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关键词： Infliximab   Cyclophosphamide   Myelosuppression   Splenotoxicity   Rats  

摘要： PurposeCyclophosphamide is a widely used anticancer agent, though its clinical application is often constrained by myelotoxicity. Infliximab, a monoclonal antibody targeting TNF-alpha, may alleviate this toxicity by mitigating oxidative stress. This study aimed to assess the protective effects of infliximab against cyclophosphamide-induced myelotoxicity, focusing on bone marrow and spleen-related *** Wistar rats (260 +/- 20 g) were randomly divided into four groups (n = 5 each): Control (normal saline), Infliximab (7 mg/kg, IP), Cyclophosphamide (200 mg/kg, IP), and Infliximab + Cyclophosphamide (same respective doses with a four-day interval between administrations). Nine days after the initiation of the experiment, bone marrow and spleen histopathology, bone marrow cellularity, spleen index, and levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in bone marrow tissue, along with serum TNF-alpha and G-CSF concentrations, were *** prevented myelofibrosis in bone marrow tissue;however, it did not mitigate cellularity depletion. It failed to counteract the effects of cyclophosphamide on spleen histology and the spleen index. Additionally, infliximab enhanced antioxidant activity in the bone marrow. Moreover, inhibition of TNF-alpha was associated with an increase in G-CSF *** infliximab improved molecular pathways associated with cyclophosphamide-induced bone marrow and hematologic toxicity in the rat model, it did not lead to significant improvements in clinical manifestations.

关键词： Anterior uveitis   Cytomegalovirus   Human leukocyte antigen-B27   Retinal microvasculature   Choriocapillaris  

摘要： PurposeThis study assessed posterior segment microvascular changes in patients with cytomegalovirus (CMV) anterior uveitis (AU) during acute episodes by comparing retinal and choroidal changes to those in patients with HLA-B27 AU and healthy controls, aiming to evaluate their impact on visual *** this retrospective study, 85 patients with CMV AU, 93 with HLA-B27 AU, and 80 healthy controls underwent comprehensive ocular evaluations, including optical coherence tomography (SS-OCT) and OCT angiography (OCTA). Retinal thickness, vascular density (VD), and choroidal parameters were evaluated, and statistical comparisons were made among *** microvascular changes were observed in both uveitis groups. In CMV AU, parafoveal superficial vascular plexus (SVP) VD, deep capillary plexus (DCP) VD, and choriocapillaris flow deficit (CCFD) areas were significantly associated with visual acuity. CMV AU patients showed lower parafoveal SVP and DCP VD and larger CCFD areas than healthy controls. Compared to HLA-B27 AU, CMV AU exhibited a lower DCP VD and higher CCFD area, indicating distinct retinal and choroidal *** microvascular changes occur in acute AU, affecting visual acuity, even without evident retinal or vitreous involvement. The effects of CMV AU on the retinal and choroidal microvasculature highlight the need for posterior segment evaluation to manage AU. What is known:CMV anterior uveitis is typically seen as an anterior segment disease with little focus on posterior *** is new:CMV AU shows distinct choroidal and retinal microvascular changes compared to HLA-B27 AU and healthy *** segment changes in CMV AU correlate with visual acuity, highlighting their clinical importance.

关键词： Triple-negative breast cancer   High-intensityfocusedultrasound   CD8+T cell   Januskinase/signal transducers and activators of transcription   Il-2rb   IL-2   Immunotherapy  

摘要： Triple-negative breast cancer (TNBC) is characterized by a lack of effective targeted therapies and a challenging immunosuppressive microenvironment that limits the efficacy of immunotherapy. This study explores the potential of high-intensity focused ultrasound (HIFU) in modulating the immune response. Using the 4T1 mouse tumor model, we assessed the effects of thermal (T-HIFU) and mechanical (M-HIFU) HIFU on CD8+ T cells. Proteomic analysis revealed that T-HIFU and M-HIFU increased Il-2rb expression on CD8+ T cells, activating the JAK-STAT pathway and enhancing the efficacy of IL-2, leading to improved tumor growth inhibition and survival rates. The combination of HIFU and IL-2 demonstrated synergistic antitumor effects, indicating a new strategy for enhancing immunotherapy in TNBC. This approach uniquely boosts antitumor immunity by upregulating Il-2rb on CD8+ T cells, offering a promising avenue for overcoming the immunosuppression in TNBC.

