesize that A. pleuropneumoniae infection of PAMs regulates APP production and cleavage to control Aβ levels. Different quantities of Aβ induce PAMs to produce varying amounts of cytokines, leading to different pathological processes in porcine pleuropneumonia.

关键词： APML   Cryptic PML::RARA fusion   HLA-DR  

摘要： We report the case of a 42-year-old female presented with cytopenia and abnormal promyelocytes on blood film. The promyelocytes were HLA-DR positive by flow cytometry. The rapid FISH for PML::RARA was negative. Myeloid NGS identified PML::RARA fusion, which was confirmed by molecular karyotyping and PCR. She was treated with ATRA and ATO to complete molecular remission. This case highlighted the importance of using rapid RNA sequencing to identify cryptic fusion and rare fusions and combining morphologic, immunophenotypic, cytogenetic and molecular analyses to ensure correct diagnosis and optimal management.

摘要： T cell priming is characterized by an initial activation phase that involves stable interactions with dendritic cells (DCs). How activated T cells receive the paracrine signals required for their differentiation once they have disengaged from DCs and resumed their migration has been unclear. We identified a distinct priming phase that favors CD8 T cells expressing receptors with high affinity for antigen. CXCR3 expression by CD8 T cells was required for their hours-long reengagement with DCs in specific subfollicular niches in lymph nodes. CD4 T cells paused briefly at the sites of CD8 T cell and DC interactions and provided Interleukin-2 (IL-2) before moving to another DC. Our results highlight a previously unappreciated phase of cell-cell interactions during T cell priming and have direct implications for vaccinations and cellular immunotherapies.

摘要： The immune system plays a major role in the regulation of adipose tissue homeostasis. Viral infection often drives fat loss, but how and why this happens is unclear. Here, we show that visceral adipose tissue transiently decreases adiposity following viral infection. Upon pathogen encounter, adipose tissue upregulates surface expression of ligands for activating receptors on natural killer cells, which drives IFNγ secretion. This cytokine directly stimulates adipocytes to shift their balance from lipogenesis to lipolysis, which leads to release of lipids in circulation, most notably of free fatty acids. The free fatty acid oleic acid stimulates early-activated B cells by promoting oxidative phosphorylation. Oleic acid promoted expression of co-stimulatory B7 molecules on B cells and promoted their ability to prime CD8 T cells. Inhibiting lipid uptake by activated B cells impaired CD8 T cell responses, causing an increase of viral replication in vivo. Our findings uncover a previously unappreciated mechanism of metabolic adaptation to infection and provide a better understanding of the interactions between immune cells and adipose tissue in response to inflammation.

关键词： Cellular crosstalk   Chronic kidney diseases   Local interstitial acidosis   Local inflammation   IL-6 effects   p38-signaling  

摘要： BACKGROUND:Local interstitial acidosis in chronic kidney disease (CKD) induces inflammatory responses and dedifferentiation of proximal tubule cells (PTCs), disrupting cellular crosstalk through cytokine and COX-2 metabolite secretion. This promotes a switch to an inflammatory fibroblast phenotype, further exacerbating inflammation and PTC dedifferentiation. p38-signaling and downstream transcription factors, including P-CREB and c-fos, contribute to these responses. This study investigates the impact of acidosis on inflammatory responses in PTCs and fibroblasts, focusing on cellular crosstalk and the role of p38-signaling. METHODS:HK-2 (human PTCs) and CCD-1092Sk (human fibroblasts) were exposed to acidic or control media in mono- and coculture for 30 min, 3 h, or 48 h. Protein expression of IL-6, phosphorylated (P-) and total CREB, P- and total SRF, c-fos, and P- and total p38 was analyzed by western blot. IL-6 secretion was measured using ELISA. The impact of p38 and IL-6 receptor activity was assessed by pharmacological intervention. RESULTS:In coculture, acidosis initially caused a transient decrease in IL-6 secretion but significantly increased IL-6 levels after 48 h. Acidosis induced intracellular IL-6 expression in HK-2 cells within 3 h independent of culture conditions, with sustained IL-6 protein increase after 48 h only in coculture. Acidosis also enhanced P-CREB and c-fos expression in coculture during the first 3 h. Regardless of culture conditions, acidosis increased IL-6, c-fos, and P-SRF expression in CCDSK cells after 48 h. P-CREB and COX-2 expression were elevated in CCDSK in coculture. Acidosis-mediated effects on IL-6, P-CREB, and P-SRF expression were p38-dependent in both cell lines. Finally, we assessed the pH-dependency of IL-6 action and found that IL-6 addition increased COX-2 expression via the IL-6 receptor in acidic but not control media. Thus, acidosis enhances IL-6 secretion and potentiates its receptor-mediated biological effects. CON

