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Simple Summary: The obesity epidemic in the USA is increasing the risk of aggressive triple-negative breast cancer (TNBC) in obese women. This study investigated the potential impact of obesity on the advancement of TNBC by amplifying leukemia inhibitory factor receptor (LIFR) signaling. We tested the effects of LIFR inhibition using EC359 on TNBC cells in obesity conditions. The obesity environment increased TNBC cell growth and invasion, and treatment with EC359 effectively reduced these effects. Using TNBC cells, patient-derived organoids, and mouse models, we showed that EC359 can inhibit obesity-linked TNBC progression. Collectively, our results suggest targeting LIFR signaling as a potential treatment for obesity-related TNBC. American women with obesity have an increased incidence of triple-negative breast cancer (TNBC). The impact of obesity conditions on the tumor microenvironment is suspected to accelerate TNBC progression; however, the specific mechanism(s) remains elusive. This study explores the hypothesis that obesity upregulates leukemia inhibitory factor receptor (LIFR) oncogenic signaling in TNBC and assesses the efficacy of LIFR inhibition with EC359 in blocking TNBC progression. TNBC cell lines were co-cultured with human primary adipocytes, or adipocyte-conditioned medium, and treated with EC359. The effects of adiposity were measured using cell viability, colony formation, and invasion assays. Mechanistic studies utilized RNA-Seq, Western blotting, RT-qPCR, and reporter gene assays. The therapeutic potential of EC359 was tested using xenograft and patient-derived organoid (PDO) models. The results showed that adipose conditions increased TNBC cell proliferation and invasion, and these effects correlated with enhanced LIFR signaling. Accordingly, EC359 treatment reduced cell viability, colony formation, and invasion under adipose conditions and blocked adipose-mediated organoid growth and TNBC xenograft tumor growth. RNA-Seq analysis identified critical pathways modulated by LIF/LIFR signaling in diet-induced obesity mouse models. These findings suggest that adiposity contributes to TNBC progression via the activation of the LIF/LIFR pathway, and LIFR inhibition with EC359 represents a promising therapeutic approach for obesity-associated TNBC. [ABSTRACT FROM AUTHOR]

Background: While the effect of biomaterials covering the pulp tissue is considered in the success of pulpotomy treatment, the level of pulpal inflammation is still very important for treatment success. The aim of this study was to compare IL-6 and IL-8 levels, known as good indicators of pulpal inflammation, with a new biomarker, presepsin, and to evaluate the impact of biomarker levels along with the pulp capping agents used in the treatment on the one-year success of pulpotomy treatment. Methods: The study included 120 primary second molar teeth with pulpotomy indications from 75 children. To determine the pulpal inflammation status, pulpal bleeding samples were taken during treatment, and the levels of IL-6, IL-8, and presepsin were measured. During the pulpotomy treatment, MTA, NeoMTA™, and Biodentine™, and ZOE were randomly applied to groups of thirty teeth each. Patients were monitored for a period of 12 months post-treatment. Results: IL-8, IL-6, and presepsin levels were significantly higher in teeth with pathology (p < 0.001). Biomarker levels were found to be higher in the NeoMTA and Biodentine groups, but this did not result in a statistically significant difference. (p > 0.05) Following pulpotomy treatment, the most successful material groups in order were MTA, ZOE, NeoMTA™, and Biodentine™. Conclusion: Presepsin may be a usable indicator in predicting the level of inflammation. At the end of the one-year follow-up of pulpotomy treatment, more pathology was observed in the NeoMTA and Biodentine groups, where biomarker levels were higher, while no pathology was found in the MTA group, where biomarker levels were lower. Trial registration: NCT06398327/ 20,240,503. [ABSTRACT FROM AUTHOR]

Simple Summary: Roughly 430,000 new cases of renal cell carcinoma (RCC) occurred worldwide in 2022, and about one-third of RCC cases are diagnosed at an advanced stage of disease (aRCC). When patients with aRCC fail first-line treatment, they commonly receive one of the recommended second-line treatments, i.e., axitinib, cabozantinib, lenvatinib plus everolimus, pazopanib, sunitinib, or tivozanib. Axitinib is a second-generation tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor tyrosine kinases 1, 2, and 3. It has been available since 2011 for the treatment of aRCC after the failure of prior therapy with sunitinib or cytokines. The aim of our research was to understand how axitinib compares with other treatment options considering data from clinical trials and observational studies that reflect real-world clinical practice. Therefore, we conducted a systematic literature review to summarise evidence on commonly used and recommended treatments in aRCC after the failure of prior therapy with sunitinib or cytokines. Background: We conducted a systematic literature review (SLR) to identify clinical evidence on treatments in advanced renal cell carcinoma (aRCC) after the failure of prior therapy with cytokines, tyrosine kinase inhibitors, or immune checkpoint inhibitors. Herein, we summarise the evidence for axitinib in aRCC after the failure of prior therapy with cytokines or sunitinib. Methods: This SLR was registered with PROSPERO (CRD42023492931) and followed the 2020 PRISMA statement