Interleukin-7 Levels Research Articles

Investigating the causal impact of gut microbiota on arthritis via inflammatory proteins using mendelian randomization

Previous studies have suggested a potential association between the gut microbiota and arthritis. However, the causal links between the gut microbiota and various types of arthritis, as well as the potential mediating role of inflammatory proteins, remain unclear. Mendelian randomization was used to explore the causal relationships between gut microbiota, inflammatory proteins, and various forms of arthritis (osteoarthritis, rheumatoid and psoriatic arthritis, and ankylosing spondylitis [AS]). The inverse variance-weighted method was the primary analytical approach used. Furthermore, we examined the mediating role of inflammatory proteins in the pathway linking the gut microbiota to arthritis. Sensitivity analyses were performed to verify the robustness of the findings, and enrichment analyses were conducted to investigate the biological functions and pathways involved. We identified 11 positive and 14 negative causal effects linking the genetic liability of the gut microbiota to arthritis. Similarly, 9 positive and 8 negative causal effects between inflammatory proteins and arthritis were identified. Notably, an increased abundance of the order Bacillales (odds ratio [OR] = 1.199, 95% confidence interval [CI] = 1.030–1.394, P = 0.019) and higher interleukin-7 levels (OR = 1.322, 95% CI = 1.004–1.741, P = 0.046) significantly elevated the risk of AS. Furthermore, interleukin-7 mediated 13.8% of the effect caused by the order Bacillales, with a mediation effect size of β = 0.025 (95% CI = 0.001–0.064). Sensitivity and supplementary analyses revealed no significant evidence of horizontal pleiotropy or heterogeneity. Overall, our findings demonstrate causal links between the gut microbiota, inflammatory proteins, and four arthritis types, highlighting the gut microbiota as a potential therapeutic target. Crucially, interleukin-7 not only strongly correlated with AS but also partially mediated the effect exerted by the gut microbiota on AS, suggesting that managing the gut microbiota to modulate inflammatory proteins could serve as an effective therapeutic strategy for arthritis.

Causal relationship between inflammatory cytokines and polycystic ovary syndrome: a bidirectional mendelian randomization study.

Polycystic ovary syndrome (PCOS) is defined as a chronic low-grade inflammatory reproductive endocrine disorder. PCOS can induce various metabolic disorders, which are associated with a state of mild and slow-acting inflammation. Nevertheless, the causal relationship between polycystic ovary syndrome and inflammatory factors is uncertain. The causality between inflammatory cytokines and PCOS was analyzed by bidirectional Mendelian randomization (MR) in this current probe. We performed an interactive MR study to assess the causal relationships between 91 inflammatory cytokines and PCOS using Genome Wide Association Study (GWAS) data. We underwent dual-sample MR analysis with inverse variance weights (IVW) as the predominant MR methodology with multiple validity and heterogeneity analyses. MR-Egger, weighted median, simple mode, weighted mode and MR-PRESSO were analyzed as multiple likelihood sensitivity analyses to enhance the final results.The results came out interleukin-1-alpha (IL-1A) levels (odds ratio [OR] = 1.051, 95% fiducial interval [95% CI] = 1.009-1.095, P = 0.02) and oncostatin-M (OSM) levels ( [OR] = 1.041, [95% CI] = 1.001-1.082, P = 0.04) were positively associated with the development of PCOS. Moreover, interleukin-7 (IL-7) levels ([OR] = 0.935, [95% CI] = 0.884-0.989, P = 0.02); interleukin-15 receptor subunit alpha (IL15RA) levels ([OR] = 0.959, [95% CI] = 0.929-0.99, P = 0.01); and C-X-C motif chemokine 11 (CXCL11) levels ([OR] = 0.959, [95% CI] = 0.922-0.996. P = 0.03) were strongly negatively associated with PCOS. However, we did not find any strong positive results in the reverse analysis, suggesting that although inflammatory factors contribute to the pathogenesis of PCOS, PCOS itself does not trigger inflammatory factor production.Our study provides genetic evidence for the connection between systemic inflammatory regulators and PCOS. Treatments targeting specific inflammatory factors may help to mitigate the risk of PCOS. The levels of five of the 91 inflammatory factors included in this study, namely, IL1A and OSM, were associated with PCOS. IL1A and OSM contribute to the progression of PCOS while IL-7, IL15RA, and CXCL11 levels are negatively correlated with the development of PCOS.

Comparative Analysis of Corneal Wound Healing: Differential Molecular Responses in Tears Following PRK, FS-LASIK, and SMILE Procedures.