关键词： ADAMTS-8   TNF   Colorectal cancer   NF-kappa B   PI3K   And SAPK/JNK  

摘要： Tumor necrosis factor-alpha (TNF-alpha) is associated with the metastatic phenotype and regulates cellular communication in Colorectal Cancer (CRC). This study investigates the effects of TNF-alpha on the expression of the ADAMTS-8 gene in SW480 colorectal cancer cells, focusing on both mRNA and protein levels, as well as the underlying intracellular signaling pathways activated in response to TNF-alpha. SW480 cells were treated with TNF-alpha at varying concentrations (10, 20, and 40 ng/mL) for 24, 48, and 72 h. Utilizing the MTT assay, a significant reduction in cell viability was observed at 48 and 72 h across all doses, indicating a cytostatic effect of TNF-alpha. The transcriptional activity of ADAMTS-8 was assessed through transient transfection of full-length and truncated promoter constructs, revealing that TNF-alpha significantly upregulated ADAMTS-8 expression through specific promoter regions. Quantitative RT-PCR and Western blot analyses demonstrated a time- and dose-dependent increase in both mRNA and protein levels of ADAMTS-8 in cells treated with 10 and 20 ng/mL of TNF-alpha. TNF-alpha strongly increased the transcriptional activity of several truncated ADAMTS-8 promoter constructs. Further exploration of intracellular signaling pathways revealed the activation of NF-kappa B, PI3K, and SAPK/JNK pathways, with limited activation of p38/MAPK. Inhibition studies employing specific pathway inhibitors indicated that blockade of NF-kappa B, PI3K, p38/MAPK, and JNK signaling pathways significantly suppressed TNF-alpha-induced ADAMTS-8 expression at both mRNA and protein levels. Additionally, Chromatin Immunoprecipitation (ChIP) assays confirmed the binding of NF-kappa B, STAT-3, ELK-1, c-Jun, and ATF-1 to the ADAMTS-8 promoter in response to TNF-alpha treatment. These findings suggest a multifaceted regulatory mechanism wherein TNF-alpha promotes ADAMTS-8 expression by activating key transcription factors and associated signaling cascades-in silico analysis

关键词： Acute Graft-versus-Host Disease (aGVHD)   HLA Mismatch Combination   Unrelated Cord Blood Transplantation (UCBT)  

摘要：

摘要： Immunotherapy has emerged as a promising strategy against cancer, but many patients fail to achieve durable responses. Inefficiency of immunotherapy is often caused by the immunosuppressive tumor microenvironment. Previously, we demonstrated that treatment with an Fc alpha RI-stimulating bi-specific antibody (BsAb), designed to recruit myeloid cells as cytotoxic effector cells, significantly decreased tumor growth in a murine cancer model. Nonetheless, complete tumor eradication was not achieved. In this study, we investigated if co-treatment with the pro-inflammatory cytokine TNF-alpha enhances the therapeutic efficacy of Fc alpha RI BsAb. Although TNF-alpha did not affect antibody-dependent cellular phagocytosis (ADCP) of tumor cells, macrophage polarization, or antibody-dependent cellular cytotoxicity (ADCC) by natural killer cells, its combination with Fc alpha RI BsAb increased tumor cell trogocytosis, neutrophil degranulation and tumor cell death. To exploit this synergy, we engineered a TNF-alpha x Fc alpha RI bi-specific immunocytokine (Fc alpha RI-TNF). Surface plasmon resonance and cellular binding assays demonstrated that Fc alpha RI-TNF retained binding affinities for Fc alpha RI, Fc gamma RIII, and the tumor-associated antigen EGFR comparable to Fc alpha RI BsAb. Consistent with the combination of TNF-alpha and Fc alpha RI BsAb, Fc alpha RI-TNF neither influenced macrophage function nor polarization but enhanced neutrophil-mediated tumor killing in vitro. Intravital imaging in a murine MC38-cEGFR tumor model showed that Fc alpha RI-TNF promoted in vivo neutrophil activation and swarming behavior. These findings suggest that Fc alpha RI-TNF represents a promising candidate to improve neutrophil-driven immunotherapy of cancer.