and the Cochrane guidelines. Comprehensive searches were conducted in MEDLINE and Embase as well as for conference proceedings. Study eligibility was defined according to population, intervention, comparator, outcome, and study design. Results: Of 1252 titles/abstracts screened, 266 peer-reviewed publications were reviewed, of which 182 were included. In addition, 28 conference abstracts were eligible. Data on axitinib were reported in 55 publications, of which 16 provided efficacy and/or safety outcomes on axitinib after therapy with sunitinib or cytokines. In these patients, median progression-free and overall survival ranged between 5.5 and 8.7 months and 11.0 and 69.5 months, respectively. Conclusions: Axitinib is commonly used in clinical practice and has a well-characterised safety and efficacy profile in the treatment of patients with aRCC after the failure of prior therapy with sunitinib or cytokines. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes (T2D) has become an epidemic. Delays in diagnosis and as a consequent late treatment has resulted in high prevalence of complications and mortality. Secreted frizzled-related protein 4 (SFRP4), has been recently identified as a potential early biomarker of T2D related to obesity, due to its association with low grade inflammation in adipose tissue and impaired glucose metabolism. We aimed to evaluate the role of SFRP4 in prediabetes and T2D in a Mexican population. Methods: This was a cross-sectional study that included 80 subjects with T2D, 50 subjects with prediabetes and 50 healthy individuals. Fasting SFRP4 and insulin concentrations were measured by ELISA. Human serum IL-10, IL-6, IL-1β and IL-8 levels were quantified by flow cytometry. Genotyping was performed by TaqMan® probes. Results: Prediabetes and T2D patients had significantly higher SFRP4 levels than controls (P < 0.05). In turn, prediabetes subjects had higher SFRP4 concentrations than control subjects (P < 0.05). Additionally, the prediabetes and T2D groups had higher concentrations of proinflammatory molecules such as IL-6, IL-1β and IL-8, and lower concentrations of IL-10, an anti-inflammatory cytokine, than controls (P < 0.001). The serum SFRP4 concentrations were positively correlated with parameters that are elevated in prediabetes and T2D states, such as, HbA1c and homeostasis model assessment insulin resistance (HOMA-IR), (r = 0.168 and 0.248, respectively, P < 0.05). Also, serum SFRP4 concentrations were positively correlated with concentrations of pro-inflammatory molecules (CRP, IL-6, IL-1β and IL-8) and negatively correlated with the anti-inflammatory molecule IL-10, even after adjusting for body mass index and age (P < 0.001). The genetic variant rs4720265 was correlated with low HDL concentrations in T2D (P < 0.05). Conclusions: SFRP4 correlates positively with the stage of prediabetes, suggesting that it may be an early biomarker to predict the risk of developing diabetes in people with high serum concentrations of SFRP4, although further longitudinal studies are required. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer, notorious for its aggressive nature and complex desmoplastic tumor microenvironment, poses substantial treatment challenges, particularly in terms of early detection, and often exhibits resistance to standard chemotherapy and immunotherapy. Trametinib is a new therapeutic drug, a selective inhibitor of MEK1 and MEK2, which has shown promise in addressing these challenges. It not only hampers cancer cell division, angiogenesis, and metastatic spread but also significantly modifies the tumor microenvironment. This modification includes altering the activities of fibroblasts and immune cells, which are crucial in the cancer's progression and response to treatments. Several pivotal studies have highlighted trametinib's efficacy in reducing the proliferation of pancreatic cancer cells and enhancing the effectiveness of combined treatment regimens, especially in cases that show resistance to conventional therapies. The drug's potential to improve patient outcomes is currently under investigation in various clinical trials. These trials, encompassing different stages and forms of pancreatic cancer, are instrumental in determining the optimal use of trametinib, both as a single agent and in combination with other drugs. The ongoing research is crucial in defining trametinib's role in the evolving therapeutic landscape for pancreatic cancer, aiming to provide new avenues for treatment and potentially improve survival rates in this challenging disease area. Pancreatic cancer is characterized by fibrosis/desmoplasia in the tumor microenvironment, which is primarily mediated by pancreatic stellate cells and cancer-associated fibroblasts. HGF/c-MET signaling, which is instrumental in embryonic development and wound healing, is also implicated for its mitogenic and motogenic properties. In pancreatic cancer, this pathway, along with its downstream signaling pathways, is associated with disease progression, prognosis, metastasis, chemoresistance, and other tumor-related factors. Other features of the microenvironment in pancreatic cancer with the HGF/c-MET pathway include hypoxia, angiogenesis, metastasis, and the urokinase plasminogen activator positive feed-forward loop. All these attributes critically influence the initiation, progression, and metastasis of pancreatic cancer. Therefore, targeting the HGF/c-MET signaling pathway appears promising for the development of innovative drugs for pancreatic cancer treatment. One of the primary downstream effects of c-MET activation