In this study, we aimed to analyze the changes in the expression profiles of selected messenger RNAs (mRNAs) and their encoded proteins in the tears of patients undergoing photorefractive keratectomy (PRK), femtosecond-assisted laser in situ keratomileusis (FS-LASIK), and small-incision lenticule extraction (SMILE) procedures. A total of 120 patients were divided into three groups based on the laser vision correction (LVC) procedure: PRK, FS-LASIK, or SMILE. Tear samples were collected preoperatively and at 1, 7, 30, and 180 days postoperatively. The expression levels of selected messenger RNAs (mRNAs) and proteins were analyzed by using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. PRK and FS-LASIK elicited significantly stronger biological responses than SMILE. Interleukin-15 (IL-15) expression increased notably in the PRK and FS-LASIK groups, with mRNA levels reaching fold changes of 4.65 ± 0.65 and 4.99 ± 0.28, respectively, on day 1, compared with only 2.09 ± 0.23 in the SMILE group. Vascular endothelial growth factor A (VEGFA) levels were also elevated in the PRK (2.98 ± 0.23 fold change) and FS-LASIK groups (3.45 ± 1.09 fold change) on day 1, while the SMILE group showed minimal fluctuations. The protein concentration analysis based on the ELISA confirmed these trends, with IL-15 levels peaking at 54.2 ± 2.5 pg/mL in the PRK group and 52.8 ± 3.1 pg/mL in the FS-LASIK group, compared with 32.4 ± 1.9 pg/mL in the SMILE group on day 1. Similarly, VEGFA protein concentrations were the highest in the PRK (72.4 ± 4.1 pg/mL) and FS-LASIK patients (69.5 ± 3.8 pg/mL) on day 1 but remained low in the SMILE patients (45.6 ± 2.3 pg/mL). By day 180, gene expression and protein levels in all groups had stabilized, returning to near-preoperative values. PRK and FS-LASIK induced more pronounced molecular and protein-level changes during corneal wound healing than the less invasive SMILE procedure, indicating stronger biological responses. These findings suggest that tailored postoperative care based on the specific procedure could optimize healing and patient outcomes. However, further research with larger sample sizes and longer follow-ups is needed to confirm these observations and develop personalized treatment strategies.

Exploring the impact of inflammatory cytokines on alcoholic liver disease: a Mendelian randomization study with bioinformatics insights into potential biological mechanisms

ABSTRACT Background: Alcoholic liver disease (ALD) significantly contributes to global morbidity and mortality. The role of inflammatory cytokines in alcohol-induced liver injury is pivotal yet not fully elucidated. Objectives: To establish a causal link between inflammatory cytokines and ALD using a Mendelian Randomization (MR) framework. Methods: This MR study utilized genome-wide significant variants as instrumental variables (IVs) for assessing the relationship between inflammatory cytokines and ALD risk, focusing on individuals of European descent. The approach was supported by comprehensive sensitivity analyses and augmented by bioinformatics tools including differential gene expression, protein-protein interactions (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and analysis of immune cell infiltration. Results: Our findings reveal that increased levels of stem cell growth factor beta (SCGF-β, beta = 0.141, p = .032) and interleukin-7 (IL-7, beta = 0.311, p = .002) are associated with heightened ALD risk, whereas higher levels of macrophage inflammatory protein-1α (MIP-1α, beta = -0.396, p = .004) and basic fibroblast growth factor (bFGF, beta = -0.628, p = .008) are linked to reduced risk. The sensitivity analyses support these robust causal relationships. Bioinformatics analyses around inflammatory cytokine-associated SNP loci suggest multiple pathways through which cytokines influence ALD. Conclusion: The genetic evidence from this study convincingly demonstrates that certain inflammatory cytokines play directional roles in ALD pathogenesis. These findings provide insights into the complex biological pathways involved and underscore the potential for developing targeted therapies that modulate these inflammatory responses, ultimately improving clinical outcomes for ALD patients.

The causal relationship between 91 inflammatory cytokines and Gestational Diabetes Mmellitus: A bidirectional two-sample Mendelian randomization study

BackgroundGestational Diabetes Mellitus (GDM) poses significant risks to maternal and fetal health, yet its precise etiology remains unclear. Observational studies have demonstrated a link between specific inflammatory cytokines and the occurrence of GDM, but the causal relationships remain uncertain. MethodsUtilizing publicly accessible genetic data, we performed a bidirectional two-sample mendelian randomization (MR) analysis to elucidate the causal association between 91 inflammatory cytokines and GDM. Sensitivity analysis was carried out to evaluate the robustness, heterogeneity, and potential presence of horizontal pleiotropy within the results. ResultsElevated levels of Interleukin-7 (IL7) and Neurturin (NRTN) (OR=1.104, 95 % CI=1.003–1.216, p = 0.042; OR=1.102, 95 % CI=1.023–1.187, p = 0.010), along with decreased levels of Glial cell line-derived neurotrophic factor (GDNF), Interleukin-12 subunit beta (IL12β), and Interleukin-20 (IL20) (OR=0.911, 95 % CI=0.849–0.979, p = 0.010;OR=0.955, 95 % CI=0.916–0.996, p = 0.033; OR=0.892, 95 % CI=0.819–0.971, p = 0.008), are associated with increased GDM risk. Additionally, GDM occurrence correlates with increased Matrix metalloproteinase-10 (MMP-10) and decreased Interleukin-20 receptor subunit alpha (IL-20Rα) levels (OR=1.042, 95 % CI=1.002–1.084, p = 0.038; OR=0.949, 95 % CI=0.909–0.992, p = 0.021). Sensitivity analyses detected no significant heterogeneity or pleiotropy. ConclusionThis study has clarified the causal link between inflammatory cytokines and GDM, thereby enhancing our comprehension of the potential mechanisms involved in GDM pathogenesis. These findings offer new insights into the etiology, diagnosis, and therapeutic strategies for GDM.

