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关键词： Cancer immunotherapy   Coagulation   Immunology   Oncology   Platelets   Vascular biology  

摘要： Malignancies increase the risk for thrombosis and metastasis dependent on complex interactions of innate immune cells, platelets, and the coagulation system. Immunosuppressive functions of platelets and macrophage-derived coagulation factors in the tumor microenvironment (TME) drive tumor growth. Here we show that patients with malignancies and tumor-bearing mice have increased levels of coagulation factor (F) X expressing circulating monocytes engaged in platelet aggregate formation. This interaction and resulting thrombin generation on platelets interferes with monocyte differentiation and antigen uptake of antigen-presenting cells (APCs). Myeloid cell-specific deletion of FX or abrogated FXa signaling via protease activated receptor 2 (PAR2) averts the suppressive activity of platelets on tumor cell debris uptake and promotes the immune stimulatory activity of APCs in the TME. Myeloid cell FXa-PAR2 signaling deficiency specifically enhances activation of the cGAS-STING-IFN-I pathway with a resulting expansion of antigen experienced progenitor exhausted CD8+ T cells. Pharmacological blockade of FXa with direct oral anticoagulants expands T cell priming-competent immune cells in the TME and synergizes with the reactivation of exhausted CD8+ T cells by immune checkpoint inhibitors for improved anti-tumor responses. These data provide mechanistic insights into the emerging clinical evidence demonstrating the translational potential of FXa inhibition to synergize with immunotherapy.

关键词： AIRE gene   CD40 gene   HLA-DRB1 gene   polymorphism   rheumatoid arthritis   TRAF1/C5 gene  

摘要： The main objective of the study was to determine the association of genes AIRE (rs2075876), CD40 (rs4810485), HLA-DRB1 (rs6457617) and TRAF1/C5 (rs10818488) polymorphisms with rheumatoid arthritis (RA) from the population of Pakistan. Blood samples of 300 RA patients and 300 healthy controls were taken from different hospitals in Pakistan. Extraction of DNA was carried out;a specific region of DNA was amplified using PCR. Polymorphic analysis was performed for genes AIRE (rs2075876), CD40 (rs4810485), HLA-DRB1 (rs6457617) and TRAF1/C5 (rs10818488). The demographic parameters, like age, showed statistically significant association and increased the risk of the disease up to 2-fold (odds ratio [OR] = 2.57;95% confidence interval [CI] = 1.60-4.12;p = 0.0001). Gender and family history did not show any significant association with arthritis (OR = 1.12;95% CI = 0.69-1.81;p = 0.6260;OR = 0.70;95% CI = 0.44-1.11;p = 0.1313, respectively). In the case of smoking status, the difference was statistically significant for both smokers and non-smokers. In smokers, there was a decreased risk of RA (OR = 0.45;95% CI = 0.28-0.73;p = 0.0011), and in non-smokers, there was an increased risk of disease up to 2-fold (OR = 2.17;95% CI = 1.36-3.47;p = 0.0011). In AIRE gene, heterozygous (AG) of rs2075876 showed a highly significant association with increased risk of RA up to 3-fold (OR = 3.39;95% CI = 2.08-5.54;p = 0.0001), whereas homozygous mutant (GG) also showed significant association (OR = 0.43;95% CI = 0.26-0.72;p = 0.0014) but with decreased risk. In CD40 gene, heterozygous (AG) of rs4810485 showed significant association with a decreased risk of RA (OR = 0.59;95% CI = 0.377-0.945;p = 0.027), whereas the homozygous mutant (GG) of rs4810485 showed highly significant association by increasing risk of up to 4-fold (OR = 4.318;95% CI = 2.553-7.303;p = 0.0001). In HLA-DRB1 gene, heterozygous (CT) of rs6457617 showed significant association with a decreased risk of disease (OR = 0.52;9

关键词： IL-15   NK cell   NKp30   TriKE   Tumor immunotherapy  

摘要： Natural killer (NK) cells represent a promising effector population for tumor immunotherapy. Conventional NK cell engagers (NKCEs), primarily targeting CD16a, show efficacy but face limitations due to receptor polymorphisms and off-target toxicity. Here, we report the development and characterization of a novel trispecific NK cell engager (TriKE) simultaneously targeting the activating receptor NKp30 and the tumor-associated antigen HER2, integrated with a modified interleukin-15 (IL-15 N72D) fused to the IL-15Rα sushi domain (IL-15RαSu) to enhance NK cell proliferation and persistence. Protein expression and affinity analyses confirmed the proper formation of the fusion protein with high-affinity binding to NKp30, HER2, and IL-15 receptor components. Flow cytometry demonstrated dose-dependent binding of the TriKE to primary human NK cells and HER2+ tumor cells. Functionally, the TriKE induced significantly greater NK cell activation, as measured by CD69 expression, compared to a bispecific engager lacking IL-15. Importantly, cytotoxicity assays revealed superior NK-mediated killing of HER2+ tumor cells upon prolonged exposure, highlighting the immunostimulatory effect of the IL-15 moiety. These results establish the αNKp30 TriKE as a potent platform to redirect NK cytotoxicity against HER2+ tumors, combining targeted receptor engagement with cytokine-driven activation to enhance NK cell-based cancer immunotherapy.