is the MAPK/ERK (Ras, Ras/Raf/MEK/ERK) signaling cascade, and MEK (Mitogen-activated protein kinase kinase) inhibitors have demonstrated therapeutic value in RAS-mutant melanoma and lung cancer. Trametinib is a selective MEK1 and MEK2 inhibitor, and it has evolved as a pivotal therapeutic agent targeting the MAPK/ERK pathway in various malignancies, including BRAF-mutated melanoma, non-small cell lung cancer and thyroid cancer. The drug's effectiveness increases when combined with agents like BRAF inhibitors. However, resistance remains a challenge, necessitating ongoing research to counteract the resistance mechanisms. This review offers an in-depth exploration of the HGF/c-MET signaling pathway, trametinib's mechanism, clinical applications, combination strategies, and future directions in the context of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is currently the second leading cause of cancer death worldwide. Cytokines are small proteins that carry messages between cells and are known to play an important role in the body's response to inflammation and infection. Cytokines are important for immunity in lung cancer. The immune system relies heavily on cytokines which can also be produced in the laboratory for therapeutic use. Cytokine therapy helps the immune system to stop the growth or kill cancer cells including lung cancer cells. High doses of cytokines are required to induce a beneficial response in cancer patients, but doing so leads to many problems, including their short lifespan and toxicity. New technologies are being developed to help improve the targeting of cytokines and alter their side effects. Lung cancer is currently the second leading cause of cancer death worldwide. In recent years, checkpoint inhibitor immunotherapy (ICI) has emerged as a new treatment. A better understanding of the tumor microenvironment (TMJ) or the immune system surrounding the tumor is needed. Cytokines are small proteins that carry messages between cells and are known to play an important role in the body's response to inflammation and infection. Cytokines are important for immunity in lung cancer. They promote tumor growth (oncogenic cytokines) or inhibit tumor growth (anti-tumour cytokines) by controlling signaling pathways for growth, proliferation, metastasis, and apoptosis. The immune system relies heavily on cytokines. They can also be produced in the laboratory for therapeutic use. Cytokine therapy helps the immune system to stop the growth or kill cancer cells. Interleukins and interferons are the two types of cytokines used to treat cancer. This article begins by addressing the role of the TMJ and its components in lung cancer. This review also highlights the functions of various cytokines such as interleukins (IL), transforming growth factor (TGF), and tumor necrosis factor (TNF). [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to investigate the association of neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios (PLR) with standard inflammation parameters, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), complement component C3, anti-double-stranded deoxyribonucleic acid (anti-dsDNA), anti-nucleosome and anti-C1q antibodies, and serum and urinary monocyte-chemoattractant protein-1 (MCP-1) with disease activity in patients with systemic lupus erythematosus (SLE). Results: This study included 160 patients (145 female and 15 male patients), hospitalized at the Rheumatology Department. A positive correlation between NLR and ESR (p < 0.01), anti-dsDNA antibodies (p < 0.05), and PLR (p < 0.001) was obtained, with a negative correlation with C3 (p < 0.005). PLR shows a positive correlation with ESR (p < 0.001), CRP (p < 0.005), anti-dsDNA antibodies (p < 0.001), anti-nucleosome antibodies (p < 0.05), and urine MCP-1 (p < 0.05), with a negative correlation with C3 (p < 0.005). Univariate analysis showed that all the examined laboratory parameters were independent predictors of disease activity (p < 0.001), while the method of standard multiple regression analysis revealed the most significant ESR and serum MCP-1 (p < 0.05). Conclusions: NLR and PLR, as inexpensive and accessible biomarkers, can help in routine clinical practice for the estimation of disease activity in SLE patients. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies (mAbs) are described as brand-new tools used in the therapy of cancer, autoimmune and infectious diseases, transplant rejection, and some other new indications. MAbs have been shown to create some adverse events such as hypersensitivity reactions, immunological problems, cardiovascular diseases, respiratory events, proteinuria, nephrotoxicity, dermatologic events, and cytopenia. In this review, our purpose is to overview the indications and the unwanted events matched with these drugs and negotiate the developments in the development of these drugs that are able to increase the efficacy and decrease the safety problems. [ABSTRACT FROM AUTHOR]