Remodeling p38 signaling in muscle controls locomotor activity via IL-15.

Skeletal muscle has gained recognition as an endocrine organ releasing myokines upon contraction during physical exercise. These myokines exert both local and pleiotropic health benefits, underscoring the crucial role of muscle function in countering obesity and contributing to the overall positive effects of exercise on health. Here, we found that exercise activates muscle p38γ, increasing locomotor activity through the secretion of interleukin-15 (IL-15). IL-15 signals in the motor cortex, stimulating locomotor activity. This activation of muscle p38γ, leading to an increase locomotor activity, plays a crucial role in reducing the risk of diabetes and liver steatosis, unveiling a vital muscle-brain communication pathway with profound clinical implications. The correlation between p38γ activation in human muscle during acute exercise and increased blood IL-15 levels highlights the potential therapeutic relevance of this pathway in treating obesity and metabolic diseases. These findings provide valuable insights into the molecular basis of exercise-induced myokine responses promoting physical activity.

Interactions between circulating inflammatory factors and autism spectrum disorder: a bidirectional Mendelian randomization study in European population.

Extensive observational studies have reported an association between inflammatory factors and autism spectrum disorder (ASD), but their causal relationships remain unclear. This study aims to offer deeper insight into causal relationships between circulating inflammatory factors and ASD. Two-sample bidirectional Mendelian randomization (MR) analysis method was used in this study. The genetic variation of 91 circulating inflammatory factors was obtained from the genome-wide association study (GWAS) database of European ancestry. The germline GWAS summary data for ASD were also obtained (18,381 ASD cases and 27,969 controls). Single nucleotide polymorphisms robustly associated with the 91 inflammatory factors were used as instrumental variables. The random-effects inverse-variance weighted method was used as the primary analysis, and the Bonferroni correction for multiple comparisons was applied. Sensitivity tests were carried out to assess the validity of the causal relationship. The forward MR analysis results suggest that levels of sulfotransferase 1A1, natural killer cell receptor 2B4, T-cell surface glycoprotein CD5, Fms-related tyrosine kinase 3 ligand, and tumor necrosis factor-related apoptosis-inducing ligand are positively associated with the occurrence of ASD, while levels of interleukin-7, interleukin-2 receptor subunit beta, and interleukin-2 are inversely associated with the occurrence of ASD. In addition, matrix metalloproteinase-10, caspase 8, tumor necrosis factor-related activation-induced cytokine, and C-C motif chemokine 19 were considered downstream consequences of ASD. This MR study identified additional inflammatory factors in patients with ASD relative to previous studies, and raised a possibility of ASD-caused immune abnormalities. These identified inflammatory factors may be potential biomarkers of immunologic dysfunction in ASD.

Associations of inflammatory and metabolic biomarkers with incident erosive hand osteoarthritis in the osteoarthritis initiative cohort

Erosive hand osteoarthritis (eHOA) is a subtype of hand osteoarthritis (OA) that develops in finger joints with pre-existing OA and is differentiated by clinical characteristics (hand pain/disability, inflammation, and erosions) that suggest inflammatory or metabolic processes. This was a longitudinal nested case-cohort design among Osteoarthritis Initiative participants who had hand radiographs at baseline and 48-months, and biospecimens collected at baseline. We classified incident radiographic eHOA in individuals with ≥1 joint with Kellgren-Lawrence ≥2 and a central erosion present at 48-months but not at baseline. We used a random representative sample (n=1282) for comparison. We measured serum biomarkers of inflammation, insulin resistance and dysglycemia, and adipokines using immunoassays and enzymatic colorimetric procedures, blinded to case status. Eighty-six participants developed incident radiographic eHOA. In the multivariate analyses adjusted for age, gender, race, smoking, and body mass index, and after adjustment for multiple analyses, incident radiographic eHOA was associated with elevated levels of interleukin-7 (risk ratio (RR) per SD=1.30 [95% confidence interval (CI) 1.09, 1.55] p trend 0.01). This exploratory study suggests an association of elevated interleukin-7, an inflammatory cytokine, with incident eHOA, while other cytokines or biomarkers of metabolic inflammation were not associated. Interleukin-7 may mediate inflammation and tissue damage in susceptible osteoarthritic finger joints and participate in erosive progression.

