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关键词： TGF beta   IL-6   immunosuppression   tumor microenvironment   vaccines  

摘要： Although interleukin (IL)-6 is considered immunosuppressive and tumor-promoting, emerging evidence suggests that it may support antitumor immunity. While combining immune checkpoint inhibitors (ICIs) and radiotherapy in patients with pancreatic cancer (PC) has yielded promising clinical results, the addition of an anti-IL-6 receptor (IL-6R) antibody has failed to elicit clinical benefits. Notably, a robust TGF beta-specific immune response at baseline in PC patients treated solely with ICIs and radiotherapy correlated with improved survival. Recent preclinical studies demonstrated the efficacy of a TGF beta-based immune modulatory vaccine in controlling PC tumor growth, underscoring the important role of TGF beta-specific immunity in PC. Here, we explored the importance of IL-6 for TGF beta-specific immunity in PC. In a murine model of PC, coadministration of the TGF beta-based immune modulatory vaccine with an anti-IL-6R antibody rendered the vaccine ineffective. IL-6R blockade hampered the development of vaccine-induced T-cells and tumoral T-cell infiltration. Furthermore, it impaired the myeloid population, resulting in increased tumor-associated macrophage infiltration and an enhanced immunosuppressive phenotype. In PC patients, in contrast to those receiving only ICIs and radiotherapy, robust TGF beta-specific T-cell responses at baseline did not correlate with improved survival in patients receiving ICIs, radiotherapy and IL-6R blockade. Peripheral blood immunophenotyping revealed that IL-6R blockade altered the T-cell and monocytic compartments, which was consistent with the findings in the murine model. Our data suggest that the antitumor efficacy of TGF beta-specific T cells in PC depends on the presence of IL-6 within the tumor. Consequently, caution should be exercised when employing IL-6R blockade in patients receiving cancer immunotherapy.

关键词： Graft versus host disease - GVHD   Graft versus leukemia   Hematologic Malignancies   T cell   Transplant  

摘要： Allogeneic stem cell transplantation (alloSCT) provides a curative treatment option for hematological malignancies. After HLA-matched alloSCT, donor-derived T cells recognize minor histocompatibility antigens (MiHAs), which are polymorphic peptides presented by HLA on patient cells. MiHAs are absent on donor cells due to genetic differences between patient and donor. T cells targeting broadly expressed MiHAs induce graft-versus-leukemia (GvL) reactivity as well as graft-versus-host disease (GvHD), while T cells for MiHAs with restricted or preferential expression on hematopoietic or non-hematopoietic cells may skew responses toward GvL or GvHD, respectively. Besides tissue expression, overall strength of GvL and GvHD is also determined by T-cell frequencies against MiHAs. Here, we explored the use of DNA barcode-labeled peptide-MHC multimers to detect and monitor antigen-specific T cells for the recently expanded repertoire of HLA-I-restricted MiHAs. In 16 patients who experienced an immune response after donor lymphocyte infusion, variable T-cell frequencies up to 30.5% of CD8(+) T cells were measured for 49 MiHAs. High T-cell frequencies above 1% were measured in 12 patients for 19 MiHAs, with the majority directed against mismatched MiHAs, typically 6-8 weeks after donor lymphocyte infusion and at the onset of GvHD. The 12 patients included 9 of 10 patients with severe GvHD, 2 of 3 patients with limited GvHD and 1 of 3 patients without GvHD. In conclusion, we demonstrated that barcoded peptide-MHC multimers reliably detect and allow monitoring for MiHA-specific T cells during treatment to investigate the kinetics of immune responses and their impact on development of GvL and GvHD after HLA-matched alloSCT.

关键词： 中医推拿   寒痹散穴位贴敷   风寒湿痹型肩周炎   肩关节功能   C反应蛋白   白细胞介素-6   一氧化氮  

摘要： 目的 探究中医推拿联合寒痹散穴位贴敷对风寒湿痹型肩周炎患者肩关节功能及血清C反应蛋白（CRP）、白细胞介素-6（IL-6）、一氧化氮（NO）水平的影响。方法 选取2022年5月至2023年5月在本院诊治的82例肩周炎患者为研究对象，按照随机数字表法分为穴位组和研究组，各41例。穴位组给予寒痹散穴位贴敷治疗，研究组给予中医推拿和寒痹散穴位贴敷治疗。分析两组中医症状、肩关节功能、炎症因子、NO水平、一氧化氮合成酶（NOS）水平、疗效及不良反应发生情况。结果 治疗后两组肩部窜痛评分、遇风寒痛增评分、畏风恶寒评分、CRP水平、IL-6水平、白细胞介素-2（IL-2）水平、NO水平、NOS水平较治疗前降低（P<0.05），且研究组低于穴位组（P<0.05）。治疗后两组肌力评分、日常生活能力评分、关节活动度评分较治疗前升高（P<0.05），且研究组高于穴位组（P<0.05）。治疗后总有效率研究组高于穴位组（P<0.05）。两组患者不良反应发生率相近（P>0.05）。结论 中医推拿联合寒痹散穴位贴敷治疗风寒湿痹型肩周炎可较好缓解中医症状，提高肩关节功能、疗效，降低炎症因子水平、NO水平、NOS水平，不良反应发生率较低。