关键词： CD8+ T cell   HLA transgenic rabbit   HSV-1   herpes   ocular   prime/pull/keep vaccine  

摘要： Herpes simplex virus type 1 (HSV-1) continues to be one of the most prevalent viral infections globally, with approximately 3.72 billion individuals affected worldwide. A clinical herpes vaccine is still lacking. In the present study, a novel prime/pull/keep vaccine was tested in a human leukocyte antigen transgenic rabbit model of ocular herpes (HLA-A*0201 Tg rabbit). Ten asymptomatic (ASYMP) CD8(+) T-cell peptide epitopes and 3 CD4(+) T-cell epitopes were selected from the HSV-1 glycoproteins D and B (gD and gB), viral tegument proteins (VP11/12 and VP13/14), and the DNA replication-binding helicase (UL9), all preferentially recognized by CD8(+) and CD4(+) T cells from "naturally protected" HSV-1-seropositive healthy ASYMP individuals (who never had recurrent corneal herpetic disease). HLA Tg rabbits were ocularly infected with HSV-1, then during latency at day 30 post-infection, the rabbits were ocularly vaccinated with a recombinant neurotropic AAV8 vector (10(7)GC/ eye) encoding for the 10 CD8(+) T-cell peptide and 4 CD4(+) T-cell peptide (prime), T-cell attracting CXCL-11 (pull), and T-cell keeping IL-2/IL-15 cytokines (keep). The rabbits were followed up for corneal disease and viral loads in tears for 28 days. The frequency, function, and protective efficacy of HSV-specific CD8(+) T cells induced by the prime/pull/keep vaccine were assessed in the trigeminal ganglia (TG), cornea, spleen, and peripheral blood. Compared to the mock group (unvaccinated), the peptides/CXCL11/IL-2/IL-15 vaccine generated frequent resident CD8(+) T cells that infiltrated the TG. In ocularly HSV-1-infected and prime/pull/keep vaccinated rabbits, CD8(+) T cell mobilization and retention into TG were associated with a significant reduction in corneal herpes infection and disease. These findings draw attention to the novel prime/pull/keep therapeutic vaccine strategy to mobilize and retain antiviral T cells to tissues protecting them against herpetic infection and disease.

关键词： IL-17   anastomotic leakage   intraoperative hypothermia   rectal cancer   risk factor  

摘要： OBJECTIVE:In this prospective observational cohort study, we aim to investigate the risk factors for early postoperative anastomotic leakage (AL) in patients undergoing rectal cancer resection. METHODS:This study included 459 patients with rectal cancer who underwent treatment at our hospital from January 2021 to October 2022. All patients were hospitalized for 1 week postoperatively and observed for the occurrence of AL. Fasting venous blood samples (5 mL) were collected from all cases 1 day before surgery and 1, 2, and 3 days after surgery, and serum levels of interleukins (IL)-17, IL-6, IL-1β, tumor necrosis factor-α, and C-reactive protein (CRP) were determined using enzyme-linked immunosorbent assay. Demographic, clinical data, intraoperative hypothermia, and nutritional indicators were collected for all patients. Statistical analysis was performed using SPSS 25.0 software. RESULTS:AL patients had significantly lower hemoglobin, albumin (ALB) levels, and a higher proportion of intraoperative hypothermia compared to patients in the non-AL group (P < .05). On the first, second, and third days after surgery, patients in the AL group had significantly higher levels of serum CRP, IL-1β, and IL-17 compared to the non-AL group. Pearson's correlation analysis showed a positive correlation between serum IL-17 levels and CRP levels. Serum IL-17 had the highest predictive value for early AL, with an area under the curve (AUC) of 0.755 cutoff value of 94.77 pg/mL, a sensitivity of 70.1%, and a specificity of 66.0%. Moreover, logistic regression analysis indicated that intraoperative hypothermia, decreased ALB levels, and increased CRP, IL-1β, and IL-17 levels on the first day after surgery were identified as risk factors for early AL in rectal cancer patients. CONCLUSIONS:This study found a significant elevation of IL-17 levels in the serum of patients who experienced early postoperative AL. Furthermore, intraoperative hypothermia and elevated IL-17 levels on the first day

关键词： Aortic dissection/aneurysms   Inflammation   Mitochondrial uncoupling proteins 1   Phenotype switching   TLR4/NLRP3/IL-1β signaling pathway  