Objective: Evidence regarding effectiveness of interleukin‐1 receptor antagonism in multisystem inflammatory syndrome in children (MIS‐C) is lacking. We characterized variation in initial treatment with anakinra and evaluated cardiovascular outcomes associated with adding anakinra to standard initial therapy. Methods: We conducted a retrospective cohort study of MIS‐C cases in a US surveillance registry from November 2020 to December 2021. Day 0 was the first calendar day of immunomodulatory treatment. Factors associated with initial anakinra use (days 0–1) were identified. We compared cases in patients ages 2–20 years receiving intravenous immunoglobulin (IVIG) and glucocorticoids versus anakinra plus IVIG and/or glucocorticoids on days 0–1, using inverse probability weighting to balance disease severity. Primary outcomes were vasopressor requirement on day 3 and impaired left ventricular ejection fraction on days 3–4. The secondary outcome was 50% reduction in C‐reactive protein on day 3. Results: Among 1,516 MIS‐C cases at 44 sites, 193 (13%) patients received anakinra alone or with other immunomodulators as initial treatment (range 0–74% by site). Site accounted for 59% of residual variance in anakinra use. After balancing disease severity, initial treatment with anakinra plus IVIG and/or glucocorticoids (n = 121) versus IVIG plus glucocorticoids (n = 389) was not associated with significant differences in vasopressor requirement (25.6% versus 20.1%, respectively; risk ratio [RR] 1.27 [95% confidence interval (95% CI) 0.88–1.84]), ventricular dysfunction (33.7% versus 25.7%, respectively; RR 1.31 [95% CI 0.98–1.75]), or C‐reactive protein reduction. Conclusion: We identified substantial variation in initial anakinra use in a real‐world population of children with MIS‐C, but no average short‐term improvement in cardiovascular outcomes associated with early addition of anakinra to IVIG and/or glucocorticoids compared to IVIG and glucocorticoids alone. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite multi-modal treatment consisting of surgery, chemotherapy, and radiation, glioblastoma inevitably recurs due to its diffuse infiltrative nature. Anti-tumor immune responses, supported by pro-inflammatory cytokines, that can seek out remote cancer vestiges will likely become part of the therapeutic armamentarium but will require thoughtful selection, combinatorial vetting, and innovative delivery strategies. Cytokines play an important role in regulating the immune response. Although there is great interest in exploiting cytokines for cancer immunotherapy, their clinical potential is limited by their pleiotropic properties and instability. A variety of cancer cell-intrinsic and extrinsic characteristics pose a barrier to effective treatments including cytokines. Recent studies using gene and cell therapy offer new opportunities for targeting cytokines or their receptors, demonstrating that they are actionable targets. Current efforts such as virotherapy, systemic cytokine therapy, and cellular and gene therapy have provided novel strategies that incorporate cytokines as potential therapeutic strategies for glioblastoma. Ongoing research on characterizing the tumor microenvironment will be informative for prioritization and combinatorial strategies of cytokines for future clinical trials. Unique therapeutic opportunities exist at the convergence of cytokines that play a dual role in tumorigenesis and immune modulation. Here, we discuss the underlying strategies in pre- and clinical trials aiming to enhance treatment outcomes in glioblastoma patients. [ABSTRACT FROM AUTHOR]

Objective: Radiation‐induced skin injury (RISI) remains a serious concern during radiotherapy. IL‐10 is considered as an immune suppressive cytokine by inhibiting the secretion of the proinflammatory cytokines in cells. The aim of this study was to evaluate the protective role of Erb (IL10) 2 against ionizing radiation. Methods: We fused Interleukin 10 (IL‐10) dimer onto an anti‐epidermal growth factor receptor antibody Cetuximab (Erbitux) to form a new bispecific protein Erb‐(IL10)2. The protective effect and biological activity of Erb‐(IL10)2 was measured in model of RISI. Results: Under the condition of 20 Gy irradiation, surviving cells in the IR group decreased significantly compared with the non‐IR group (p = 0.0021). The survival rates of HaCaT (p = 0.0038) and WS1 (p = 0.0003) cells were significantly increased after IL‐10 treatment. The apoptosis rates of HaCaT (p = 0.0048) and WS1 (p = 0.0074) cells in the IL‐10 group were significantly lower compared to the NC group. Under 20 Gy irradiation conditions, IL‐10 fusion protein reduced the level of reactive oxygen in HaCaT (p = 0.0046) and WS1 (p<0.0001) cells compared to the control group. Relatively normal granular mitochondrial morphology was observed in the IL‐10 group after 20 Gy X‐ray irradiation compared with the NC group. Ater 35 Gy electron radiation, the levels of reactive oxygen species in the skin tissue of C57/B6 mice injected with IL‐10 fusion protein were significantly lower than those in the PBS group (p = 0.001). Compared with the PBS group and the other IL‐10 groups, the group treated with 0.2 mg/kg IL‐10 showed a significant decrease in MDA level (p = 0.0024). Compared with the PBS group, the thickness of the stratum corneum in groups treated with 0.05, 0.1 and 0.2 mg/kg IL‐10 decreased, and the skin appendages were well‐preserved. In the group treated with 0.2 mg/kg IL‐10, the skin tissue structure was still relatively intact, and the masson staining area was smaller than that of the PBS group. Conclusion: IL‐10 plays a role in inhibiting radioactive fibrosis in radioactive skin injury. IL‐10 has a protective effect on skin cell damage after ionizing radiation irradiation both in vitro and in vivo. Moreover, IL‐10 plays a role in inhibiting radioactive fibrosis in radioactive skin injury. [ABSTRACT FROM AUTHOR]