关键词： Unresectable hepatocellular carcinoma   Atezolizumab plus bevacizumab   Interleukin-6  

摘要： Background This study aims to identify biomarkers for treatment response of atezolizumab plus bevacizumab (Atezo+Bev) in patients with hepatocellular carcinoma (HCC). Methods 96 patients who received Atezo+Bev or lenvatinib as a first-line systemic therapy were enrolled as the training group after propensity score matching (PSM), and 42 patients treated with Atezo+Bev were enrolled as the validation group. 17 serum cytokines were measured by Luminex multiplex assay at the start of treatment. For further assessment of the association between cytokine levels and the tumor microenvironment (TME), immunohistochemistry (IHC) was performed on pre-treatment liver biopsy specimens. Results In the derivation set, multivariate analysis identified elevated IL-6 as an independent risk factor in the Atezo+Bev group (HR 5.80: p<0.01), but not in the lenvatinib group;in a subset analysis of patients with low IL-6, PFS was longer in the Atezo+Bev training group than in the lenvatinib group (p = 0.02). A validation study also showed a significantly longer prognosis in the low IL-6 group for both PFS (p = 0.0001) and OS (p = 0.03). Serum IL-6 had a positive correlation with tumor IL-6 expression (rho = 0.56, p < 0.0001) and an inverse correlation with the CD8/CD163-positive cell count ratio (rho = -0.4, p < 0.01). Conclusion Serum IL-6 levels are thought to be involved in the suppression of tumor immunity and are useful in predicting the therapeutic effect of Atezo+Bev treatment.

关键词： Atopic dermatitis   biologics   efficacy   interleukin-13   lebrikizumab   patient profile   safety  

摘要： Introduction: Atopic dermatitis (AD) is a common chronic inflammatory skin disease. Moderate-to-severe AD severely affects patients' quality of life. New drugs selectively targeting molecular pathways involved in the pathogenesis of the disease led to a new era for the treatment of AD. However, the current available options are limited and do not completely fulfill patients' needs. Recently, lebrikizumab, a new humanized monoclonal antibody targeting IL-13, has been approved for treating moderate-to-severe AD. Areas covered: By analyzing scientific literature reporting lebrikizumab phase 3 pivotal clinical studies and summarizing recent advances in AD pathogenesis, in this article we focused on the mechanism of action of lebrikizumab in comparison to other biologics used for treating AD and discussed clinical data that led to the approval of this biologic agent. Expert opinion: Among biologics approved for moderate-to-severe AD, lebrikizumab is characterized by a unique mechanism of action and an attractive maintenance regimen, besides good efficacy and safety profiles. Moreover, clinical evidence suggests that patients na & iuml;ve or pre-treated with other biologics and affected by AD localized in sensitive areas and by type 2 comorbidities might be successfully treated with lebrikizumab.

关键词： Breast Cancer   Interleukin-2   Metastasis   Tumor  

摘要： Background:Interleukin-2 (IL-2) is a well-known cytokine that plays a crucial role in stimulating immune cells, including natural killer (NK) cells and cytotoxic T cells. It has been studied as an immunotherapy for a variety of diseases, including cancer. However, due to its short serum half-life, high doses of IL-2 are required which can result in systemic toxicities like capillary leak syndrome. Objective:To demonstrate the enhanced antitumor efficacy of Albumin Binding Domain-conjugated IL-2 (ABD-IL-2) at a lower dose compared to IL-2. Methods:IL-2 and ABD-IL-2 were purified using Ni-NTA resin with a histidine sequence added to their C-terminal region for purification purpose. Peripheral blood lymphocytes were stimulated with IL-2 and ABD-IL-2 to assess their function. 4T1 cells were injected into BALB/c mice to establish a breast cancer model with metastasis evaluated in the lungs. Results:Both recombinant proteins significantly stimulated T lymphocyte proliferation compared to the negative control (P=0.000, P=0.001). Administration of both proteins reduced the size of isolated tumors in the breast cancer mouse model. The control group had more nodules and larger lung metastatic centers (P=0.000). Metastasis to secondary lymphoid organs occurred only in the control group. Conclusion:By using ABD-IL-2 at a one-third concentration compared to IL-2, we aimed to reduce administration toxicity associated with high doses of IL-2 in immunotherapy. This approach shows potential for improving IL-2-based treatments while minimizing adverse effects.