关键词： Senescence   Polymer dot   Aging factor   Aptasensor   Wireless sensing  

摘要： Background: The senescence-associated secretory phenotype (SASP) is closely linked to aging by promoting inflammation and tissue degradation. Sensing SASP is crucial for early detection of and intervention in agerelated diseases to enhance therapeutic outcomes. Herein, SASP-selective sensors (transforming growth factor [TGF]-(31 and interleukin [IL]-6 probes) were designed by utilizing TGF-(31/IL-6 aptamers-functionalized copperimmobilized polymer dots that promoted specific binding between TGF-(31/IL-6 aptamers on the probe surface with aging factors (TGF-(31 and IL-6). Results: The selective binding was reflected by changes in the conductivity of the probes. The TGF-beta 1 and IL-6 probes showed high sensitivity towards TGF-beta 1 and IL-6, with limits of detection of 193.09 pg/mL for the TGF-beta 1 (R2 = 0.9989) and 16.49 pg/mL (R2 = 0.9998) for IL-6 probes. In vitro study using senescent cells confirmed that the probes could selectively detect TGF-beta 1 and IL-6, indicated by increased resistance with longer incubation times (TGF-beta 172h = 2.775 M Omega, IL-672h = 2.401 M Omega). Furthermore, the TGF-beta 1 and IL-6 probes exhibited excellent detection performance in in vivo samples from aging mouse models when monitoring the levels of TGF-beta 1 and IL-6 at different times after lenti soup injection and at different mouse ages (6-20 months). Additionally, the electrical signals generated during sensing can be displayed on a smartphone via a wireless sensing system. Significance: TGF-beta 1 and IL-6 probes provide a sensitive, specific and accessible diagnostic platform for senescence aging factors monitoring, which are expected to be an essential tool that transforms the analysis of aging and age-related diseases.

关键词： 大叶蔷薇   银屑病   网络药理学   细胞凋亡   NF-κB信号通路  

摘要： 目的 运用基于代谢组学和蛋白质组学的网络药理学，研究大叶蔷薇果实醇提取物（ethanolic extract of Rosa macrophylla Lindl. Fruits，EERMF）是否具有银屑病治疗潜力及作用机制，并通过体外细胞实验加以验证。方法 利用超高效液相色谱-质谱联用（UPLC-MS/MS）技术对EERMF的化学成分进行分析；采用CCK-8法和Elisa法评估EERMF对TNF-α刺激下HaCaT细胞增殖及炎症反应的影响；采用4D Label Free定量蛋白质组学方法分析EERMF作用下HaCaT细胞中的差异蛋白表达；利用网络药理学的方法筛选大叶蔷薇果实治疗银屑病的有效成分和作用靶点，并预测其发挥作用的相关信号通路；利用Hoechst33258染色法检测TNF-α刺激下HaCaT细胞的凋亡水平；利用Western blot检测相关通路蛋白表达水平及其磷酸化水平。结果 体外细胞实验结果显示，EERMF可显著抑制TNF-α诱导的HaCaT细胞增殖和炎症反应；网络药理学结果分析表明，EERMF可通过Androsin、Ferulaldehyde、ferulate等关键成分，作用于NFKB1、PLAU、RELA等NF-κB通路相关靶点，调控Bcl-2/Bax相关凋亡信号通路以及抑制NF-κB信号通路而起到治疗银屑病的作用。结论 大叶蔷薇果实醇提物可通过多成分、多靶点调控凋亡信号通路和NF-κB信号通路而实现对银屑病角质形成细胞增殖与炎症反应的双重调节。

关键词： SARS-CoV-2   AMP-activated protein kinase   autophagy   lipid metabolism   antiviral agents  