Simple Summary: This was a phase III randomized controlled trial investigating the outcomes of low-dose interleukin-2 (IL-2) plus interferon alfa (IFNα) versus sunitinib as the first line and axitinib as the second line in patients with low- and intermediate-risk metastatic renal cell carcinoma (mRCC). There was a trend toward better total progression-free survival up to the end of the second line for IL-2 + IFNα but no significant advantage in terms of overall survival. The study was underpowered to draw any definitive conclusions. The results showed no clear advantage of IL-2 + IFNα over sunitinib in the first line; however, it may be an option in some relatively low-risk mRCC cases due to the difference in the adverse events profile. This trial was registered with the University Hospital Medical Information Network (UMIN), center identifier UMIN 000012522. Background: The sequence of first-line cytokine and second-line molecular targeted therapies may be suitable for some patients with metastatic renal cell carcinoma (mRCC) because of the expectation of complete remission and durable response achieved with cytokine therapy. Methods: This was a phase III randomized controlled trial investigating the outcomes of low-dose interleukin-2 (IL-2) plus interferon alfa (IFNα) versus sunitinib as the first line and axitinib as the second line in patients with low- and intermediate-risk mRCC. Results: Thirty-five patients were randomly assigned. The total progression-free survival (PFS) to the end of the second line was 29.0 months (95% CI, 11.7–46.3) in the IL-2 + IFNα group and 16.3 months (95% CI, 6.3–26.4) in the sunitinib group. The PFS hazard ratio for the IL-2 + IFNα group relative to the sunitinib group was 0.401 (95% CI, 0.121–1.328; p = 0.135). The hazard ratio for overall survival (OS) was 1.675 (95% CI, 0.418–6.705; p = 0.466), which was better in the sunitinib group than in the IL-2 + IFNα group but not statistically significant. The types of adverse events (AEs) differed significantly, although there was no significant difference in the incidence of AEs. Conclusions: There was a trend toward better total PFS for IL-2 + IFNα, but it was not significant. There was also no advantage of IL-2 + IFNα in terms of OS. The study was underpowered to draw any definitive conclusions. The results showed no clear advantage of IL-2 + IFNα over sunitinib in the first-line setting; however, it may be an option in some relatively low-risk mRCC cases due to the difference in the AE profile. This trial was registered with the University Hospital Medical Information Network (UMIN), center identifier UMIN 000012522. [ABSTRACT FROM AUTHOR]

Objective: To determine the efficacy of CXCL5 administration in lupus‐prone MRL/lpr (Faslpr) mice and elucidate its working mechanisms. Methods: CXCL5 expression in blood (obtained from SLE patients and Faslpr mice) and major internal organs (obtained from Faslpr mice) was examined by Luminex, real‐time polymerase chain reaction, and immunofluorescent staining analyses. Pharmacokinetic studies were performed in Faslpr mice and healthy Institute of Cancer Research mice. Efficacy of CXCL5 administration was demonstrated in Faslpr mice, and the working mechanism of CXCL5 treatment was elucidated by flow cytometry, Luminex, and RNA sequencing. Results: In SLE patients, serum CXCL5 levels were significantly lower than in healthy individuals (P < 0.0001) and negatively correlated with disease activity (P = 0.004). In Faslpr mice, disease severity progressed with age and was negatively associated with plasma CXCL5 levels. Intravenous administration of CXCL5 to Faslpr mice restored endogenous circulatory CXCL5, improved mice survival, and reduced anti–double‐stranded DNA antibodies, proteinuria, lupus nephritis activity and chronicity indices, renal complements, and neutrophil extracellular traps over short‐term (10 weeks) and long‐term (2 years) time periods. In vitro and in vivo assays demonstrated that CXCL5 dictated neutrophil trafficking and suppressed neutrophil activation, degranulation, proliferation, and renal infiltration. Renal and splenic RNA sequencing further showed that CXCL5‐mediated immunomodulation occurred by promoting energy production in renal‐infiltrated immune cells, activating certain T cells, and reducing tissue fibrosis, granulocyte extravasation, complement components, and interferons. Further factorial design results indicated that CXCL5 appears to enhance host tolerability to cyclophosphamide in vulnerable individuals. Conclusion: We found that serum CXCL5 levels were significantly lower in SLE patients than in healthy individuals and were negatively correlated with disease activity. By administering CXCL5 intravenously in a mouse model of lupus, mouse survival improved, and indices of disease activity reduced significantly. Taken together, these findings indicate CXCL5 administration may represent a novel myeloid/neutrophil‐targeting therapy for SLE. [ABSTRACT FROM AUTHOR]

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Background: It is known that coronavirus disease-2019 (COVID-19) pneumonia causes cytokine storm, and treatment modalities are being developed on inhibition of proinflammatory cytokines. We aimed to investigate the effects of anticytokine therapy on clinical improvement and the differences between anticytokine treatments. Materials and methods: A total of 90 patients with positive COVID-19 polymerase chain reaction (PCR) test were divided into three groups, group I (n = 30) was given anakinra, group II (n = 30) was given tocilizumab, and group III (n = 30) was given standard treatment. Group I was treated with anakinra for 10 days; tocilizumab, intravenously, was given in group II. Group III patients were selected from those who did not receive any anticytokine treatment other than the standard treatment. Laboratory values, Glasgow coma