Causal roles of circulating cytokines in sarcopenia-related traits: a Mendelian randomization study.

Epidemiological and experimental evidence suggests that chronic inflammation plays an important role in the onset and progression of sarcopenia. However, there is inconsistent data on the inflammatory cytokines involved in the pathogenesis of sarcopenia. Therefore, we performed a two-sample Mendelian randomization (MR) analysis to explore the causal relationship between circulating cytokines and sarcopenia-related traits. The MR analysis utilized genetic data from genome-wide association study that included genetic variations in 41 circulating cytokines and genetic variant data for appendicular lean mass (ALM), hand grip strength, and usual walking pace. Causal associations were primarily explored using the inverse variance-weighted (IVW) method, supplemented by MR-Egger, simple mode, weighted median, and weighted mode analyses. Additionally, sensitivity analyses were also performed to ensure the reliability and stability of the results. Three cytokines [hepatocyte growth factor (HGF), interferon gamma-induced protein 10 (IP-10), and macrophage colony-stimulating factor (M-CSF)] were positively associated with ALM (β: 0.0221, 95% confidence interval (CI): 0.0071, 0.0372, P= 0.0039 for HGF; β: 0.0096, 95%CI: 4e-04, 0.0189, P= 0.0419 for IP-10; and β: 0.0100, 95%CI: 0.0035, 0.0165, P= 0.0025 for M-CSF). Conversely, higher levels of interleukin-7 (IL-7), monocyte chemotactic protein 3 (MCP-3), and regulated on activation, normal T cell expressed and secreted (RANTES) were associated with decreased hand grip strength (β: -0.0071, 95%CI: -0.0127, -0.0014, P= 0.0140 for IL-7; β: -0.0064, 95%CI: -0.0123, -6e-04, P= 0.0313 for MCP-3; and β: -0.0082, 95%CI: -0.0164, -1e-04, P= 0.0480 for RANTES). Similarly, interleukin 1 receptor antagonist (IL-1RA) was negatively correlated with usual walking pace (β: -0.0104, 95%CI: -0.0195, -0.0013, P= 0.0254). Sensitivity analysis confirmed the robustness of these findings. Our study provides additional insights into the pivotal role of specific inflammatory cytokines in the pathogenesis of sarcopenia. Further research is required to determine whether these cytokines can be used as targets for the prevention and treatment of sarcopenia.

Carbon Dioxide (CO2) Dietary Emissions Are Related to Oxidative and Inflammatory Status in Adult Population.

Carbon dioxide (CO2) is a primary greenhouse gas (GHG) causing global temperature to rise. Unsustainable diets induce an increment in the risk of obesity and noncommunicable diseases but also contribute to the global GSG burden. To assess whether CO2 dietary emissions influence the inflammatory and oxidative status of subjects with metabolic syndrome (MetS). As part of the PREDIMED-Plus study, 100 adults (55-75 years old) from the Balearic Islands, Spain, were recruited and classified according to their dietary CO2 emissions. Anthropometric parameters were determined, fasting blood samples were collected and plasma, neutrophils, and peripheral blood mononuclear cells (PBMCs) were obtained. Dietary inflammatory index (DII), adherence to a Mediterranean diet (ADM), fatty liver index (FLI), and estimated glomerular filtration (eGFR) were calculated. Clinical biochemical parameters, blood count, and oxidative stress and inflammatory biomarker levels were also determined. DII was higher in participants with high dietary CO2 emissions. Adherence to the MedDiet was inversely associated with CO2 emissions. Malondialdehyde (MDA) levels were higher in urine and plasma samples from subjects with high dietary CO2 emissions. Reactive oxygen species (ROS) production by PBMCs was greater in participants with high CO2 emissions. Interleukin-15, resistin, and leptin plasma levels were increased in participants with high dietary CO2 emissions. Dietary CO2 emissions influence oxidative status and inflammation in relation to the increased prooxidative and proinflammatory status in PBMCs and plasma. These biomarkers were useful for monitoring diet sustainability and health.