摘要： Thoracic aortic aneurysms and dissection (TAAD) is a life-condition associated with high morbidity and mortality. Research has proven that inflammation contributes to the progression of TAAD. Mitochondrial uncoupling protein 1 (UCP1) can inhibit the release of inflammatory factors in perivascular adipose tissue (PVAT), regulate fat and inflammation, to confer vascular protection. However, whether UCP1 can ameliorate TAAD has not been clarified. In this study, aortas were harvested from organ donors and TAAD patients to explore the expression of UCP1 and Toll-like receptor 4 (TLR4)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/interleukin-1β (IL-1β) signaling pathway. Meanwhile, in vitro and in vivo models of TAAD were constructed to clarify the impact of UCP1 expression on VSMCs and TAAD. UCP1 expression was significantly downregulated and the TLR4/NLRP3/IL-1β signaling pathway was activated in TAAD in vivo. Moreover, UCP1 inhibited the migration, invasion, apoptosis, and phenotype switching of VSMCs in vitro. UCP1 significantly blocked the β-aminopropionitrile (BAPN)-induced TAAD formation and rupture in mice, suppressed aortic dilation, elastic fiber fragmentation, and apoptosis in the aorta. It also activated the TLR4/NLRP3/IL-1β signaling pathway to alleviate aortic inflammation and prevent the degradation of systolic phenotype proteins and phenotype switching of VSMCs. These effects suggest that UCP1 may inhibit TAAD formation by blocking the TLR4/NLRP3/IL-1β signaling pathway and VSMC phenotype switching.

关键词： IL‐1β   TLR7 agonist   cholesterolized liposome   combination therapy   immunotherapy   inflammasome   oxidized mitochondrial DNA   radiotherapy  

摘要： BACKGROUND:Radiotherapy (RT) is a key treatment modality in cancer therapy, utilizing high-energy radiation to directly kill tumor cells. Recent research has increasingly highlighted RT's potential to indirectly enhance antitumor immunity. However, this immune activation alone often fails to generate sustained systemic antitumor responses. In this study, we aimed to investigate the antitumor effects of combining cholesterolized toll-like receptor 7 (TLR7) agonist liposomes, specifically 1V209-Cho-Lip, with RT. METHODS:Mouse tumor models were used to assess the impact of combining 1V209-Cho-Lip with RT on tumor progression and modification of the tumor microenvironment. In vitro, primary mouse bone marrow-derived dendritic cells (BMDCs) were utilized to investigate changes in function and the activated pathways through RNA sequencing. Additionally, we explored the role of oxidized mitochondrial DNA (ox-mtDNA) released from irradiated tumor cells as a damage-associated molecular pattern in modulating immune responses. The involvement of interleukin-1β (IL-1β) and the inflammasome pathway in the antitumor efficacy of the combined treatment was evaluated using Il-1β and cysteinyl aspartate specific proteinase 1 knockout (Casp1) mouse models. RESULTS:The combination of 1V209-Cho-Lip and RT significantly inhibited tumor growth and induced antitumor immunity in tumor models. This combination therapy enhanced maturation, antigen presentation and IL-1β secretion of dendritic cells (DCs) in vitro. Ox-mtDNA released from irradiated tumor cells synergized with 1V209-Cho-Lip to activate the inflammasome pathway in DCs. The antitumor effect of the combined therapy was significantly reduced in Il-1β and Casp1 mice. CONCLUSIONS:This study suggests that the combination of 1V209-Cho-Lip with RT might be a promising antitumor strategy and further studies are warranted to explore the clinical relevance of this combination therapy.

关键词： IL-4Rα monoclonal antibody   Pharmacokinetics   Phase I   Population pharmacokinetic model   Safety   TQH2722  

摘要： The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics (PK) of TQH2722, an Interleukin-4 receptor alpha (IL-4Rα) monoclonal antibody, in healthy subjects. In this randomized, double-blind and placebo-controlled trial, TQH2722 was subcutaneously injected as single-ascending dose (n = 46; 50, 150, 300, 600 and 1200 mg) or multiple-ascending dose (n = 20; 150 and 600 mg; four doses every 2 weeks). Subjects were monitored for adverse events and blood samples were collected for pharmacokinetics. A population pharmacokinetic model was developed and validated. TQH2722 was well tolerated with no serious or severe adverse events observed. After a single dose, the maximum concentration occurred at 3-7 days, with t ranged from 2.65 to 17.43 days. Four repeated dosing caused about 3-fold degree of accumulation for C and AUC. Regardless of single or multiple doses, the exposure showed a nonlinear and greater than dose proportional increase. A two-compartment model taking into account the mechanistic target-mediated drug disposition process with parallel linear and nonlinear Michaelis-Menten (MM) elimination and first-order absorption well described the pharmacokinetics of TQH2722. In conclusion, TQH2722 was safe and well tolerated, and its PK profiles were well characterized, supporting its further clinical development in patients.