摘要： Objective. Still's disease is a complex, multisystemic disorder requiring prompt diagnosis and treatment. This study provides a general assessment of a Still's disease cohort aiming to evaluate the efficacy of early intervention with interleukin-1 inhibitors (IL-1i) in achieving clinical inactive disease (CID) and reducing glucocorticoid use in patients with Still's disease. Methods. We retrospectively analyzed 42 adult patients diagnosed with Still's disease after 2010 and treated with IL-1i. Patients were categorized as early treated (IL-1i started before six months from symptom onset) or late treated (IL-1i started after 6 months). CID achievement, glucocorticoid use, flares, and imaging findings were assessed. The chi-square test was employed as a statistical test, and P < 0.05 was considered significant. GraphPad Prism 8 was used for statistical analysis. Results. The median time from symptom onset to IL-1i introduction was six months (interquartile range: 2-19). Overall, 55% of patients achieved CID at six months. Early treated patients showed a trend toward higher proportion of CID achievement compared to that of late-treated patients (67% vs 38%;P = 0.17). A meta-analysis including our cohort and two other observational studies showed that early treatment was associated with an odds ratio of 6.73 (95% confidence interval: 2.31-19.64) in comparison to late treatment. All our patients initially received glucocorticoids, with 48% of those achieving CID able to discontinue glucocorticoids within six months. Ten major flares were observed, with 62% occurring after IL-1i suspension or spacing. At baseline, F-fluorodeoxyglucose positron emission tomography (PET)-computed tomography (CT) or magnetic resonance (MR) scans revealed hypermetabolic areas primarily in the bone marrow, spleen, and lymph nodes. After IL-1i introduction, these hypermetabolic regions generally showed a reduction in activity. Conclusions. Early introduction of IL-1i in patients with Still's di

关键词： Human papillomavirus   Head and neck cancer   mRNA cancer vaccine   Interleukin-12  

摘要： The incidence of head and neck cancer (HNC) caused by human papillomavirus (HPV) has increased over the past several years. The mEER murine model mimicking HNC showed relatively low efficacy following E6 and E7 immunotherapy. Therefore, this study aimed to examine the anti-tumor and anti-metastatic effects of mRNA vaccines encoding HPV 16 E7, Interleukin-12 (IL-12), and Granulocyte-Macrophage colony-stimulating factor (GM-CSF) in mEER tumor-bearing mice. C57BL/6 mice were injected with cultured mEER cells and immunized with mRNA-LNPs encoding HPV16 E7, GM-CSF, and IL-12. Tumor growth was monitored, and immune responses were analyzed using flow cytometry and Enzyme-Linked ImmunoSpot assays. When immunized with both E7 and IL-12 mRNA, the tumor size dramatically decreased regardless of tumor size, while the expression of MHC1 on tumor cells increased significantly. No tumors developed upon mEER cell re-implantation. Local expression of IL12 via mRNA delivery revealed no evidence of toxicity or reduced T-cell exhaustion markers. Furthermore, mIL12 immunization with mE7 induces E7-specific memory T cells in lung tissues, suggesting a defense against potential metastasis and recurrence. Immunization with E7 and IL-12 mRNA is a highly effective treatment option for patients with HPV-positive HNC and is potentially applicable to other cancers.

关键词： THP   BCP   Tibia destruction   DRG damage   TNF-alpha/uPA/PAR2/TRPV1  

摘要： BackgroundTreatment of bone cancer pain (BCP) remains a challenge. The current paper was to research the analgesic effect of Tetrahydropalmatine (THP) on BCP and the related *** model of BCP was constructed by injecting E0771 breast cancer cells into the tibia. Behavioral test was performed to research the effect of THP on pain nociception of BCP mice. Tibia and dorsal root ganglia (DRG) damage was evaluated by HE and Nissl staining. The construction of BCP cell models was conducted by co-culture DRG neurons with E0771 breast cancer cells. The effect of THP on the viability and apoptosis of BCP cell models was monitored by CCK-8 and Tunel assays. TNF-alpha/uPA/PAR2/TRPV1 pathway activity in DRG was detected by qRT-PCR and Western blot. Pomalidomide (PMA), exogenous TNF-alpha protein and Capsaicin were utilized to treat BCP mouse model and cell models to explore whether THP exerted analgesic effect via inactivating the TNF-alpha/uPA/PAR2/TRPV1 *** attenuated pain nociception, relieved tibia destruction, and mitigated inflammation, neuronal death and neuronal excitotoxicity in DRG of BCP mice. It enhanced the viability, but suppressed the apoptosis of BCP cell models. The activated TNF-alpha/uPA/PAR2/TRPV1 pathway in BCP mouse model and cell models was abrogated by THP treatment. PMA and THP had additive effect, which combination attenuated pain nociception, tibia and DRG damage of BCP mice, and apoptosis of BCP cell models. The pain relief and the TNF-alpha/uPA/PAR2/TRPV1 pathway inactivation induced by THP in BCP mice was abolished by exogenous TNF-alpha protein or *** exerted the analgesic role in BCP might be through inactivating the TNF-alpha/uPA/PAR2/TRPV1 pathway in DRG. It may be an effective drug for relieving BCP in patients.