Exploring the Mechanism of Chang-An-Kang on Active Ulcerative Colitis Rats Based on NF-κB/STAT3 Signaling Pathway

Objectives The objective of this study was to investigate the therapeutic effect and mechanism of Chang-An-Kang on ulcerative colitis rats. Materials and Methods The rat model of ulcerative colitis induced by 6% glacial acetic acid was established. The corresponding therapeutic drugs were given 24 h after the model was established. The pathological morphology of colon tissue was observed after 21 days of continuous administration. The levels of interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-α) were measured by ELISA kit. The expression levels of NF-κB and STAT3 proteins in colon tissue were detected by IHC. Results The results showed that the changes in the pathological and biochemical indexes of the rat colon tissue indicate that the model was successfully established. Chang-An-Kang could significantly reduce rat colon tissue damage, decrease the content of IL-6, IL-7, and TNF-α, and increase the content of IL-10. The NF-κB and STAT3 protein expression levels were decreased. Conclusion By increasing the content of anti-inflammatory factor IL-10, decreasing the content of pro-inflammatory factors IL-6 and TNF-α, and inhibiting the expression of NF-κB and STAT3 proteins, Chang-An-Kang can reduce inflammatory infiltration. It has an obvious therapeutic effect on acetic acid ulcerative colitis in rats.

Circulating cytokines and alcoholic liver disease: a two-sample bidirectional Mendelian randomization study

Background Increased inflammation in the liver during ethanol exposure is a major feature of alcoholic liver disease (ALD). An important contributing component to the development of ALD is the inflammatory response brought on by immunological response, however the connection between individual circulating cytokines and ALD is still unclear. To ascertain the causation, we conducted a two-sample bidirectional Mendelian randomization research. Methods We extracted 41 cytokines and growth factors of 8293 Europeans and ALD cases of the same ethnicity (1416 cases and 217,376 controls) from the Genome-Wide Association Studies (GWAS) database for two-sample bidirectional MR analysis. Results Our analyses suggest that higher interleukin-7 (IL-7) levels are associated with an increased risk of ALD (p = 0.028, OR = 1.191,95% CI = 1.019–1.392), while tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a protective factor for ALD (p = 0.032, OR = 0.863, 95% CI = 0.754–0.988) which can reduce the risk of disease occurrence. In addition, genetically predicted ALD does not affect the expression of circulating cytokines regulators. Conclusions Our study supports that cytokines play a pivotal role in the pathogenesis of ALD. To determine the mechanisms and pathways of action of these biomarkers, further basic research is required to ensure their clinical suitability for preventing and treating ALD.

Circulating low density neutrophils are associated with resistance to anti-PD1 immunotherapy in squamous head and neck cancer.

Identification of predictive biomarkers to Immune checkpoint inhibitors (ICIs) in head and neck cancer (HNSCC) is an unmet need. This was a prospective observational study including 25 patients with HNSCC treated with immunotherapy or chemotherapy after a prior platinum-based regimen. Low density neutrophils (LDNs) and serum markers were analyzed. In the immunotherapy cohort, patients with high LDN levels had a shorter progression free survival (PFS) (1.8 months vs. 10.9 months; *p = 0.034). Also, progressors showed higher percentage of LDNs compared to non-progressors although significance was not reached (mean 20.68% vs. 4.095%, p = 0.0875). These findings were not replicated in patients treated with chemotherapy. High levels of interleukin-7 (IL7) were correlated with a significantly longer overall survival (OS) (13.47 months 3.51 vs. months, *p = 0.013). High baseline circulating LDNs and low IL7 could identify a subset of patients intrinsically refractory to ICIs as monotherapy in HNSCC.

Serum Inflammatory and Oxidative Stress Markers in Patients with Vitiligo.

Vitiligo is a common chronic hypomelanotic skin disorder. An intricate pool of markers associated with a complex combination of biological and environmental factors is thought to be implicated in etiology. This study aims to investigate the most important markers associated with vitiligo pathogenesis, including redox status, inflammation, and immune profile, in patients with vitiligo. The study included a total of 96 subjects: 30 patients with active non-segmental vitiligo, 30 patients with stable non-segmental vitiligo, and 36 controls. The vitiligo area severity index (VASI) and vitiligo disease activity score (VIDA) were determined. The following serum parameters were assessed: antioxidant status (TAS), superoxide dismutase activity (SOD), catalase activity (CAT), glutathione peroxidase activity (GPx), glutathione-S-transferase activity (GST), malondialdehyde (MDA), advanced oxidation protein products (AOPP), C reactive protein (CRP), interleukin-15 (IL-15), and chemokines (CXCL9, CXCL10). The VASI score was not significantly different between active and stable vitiligo patients, as it was approximately 0.1. TAS, CAT, GPx, and GST were significantly lower in vitiligo patients compared to controls (p < 0.05). They were also significantly lower in active vitiligo when compared to stable vitiligo (p < 0.05). However, SOD levels were significantly higher in vitiligo patients than in controls and in the active vitiligo group than in the stable vitiligo group (p < 0.05). MDA and AOPP levels were significantly higher in patients with active and stable vitiligo compared to controls (p < 0.05). However, they did not significantly differ between active and stable vitiligo patients (p < 0.05). In both active and stable vitiligo, CRP and IL-15 were significantly higher than controls (p < 0.05). Whereas CRP was significantly higher in active (range = 2.0-7.2, mean = 4.46 ± 1.09) than in stable vitiligo (range = 1.6-6.7, mean = 3.75 ± 1.08) (p < 0.05). There was no significant difference in IL-15 levels between active and stable vitiligo. In both active and stable vitiligo, CXCL9 and CXCL10 were significantly higher than controls (p < 0.05), and they were significantly higher in active than stable vitiligo (p < 0.05). In vitiligo, oxidative damage induces an increase in pro-inflammatory IL-15, which in turn promotes IFN-γ-inducible chemokines such as CXCL9 and CXCL10. Further, there seems to be a link between the VASI score and IL-15 levels. These data imply that inhibiting IL-15 could be a promising method for developing a potentially targeted treatment that suppresses the early interplay between oxidant stress and IL-15 keratinocyte production, as well as between resident and recirculating memory T cells.