scale (GCS), and PaO2/FiO2 values were analyzed on days 1, 7, and 14. Results: The seventh-day mortality rates were 6.7% in group II, 23.3% in group I, and 16.7% in group III. In group II, the ferritin levels on the 7th and 14th days were significantly lower (p = 0.004), and the lymphocyte levels on the seventh day were significantly higher (p = 0.018). Examining the changes between the first intubation days, in the early period (seventh day), group I was found to be 21.7%, group II was 26.9%, and group III was 47.6%. Conclusion: We observed the positive effects of the use of tocilizumab on clinical improvement in the early period; mechanical ventilation requirement was delayed and at a lower rate. Anakinra treatment did not change mortality and PaO2/FiO2 rates. Mechanical ventilation requirements occurred earlier in the patients who were not receiving any anticytokine therapy. Studies with larger patient populations are needed to demonstrate the potential efficacy of anticytokine therapy. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to present our experience on anakinra, a recombinant interleukin-1 (IL-1) receptor antagonist, and efficacy results in pediatric rheumatic diseases in our clinic. Patients and methods: Between July 1st, 2016 and July 1st, 2020, a total of 33 pediatric patients (18 males, 15 females; mean age: 6±3.4 years; range 4 to 13 years) with pediatric rheumatic diseases who were treated with anakinra were retrospectively analyzed. The patients with over one-month treatment period and followed for at least one year were included. Demographic and clinical findings, outcomes, adverse events, prior and/or additional treatments were collected at baseline, at 3 and 12 months of therapy. Results: There were 33 patients with different pediatric rheumatic diseases (11 with systemic juvenile idiopathic arthritis [sJIA] complicated by macrophage activation syndrome [MAS], six with hyperimmunoglobulin-D syndrome, five with cryopyrin-associated periodic syndrome, five with familial Mediterranean fever, four with idiopathic recurrent pericarditis, one with NLRP12-associated periodic fever syndrome and one with unclassified systemic autoinflammatory disease), in the study group. The complete response was observed 69.7% of patients, partial response in 24.2%, and no response in 6.1% at three months of treatment. Inactive disease status was achieved in 45.5% of the patients with remission-on medication and 18.2% of the patients with remission-off medication at the end of a year. Anakinra was switched to other biological treatments in 51.5% of patients (n=17). Biological switch to canakinumab and tocilizumab were observed in 70.6% and 29.4% of these patients. Except for local reactions (n=2), no adverse events were observed in any of the patients. Conclusion: Anakinra appears to be a promising treatment alternative owing to its rapid effect as a result of its short half-life in autoinflammatory conditions. While short-term therapy seems to be sufficient for the sJIA complicated by MAS, the patients with systemic autoinflammatory diseases maintenance a more anakinra-dependent course. [ABSTRACT FROM AUTHOR]

Hashimoto's thyroiditis (HT) results from chemoattraction of inflammatory cells toward the thyroid gland by inducing the production of interferon-gamma (IFNγ)-induced protein 10 (IP10) by T helper (Th) 1 cells. Vitamin D may suppress the IFNγ-IP10 axis, but this new function of vitamin D has not yet been investigated in HT patients. In an intervention and control group, patients received 50000 IU cholecalciferol or placebo every week for three months, respectively. The CD4+ T cells of 40 patients were isolated, and the mRNA expression levels of vitamin D receptor (VDR), peroxisome proliferator-activated receptors (PPAR)-α, and PPAR-γ genes were determined by real-time PCR. ELISA method was used to determine serum levels of vitamin D, tumor necrosis factor-alpha (TNF-α), IFN-γ, and IP10. Vitamin D levels in the intervention group were significantly higher than in the placebo group after supplementation. PPAR-α and PPAR-γ gene expression levels did not differ significantly between the two groups. The serum levels of IP10, IFNγ, and TNF-α decreased significantly in the vitamin D group, as well as in the placebo group.  During this study, vitamin D levels significantly increased in the intervention group and inflammatory factors decreased. Based on the similar results obtained in the placebo group, further studies with larger sample sizes and longer intervention times are recommended. [ABSTRACT FROM AUTHOR]

Simple Summary: The benefits of physical exercise against cancer onset and progression, as well as the adverse effects of physical inactivity have changed the way that we utilize exercise for cancer patients. Nevertheless, although guidelines of various scientific societies and organizations propose exercise as a complementary intervention during cancer therapies, the exact cellular and molecular mechanisms by which exercise acts against cancer have not yet been elucidated. In the present review, we analyze the factors which either are secreted from skeletal muscle or are regulated by exercise and can restrain cancer evolution. We also describe the exercise-induced factors that counteract severe side effects of cancer treatment, as well as the ways that muscle-derived factors are delivered to the target cells. A growing body of in vitro and in vivo studies suggests that physical activity offers important benefits against cancer, in terms of both prevention and treatment. However, the exact mechanisms implicated