摘要： AMP-activated protein kinase (AMPK) plays a central role in regulating cell energy balance. When activated, AMPK suppresses energy-consuming pathways, such as lipid and protein synthesis, while increasing nutrient availability through the activation of autophagy. These pathways downstream of AMPK activation contribute to SARS-CoV-2 infection, which hijacks autophagy and accumulates lipid droplets in viral factories to support viral replication. Here, we assessed the antiviral activity of the direct pan-AMPK allosteric activator MK-8722 in vitro. MK-8722 efficiently inhibited infection of Alpha and Omicron SARS-CoV-2 variants in Vero76 and human bronchial epithelial Calu-3 cells at micromolar concentration. This inhibition relied on restoring the autophagic flux, which redirected newly synthesized viral proteins for degradation, and reduced lipid metabolism, which affected viral factories. Furthermore, MK-8722 treatment increased the type I interferon (IFN-I) response. Post-infection treatment with MK-8722 was enough to inhibit efficient viral replication and restore the IFN-I response. Finally, MK-8722 treatment did not alter the SARS-CoV-2-specific CD8+ T cell response mounted upon Spike vaccination. Overall, by activating AMPK, MK-8722 acts as an effective antiviral against SARS-CoV-2 infection, even when applied post-exposure, paving the way for preclinical tests aimed at inhibiting viral replication and improving patients' *** disease 2019, caused by SARS-CoV-2 infection, has led to severe acute respiratory syndrome with very high mortality. Despite available vaccines and public health measures, new SARS-CoV-2 variants emerge with increased transmissibility requiring the development of novel therapeutic strategies. Recently, the AMP-activated protein kinase (AMPK), a cellular energy sensor, has emerged as a potential broad-spectrum antiviral target, as AMPK can modulate the intracellular environment in turn impeding viral replication.

关键词： Adriamycin resistance   Atovaquone   Cancer stemness   Moesin (MSN)   Triple-negative breast cancer (TNBC)  

摘要： BackgroundResistance to chemotherapy remains a major clinical challenge in triple-negative breast cancer (TNBC), an intrinsic subtype with limited available therapeutic options. The expression of moesin (MSN) is upregulated in TNBC patients, but little is known about the role of MSN in breast *** investigated the MSN-dependent autocrine loop between extracellular interleukin 6 (IL-6) and NF-kappa B, along with a signaling cascade involving GTPase-mediated STAT3 phosphorylation. Various in vitro and in vivo assays were used to evaluate tumor initiation, growth, and stemness properties in TNBC *** MSN expression was correlated with shorter overall and disease-free survival in TNBC patients. In vivo, MSN promotes tumor initiation and growth. Mechanistically, MSN-mediated IL-6/NF-kappa B autoregulatory feedback enhances IL-6 transcription. IL-6 binding to LPAR1 activated MSN phosphorylation, which then sequentially phosphorylated the CDC42-PAK4 complex, triggering nuclear translocation of the pSTAT3-MSN complex. This led to pSTAT3-mediated activation of cancer stemness genes (IGFN1, EML1, and SRGN), contributing to Adriamycin resistance. Notably, combination treatment with the FDA-approved STAT3 inhibitor Atovaquone and Adriamycin restored drug *** findings uncover the critical role of MSN in regulating STAT3-mediated cancer stemness via the IL-6/NF-kappa B signaling axis. These results provide a strong rationale for repositioning STAT3 inhibitors such as Atovaquone as a therapeutic strategy in Adriamycin-resistant TNBC patients exhibiting pSTAT3-MSN complex upregulation.

关键词： infliximab   hydroxychloroquine   AGEP   IL17A   IL36RN   pregnant  

摘要： Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous drug reaction that typically resolves rapidly following withdrawal of the offending drug and administration of systemic corticosteroids. Infliximab, a biologic agent that inhibits TNF-alpha, is widely used in the treatment of various inflammatory diseases. Individuals with specific genetic risk factors may be more susceptible to severe drug-induced cutaneous reactions. Here, we report the first case of successful infliximab treatment in a pregnant woman with IL17A and IL36RN mutations who developed severe AGEP after 24 days of hydroxychloroquine use and failed to respond to conventional therapy.

关键词： mycobacterium avium complex   nontuberculous mycobacteria   rituximab   interferon gamma   immune deficiency   case series  

摘要： Anticytokine autoantibodies (AAbs), particularly anti-interferon-gamma (anti-IFN-gamma) AAbs, disrupt cytokine functions, leading to infections, autoimmune-like diseases, and conditions resembling interleukin-12 (IL-12)/IFN-gamma pathway defects. Advances in genetic testing have clarified overlaps between autoinflammatory, autoimmune disorders, and primary immunodeficiencies but reveal complex phenotypes and pathways. While these insights deepen our understanding of immune mechanisms, they also complicate diagnosis and treatment, with limited options for IFN-gamma deficiencies caused by genetic mutations. The adult-onset immunodeficiency with disseminated lymphadenitis due to nontuberculous mycobacteria (NTM) and other opportunistic infections has been linked to high levels of anti-IFN-gamma AAbs. This syndrome, initially identified in HIV-negative Asian patients, frequently affects individuals of Asian descent and may be associated with specific human leukocyte antigen (HLA) alleles. The presence of neutralizing anti-IFN-gamma AAbs impairs the IFN-gamma-dependent immune response, likely contributing to the persistent NTM infection. This study underscores the potential for late-onset anti-IFN-gamma AAb syndrome to manifest with disseminated NTM (dNTM) infections, highlights the importance of timely diagnosis and considers rituximab as a potential therapeutic option.