Efficacy and safety study of neoadjuvant efineptakin alfa (NT-I7) and pembrolizumab in recurrent glioblastoma.

TPS2085 Background: Glioblastoma (GBM) is the most common and aggressive form of brain tumor in adults. Despite maximal surgical resection, irradiation, and chemotherapy, median overall survival (OS) remains at only 30 weeks for recurrent GBM (rGBM) patients, emphasizing the need for novel treatments. GBM tumors are immunologically ‘cold,’ in that they have an immune-suppressive microenvironment with a low number of tumor-infiltrating lymphocytes (TIL). Interleukin 7 (IL-7) plays a key role in T cell development and survival. The physiological level of IL-7 increases to stimulate T cell expansion in lymphopenic condition. Previous studies have shown that lymphopenic GBM patients have shorter survival. However, their IL-7 levels are unexpectedly low. Efineptakin alfa (NT-I7), a long-acting IL-7, has been shown to increase effector CD8 T cells and reduce suppressor T-regulatory cells in murine GBM models, with subsequently improved OS. Further, we recently completed a Phase I study which showed that NT-I7 is safe, well- tolerated, and increased absolute lymphocyte counts (ALC) in newly diagnosed GBM patients. Phase II dosing was determined through this Phase I study reaching maximum tolerated dose. Thus, we hypothesized that NT-I7 may reverse GBM-associated immune suppression and potentiate the effect of an immune checkpoint inhibitor, leading to an increase in TILs and improved survival. Our preliminary data suggests that combining NT-I7 with pembrolizumab, an anti-PD-1 antibody, improves survival in murine glioma models. The purpose of this study is to evaluate the safety and efficacy of combining NT-I7 and pembrolizumab in rGBM patients. Methods: This is an open-label single arm one-stage Phase II study of NT-I7 and pembrolizumab as neoadjuvant and adjuvant therapy with surgery for adult patients with rGBM. We plan to enroll 30 evaluable patients, including a 6-patient safety run-in. Key eligibility criteria include candidates willing to undergo clinically indicated resection or biopsy, age ≥ 18 years, Karnofsky performance status ≥ 70, and dexamethasone dose &gt; 2 mg/day ≤ 2 days prior to registration. The primary endpoint is a 9-month OS rate. Secondary endpoints include progression-free survival, objective response rate, changes in ALC, and adverse events profile. The correlative endpoints include studies to assess the anti-glioma immune response, changes in T cell subsets, T cell effector function, cytokine analysis, and immunohistochemical analysis of GBM tissue. Longitudinal cerebrospinal fluid proteomics is optional. This study opened on 1/20/2023. Two of the planned 30 patients had been enrolled by submission on 2/14/2023. Clinical trial information: NCT05465954 .

Mycobacterium Vaccae Vaccine Improve Incomplete Immune Recovery in AIDS Patients

Background: Mycobacterium seedling is rich in co-antigens and, a good immunomodulator with bidirectional immunomodulatory function. Objectives: The present study aimed to explore whether the Mycobacterium vaccae vaccine can improve the incomplete immune recovery of acquired immunodeficiency syndrome (AIDS) patients. Methods: According to the number of patients receiving human immunodeficiency virus (HIV) long-term treatment in the Ninth People’s Hospital of Chongqing, China, 100 patients with HIV-RNA quantitation of less than 103 cepies/ml, CD4 + T cell count less than 500/UL, and CD4+T cell count of more than 50/UL after 3 years of Haart treatment were selected. In total, they were randomly assigned to one of three groups, one group received an intramuscular injection of M. vaccae vaccine, one group received an intramuscular injection of growth hormone, and the last group received only a placebo injection. The levels and changes of naive T cells, Treg cells, total CD4+ T cells, T helper 1 (Th1), T helper 2 (Th2) cells, and interleukin 7 (IL-7) cytokine were measured at baseline and after 12, 48, and 50 weeks. Results: After 48 weeks of treatment, the total CD4+T cells, Th1 cells, and naive T cells in AIDS patients increased, while IL-7 cytokines, Treg cells, and Th2 cells decreased in M. vaccae vaccine and growth hormone group. There was no change in the placebo group, indicating that M. vaccae vaccine and growth hormone can improve the immune function of AIDS patients. After treatment, in group A (M. vaccae vaccine), there was an increase in the total CD4+T cells, Th1 cells, and naive T cells as well as a decrease in Treg cells, Th2 cells, and IL-7 cytokines. The only significant difference between M. vaccae vaccine and growth hormone groups was a decrease in Th1 cells in the M. vaccae vaccine group. After a 12-week follow-up, it was found that there were no cases of secondary infection in the M. vaccae vaccine group, one case in the growth hormone group, and five cases in the placebo group, demonstrating that the secondary infection rate in M. vaccae vaccine and the growth hormone groups was lower than that in the control group. Conclusion: The M. vaccae vaccine may decrease the levels of IL-7 as well as Treg and Th2 cells by increasing the levels of CD4+T cells, Th1 cells, and pure T cells in AIDS patients, leading to the improvement of immune reconstitution of AIDS patients to some extent.