in the anticancer effects of exercise remain to be further elucidated. Muscle-secreted factors in response to contraction have been proposed to mediate the physical exercise-induced beneficial effects and be responsible for the inter-tissue communications. Specifically, myokines and microRNAs (miRNAs) constitute the most studied components of the skeletal muscle secretome that appear to affect the malignancy, either directly by possessing antioncogenic properties, or indirectly by mobilizing the antitumor immune responses. Moreover, some of these factors are capable of mitigating serious, disease-associated adverse effects that deteriorate patients' quality of life and prognosis. The present review summarizes the myokines and miRNAs that may have potent anticancer properties and the expression of which is induced by physical exercise, while the mechanisms of secretion and intercellular transportation of these factors are also discussed. [ABSTRACT FROM AUTHOR]

Treatment paradigm for metastatic clear cell renal cell carcinoma (mccRCC) has changed dramatically over the recent decades. From cytokines, interleukin-2 and interferon-α to tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors, during the last decade, combinations of immune checkpoint inhibitors have taken over first-line treatment of mccRCC. These combinations are approved based on results from large phase III clinical trials, all of which used sunitinib as the comparator. These trials include CheckMate214 (ipilimumab plus nivolumab), KEYNOTE 426 (pembrolizumab plus axitinib), JAVELIN Renal 101 (avelumab plus axitinib), CheckMate 9ER (nivolumab plus cabozantinib), and the CLEAR study (lenvatinib and pembrolizumab). Results from these studies constitute milestones for newer therapeutic approaches in mccRCC. The broadening spectrum of treatment options for patients with mccRCC with multiple first-line options currently available also means that treating physicians will need to consider each option carefully, balance clinical factors, financial considerations, and weigh toxicity profiles of each drug before deciding the optimal treatment regimen for each individual patient. We describe each frontline treatment option in detail through this review to aid the decision-making process. [ABSTRACT FROM AUTHOR]

Objectives The treatment of GCA relies on corticosteroids but is burdened by a high rate of relapses and adverse effects. Anti-IL-6 treatments show a clear benefit with a significant steroid-sparing effect, but late relapses occur after treatment discontinuation. In addition to IL-6, IL-1 also appears to play a significant role in GCA pathophysiology. We report herein the efficacy of anakinra, an IL-1 receptor antagonist, in six GCA patients exhibiting corticosteroid dependence or resistance, specifically analysing the outcome of aortitis in four of them. Methods This retrospective study analysed the cases of all GCA patients treated with anakinra from the French Study Group for Large Vessel Vasculitis. Results After a median duration of anakinra therapy of 19 (18–32) months, all six patients exhibited complete clinical and biological remission. Among the four patients with large-vessel involvement, one had a disappearance of aortitis under anakinra and three showed a decrease in vascular uptake. After a median follow-up of 56 (48–63) months, corticosteroids were discontinued in four patients, and corticosteroid dosage could be decreased to 5 mg/day in two patients. One patient relapsed 13 months after anakinra introduction in the context of increasing the daily anakinra injection interval to every 48 h. Three patients experienced transient injection-site reactions, and one patient had pneumonia. Conclusion In this short series, anakinra appears to be an efficient and safe steroid-sparing agent in refractory GCA, with a possible beneficial effect on large-vessel involvement. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of anakinra compared to triamcinolone in the treatment of gout flares. Methods: Patients for whom nonsteroidal antiinflammatory drugs and colchicine were not suitable treatments were enrolled in this multicenter, randomized, double‐blind study with follow‐up for up to 2 years. The study was designed to assess superiority of anakinra (100 or 200 mg/day for 5 days) over triamcinolone (40 mg in a single injection) for the primary end point of changed patient‐assessed pain intensity in the most affected joint (scored on a visual analog scale of 0–100) from baseline to 24–72 hours. Secondary outcome measures included: safety, immunogenicity, and patient‐ and physician‐assessed global response. Results: One hundred sixty‐five patients were randomized to receive anakinra (n = 110) or triamcinolone (n = 55). The median age was 55 years (range 25–83), 87% were men, the mean disease duration was 8.7 years, and the mean number of self‐reported flares during the prior year was 4.5. A total of 301 flares were treated (214 with anakinra; 87 with triamcinolone). Anakinra in both doses and triamcinolone provided clinically meaningful reduction in patient‐assessed pain intensity in the first and subsequent flares. For the first flare, the mean decline in pain intensity from baseline to 24–72 hours for total anakinra and triamcinolone was −41.2 and −39.4, respectively (P = 0.688). Anakinra performed better than triamcinolone for most secondary end points. There were no unexpected safety findings. The presence of antidrug antibodies was not associated with adverse events or altered pain reduction. Conclusion: Anakinra was not superior to triamcinolone for the primary end point, but had comparable efficacy in pain reduction and was favored for most secondary end points. Anakinra is an effective option for gout flares when conventional therapy is unsuitable. [ABSTRACT FROM AUTHOR]