关键词： aging   MHC   MyHC   sarcopenia   sex  

摘要： Human studies examining the cellular mechanisms behind sarcopenia, or age-related loss of skeletal muscle mass and function, have produced inconsistent results. A systematic review and meta-analysis were performed to determine the aging effects on protein expression, size, and distribution of fibers with various myosin heavy chain (MyHC) isoforms. Study eligibility included MyHC comparisons between young (18-49 yr) and older (>= 60 yr) adults, with 27 studies identified. Relative protein expression was higher with age for the slow-contracting MyHC I fibers, with correspondingly lower fast-contracting MyHC II and IIA values. Fiber sizes were similar with age for MyHC I, but smaller for MyHC II and IIA. Fiber distributions were similar with age. When separated by sex, the few studies that examined females showed atrophy of MyHC II and IIA fibers with age, but no change in MyHC protein expression. Additional analyses by measurement technique, physical activity, and muscle biopsies provided important insights. In summary, age-related atrophy in fast-contracting fibers lead to more of the slow-contracting, lower force-producing isoform in older male muscles, which helps explain their age-related loss in whole muscle force, velocity, and power. Exercise or pharmacological interventions that shift MyHC expression toward faster isoforms and/or increase fast-contracting fiber size should decrease the prevalence of sarcopenia. Our findings also indicate that future studies need to include or focus solely on females, measure MyHC IIA and IIX isoforms separately, examine fiber type distribution, sample additional muscles to the vastus lateralis (VL), and incorporate an objective measurement of physical activity.

关键词： Antiviral drugs   Bovine viral diarrhea virus   IFN-I   ISGs   fatty acid synthetase  

摘要： For many viruses, controlling the process of infection is largely dependent on the enzymes of the fatty acid synthesis (FAS) pathway. An appealing therapeutic target in antiviral research is fatty acid synthetase (FASN), a crucial enzyme in the FAS pathway. Bovine viral diarrhea, caused by the Bovine viral diarrhea virus (BVDV), is a significant viral infectious disease posing a substantial threat to global animal husbandry. Our study revealed that BVDV infection not only upregulates the expression of FAS-related enzymes in BT cells and the blood, liver, and spleen of mice but also markedly enhances the accumulation of lipid droplets, free fatty acids, and triglycerides. The FAS pathway plays a pivotal role throughout the entire BVDV replication cycle. Additionally, administration of the FASN inhibitor C75 and Acetyl CoA carboxylase-1 (ACC-1) inhibitor TOFA significantly reduced the viral content in both serum and organs of BVDV-infected mice, exhibiting inhibitory effects across diverse viral strains. Intriguingly, We found that RIG-1/TBK1-mediated IFN-I signaling inhibits SREBP-1/FAS and reduces BVDV replication. Conversely, targeting a few essential enzymes of SREBP-1/FAS also activates IFN-I signaling. More importantly, FASN inhibitor led to heightened expression of ISGs in mouse spleens by activating the RIG-1/TBK-1 pathway. These findings highlight that FASN inhibitors inhibit BVDV replication through the activation of the RIG-1/TBK-1 pathway to induce ISGs, and offering a novel therapeutic approach for combating BVDV. Thus, it is crucial to negatively regulate SREBP-1/FAS signaling molecules in order to create novel antiviral drugs that are safe, effective, and broad-spectrum.

关键词： Asymptomatic disease   Cytokines   Genetic polymorphisms   Interleukin 10   Orthoflavivirus denguei  

摘要： Infections caused by Orthoflavivirus denguei can either manifest asymptomatically or present a wide spectrum of clinical manifestations. This variety of symptoms results from its complex pathogenesis, which is influenced by viral factors, in addition to host genetics and immunological factors. It is known that anti-inflammatory cytokines can play an immunomodulatory role throughout the course of dengue. Therefore, we investigated the single nucleotide polymorphisms (SNPs) -1082 A/G (rs1800896) and -819 C/T (rs1800871) in the interleukin-10 (IL-10) gene and their possible relationship with the development of symptomatic dengue in a Brazilian population. This study, carried out in northeastern Brazil, involved 333 volunteers, including 74 patients with dengue without warning signs (DWWS), 45 patients with dengue with warning signs (DWAS), 85 patients with asymptomatic dengue infection (ASY) and 129 health controls. The genomic DNA was extracted and the SNPs were genotyped using quantitative real-time polymerase chain reaction (qPCR). The data obtained were used to conduct statistical analyses of the genotype and allele frequencies. We observed an association of A/G and G/G genotypes of the -1082 A/G SNP of the IL-10 gene with susceptibility to symptomatic dengue and DWAS regarding the asymptomatic dengue. The G allele of this SNP has also been identified as a risk factor for symptomatic dengue, DWWS and DWAS. Regarding the analyses between the SNPs -1082 A/G and -819 C/T of the IL-10 gene, there was an association of the G-C haplotype with symptomatic dengue, DWWS and DWAS, as well as a correlation of the A-C haplotype with asymptomatic dengue. Moreover, the data indicate an association between the presence of the G allele and the development of symptoms, compared to those without the G allele. Our results indicate the presence of the G allele of SNP -1082 A/G of the IL-10 gene as a risk factor for the clinical development of symptomatic dengue in the studied populati