Hydrosalpingeal fluid leads to subfertility via endometrial TNF-α and IL-7 and NF-κB signaling pathways.

To determine the concentrations of the nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α) and interleukin-7 (IL-7) in midluteal phase endometrial samples of infertile patients diagnosed with uni or bilateral hydrosalpinx (HX). A total of 24 patients who decided to undergo laparoscopic salpingectomy were included in the study. Salpingectomy indications consisted of patients with a diagnosis of hydrosalpinx (n=12) or ectopic pregnancy (n=12). Twelve healthy patients who underwent Pomeroy-type tubal ligation were considered as the second and healthy control group. The diagnosis of hydrosalpinges was made by transvaginal 2D ultrasonography or HSG. All patients in the hydrosalpinges or ectopic pregnancy group underwent laparoscopic salpingectomy. Just before salpingectomy, endometrial samples were obtained from all patients by Pipelle cannula. Endometrial sampling was performed 7-9 days after the LH surge in the control group. IL-7, NF-κB and TNF-α concentrations were measured by ELISA method in the endometrial samples of all three groups. The endometrial IL-7 concentration before salpingectomy of the patients in the hydrosalpinx group was 44.6±6.65 ng/mg wet-tissue. The IL-7 levels of the HX group were significantly higher than those of the patients in the ectopic pregnancy group (19.3±3.06 ng/mg wet tissue versus 44.6±6.65 ng/mg wet tissue, p<0.04). Similarly, IL-7 levels of the HX group were significantly higher than those of the tubal ligation group (6.08±1.48 ng/mg wet tissue versus 44.6±6.65 ng/mg wet tissue, p<0.03). The endometrial TNF-α concentration of the patients in the hydrosalpinx group was 33.20±5.40 ng/mg wet-tissue. The TNF-α value detected in the hydrosalpinx group was significantly higher than both the TNF-α value in the ectopic pregnancy group (11.8±1.07 ng/mg wet-tissue vs. 33.20±5.40 ng/mg wet-tissue, p<0.01) and the TNF-α value in the tubal ligation group (5.30±1.22 ng/mg wet-tissue vs. 33.20±5.40 ng/mg wet-tissue, p<0.01). The pre-salpingectomy endometrial NF-κB concentration of the patients in the hydrosalpinx group was 6.38±1.40 ng/mg wet-tissue. This value is higher than endometrial NF-κB levels in the ectopic pregnancy group (3.67±0.41 ng/mg wet-tissue vs. 6.38±1.40 ng/mg wet-tissue, p<0.02) and NF-κB levels in the tubal ligation group (1.07±0.38 ng/mg wet-tissue vs. 6.38±1.40 ng/mg wet-tissue, p<0.01). The presence of hydrosalpinx prevents successful implantation by increasing the levels of endometrial proinflammatory cytokines TNF-α, IL-7 and NF-κB.

The Change in Subpopulation and Function of Natural Killer Cells in Adult Patients with Infectious Mononucleosis Related Liver Injury

To investigate the changes of subpopulation and function of natural killer (NK) cells in adult patients with infectious mononucleosis related liver injury. Seventeen healthy controls, twenty-six patients of infectious mononucleosis (IM) without liver injury, and twenty-one IM patients with liver injury were enrolled in this study. Peripheral blood was collected. Plasma and peripheral blood mononuclear cells (PBMC) were purified. Plasma interleukin-15 (IL-15) level was measured by enzyme linked immunosorbent assay. Three NK cell subpopulations, including CD56+CD16-, CD56+CD16+, and CD56-CD16+ NK cells, were assessed by flow cytometry. PBMC were co-cultured with 721.221, K562, and P815-Ab cells, respectively. CD107a expression and CD16 mean fluorescence intensity (MFI) in NK cells was investigated by flow cytometry. PBMC from IM patients with liver injury were stimulated with anti-IL-15 neutralizing antibody, and the change of NK cell function was observed. One-way ANOVA and paired t test were used for statistical analysis. The percentage of CD56+CD16- NK cells in IM patients with liver injury (7.36±0.92)% and IM patients without liver injury (10.67±1.37)% were lower than that of controls (12.02±2.51)% (P<0.05). CD56+CD16- NK cell frequency in IM patients with liver injury also was lower than that in IM patients with liver injury (P<0.0001). The percentage of CD56+CD16+ NK cells in IM patients with liver injury (62.03±8.78)% and IM patients without liver injury (44.74±13.03)% were higher than that in controls (40.74±10.15)% (P<0.05). CD56+CD16+ NK cell frequency in IM patients with liver injury also was higher than that in IM patients with liver injury (P<0.0001). There was no statistical difference of CD56-CD16+ NK cell proportion among three groups (P=0.427). Plasma IL-15 level in IM patients with liver injury (309.1±68.00) pg/ml were higher than that in IM patients without liver injury (269.6±53.57) pg/ml and controls (257.4±73.93) pg/ml (P<0.05). NK cells induced target cell death through different receptors upon activation, the ratio of CD107a-positive cells in NK cells of IM patients with liver injury was higher than that in IM patients without liver injury and controls (P<0.05), while CD16 MFI in NK cells in IM patients with liver injury was lower than that in IM patients without liver injury and controls (P<0.05). The percentage of CD107a positive cells in NK cells was significantly reduced in response to anti-IL-15 neutralizing antibody stimulation in IM patients with liver injury (P<0.05). IM patients with liver injury presented imbalance of NK cell subpopulation and enhanced NK cell function. The elevation of IL-15 might contribute to promote NK cell cytotoxicity in IM patients with liver injury.

M6A RNA Methylation Decreases Atherosclerotic Vulnerable Plaque Through Inducing T Cells.

Knockdown of fat mass and obesity-associated gene (FTO) can induce N6-methyladenosine (m6A) ribonucleic acid (RNA) methylation. The objective of this study was to explore the effect of m 6A RNA methylation on atherosclerotic vulnerable plaque by FTO knockdown. A total of 50 New Zealand white rabbits were randomly divided into pure high-fat group, sham operation group, vulnerable plaque group, empty load group, and FTO knockdown group (10 rabbits/group). Flow cytometry showed that helper T (Th) cells in the FTO knockdown group accounted for a significantly higher proportion of lymphocytes than in the vulnerable plaque group and empty load group (P<0.05). Th cells were screened by cell flow. The level of m6A RNA methylation in the FTO knockdown group was significantly higher than in the vulnerable plaque group and empty load group (P<0.05). The levels of total cholesterol, triglyceride, and low-density lipoprotein C were higher at the 12th week than at the 1st week, but the high-density lipoprotein C level was lower at the 12th week than at the 1st week. At the 12th week, the interleukin-7 level was significantly lower in the adeno-associated virus-9 (AVV9)-FTO short hairpin RNA group than in the control and AVV9-green fluorescent protein groups (P<0.001). After successfully establishing a vascular parkinsonism rabbit model, m6A RNA methylation can decrease Th cells and vulnerable atherosclerotic plaques.

Twelve-week treadmill endurance training in mice is associated with upregulation of interleukin-15 and natural killer cell activation and increases apoptosis rate in Hepa1-6 cell-derived mouse hepatomas.

Regular exercise reduces the risk of malignancy and decreases the recurrence of cancer. However, the mechanisms behind this protection remain to be elucidated. Natural killer (NK) cells are lymphocytes of the innate immune system, which play essential roles in immune defense and effectively prevent cancer metastasis. Physical exercise can increase the activity of NK cells. Interleukin-15 (IL-15) is the best-studied cytokine activator of NK cells, and it was shown to have many positive functional effects on NK cells to improve antitumor responses. The aim of this study was to clarify the possible important mechanisms behind endurance exercise-induced changes in NK cell function, which may be highly correlated with IL-15. An animal model was used to study IL-15 expression level, tumor volume, cancer cell apoptosis, and NK cell infiltration after treadmill exercise. Although IL-15 was highly expressed in skeletal muscle, treadmill exercise further elevated IL-15 levels in plasma and muscle (P<0.05). In addition, tumor weight and volume of tumor-bearing mice were decreased (P<0.05), and liver tumor cell apoptosis was increased after 12 weeks of treadmill exercise (P<0.05). NK cell infiltration was upregulated in tumors from treadmill exercise mice, and the level of interferon-gamma (IFN-γ) and IL-15 were higher than in sedentary mice (P<0.05). The study indicated that regular endurance training can reduce cancer risk, which was related to increased IL-15 expression, activation of the immune killing effect of NK cells, and promotion of tumor cell apoptosis, which can ultimately control tumor growth.