A histologic hallmark of primary SS (pSS) is lymphocytic infiltration of the salivary and lacrimal glands, in particular by CD4+ T and B cells. In the early stages of the disease, infiltrates are dominated by CD4+ T cells, while B cell accumulation occurs at later stages. Activated T cells contribute to pathogenesis by producing pro-inflammatory cytokines and by inducing B cell activation, which results in the establishment of a positive feedback loop. In the inflamed glandular tissues, many different CD4+ effector subsets are present, including IFN-γ-producing Th1 cells, IL-17-producing Th17 cells and IL-21-producing T follicular helper cells. In blood from pSS patients, frequently observed abnormalities of the T cell compartment are CD4+ T cell lymphopenia and enrichment of circulating follicular helper T (Tfh) cells. Tfh cells are critical mediators of T cell–dependent B cell hyperactivity and these cells can be targeted by immunotherapy. Inhibition of T cell activation, preferably early in the disease process, can mitigate B cell activity and may be a promising treatment approach in this disease. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to analyse the features, therapeutic approaches, and outcomes for adult patients with haemophagocytic lymphohistiocytosis (HLH) at a single centre. Methods This study was a retrospective chart review of all patients >18 years of age diagnosed with HLH according to HLH-2004 or H-score criteria at Ochsner Medical Center-New Orleans between 2013 and 2019. Results A total of 29 patients with HLH met inclusion criteria. A total of 7 patients had an underlying malignancy, 12 had an autoimmune disease, 2 were transplant patients, and 2 had a combination of malignancy, autoimmune disease, or immunodeficiency. A total of 6 patients developed HLH precipitated by infection alone. All 29 patients presented with fever. A total of 28 (97%) patients met H-score criteria, and only 20 (67%) met HLH-2004 criteria. Fifteen patients were treated with the HLH-2004 protocol. Of those treated with the HLH-2004 protocol, 73% (11/15) died, 8% (1/15) had recurrence of HLH, and 20% (3/15) had resolution of HLH. A total of 14 patients were treated with targeted therapy. Of those treated with targeted therapy, 93% (13/14) had resolution of HLH and 1 died. Targeted therapy included pulse steroids, tocilizumab, anakinra, IVIG, CSA, rituximab, and/or CYC in addition to antiviral or antibiotic therapy. Conclusion Our findings suggested that the rheumatologic patient population responded well to a targeted therapeutic approach and poorly to the HLH-2004 protocol. Whether the poor outcomes found with the use of the HLH-2004 protocol are secondary to the protocol itself or the aggressive nature of malignancy-associated HLH is unclear. Further studies are needed to develop tailored therapeutic regimens. [ABSTRACT FROM AUTHOR]

The reduction in estrogen levels results in a decrease in bone density at menopause. Irisin is a myokine that modulates the benefits of exercise, which may include bone health. This study was planned to examine irisin's impact in preventing osteoporosis after ovariectomy. 4 groups of female albino rats (10 rats/group): control, sham-operated, ovariectomized (OVX-control), and OVX-irisin-treated. Serum levels of bone markers [osteocalcin (OC), bone alkaline phosphatase (BALP), tartrate-resistant acid phosphatase (TRAP), calcium (Ca++), phosphorus (P)], glucose, and insulin were being measured. Body mass index, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), dry and ash femur weight, and bone contents of Ca++ and P were investigated. The femur was examined histopathologically. The OVX-control group showed an increase in serum levels of OC, BALP, TRAP, calcium, phosphorus, BMI, glucose, insulin, and HOMA-IR (P < 0.05) and a reduction in dry and ash weight of the femur, the concentration of calcium and phosphorus content in bone ash (P < 0.05). The OVX-irisin-treated group exhibited a decrease in serum levels of OC, BALP and TRAP, calcium, phosphorus, BMI, glucose, insulin, HOMA-IR (P < 0.05), and a rise in dry and ash weight of the femur, the concentration of calcium and phosphorus in bone ash (P < 0.05). Histological examination of the distal femur diaphysis of the OVX-irisin-treated group exhibited proper bone architecture and density compared with that of the OVX-control group. It is concluded that irisin treatment in the OVX rats safeguarded the regular bone architecture and normal levels of serum bone biomarkers. Irisin may be a possible novel target in the prohibition of postmenopausal osteoporosis. [ABSTRACT FROM AUTHOR]

The management of metastatic renal cell carcinoma (mRCC) continues to be a therapeutic challenge; however, the options for systemic therapy in this setting have exploded over the past 20 years. From the advent of toxic cytokine therapy to the subsequent discovery of targeted therapy (TT) and immune checkpoint inhibitors, the landscape of viable treatment options continues to progress. With the arrival of cytokine therapy, two randomized trials demonstrated a survival benefit for upfront cytoreductive nephrectomy (CN) plus interferon therapy and this approach became the standard for surgical candidates. However, it was difficult to establish the role and the timing of CN with the subsequent advent of TT, just a few years later. More recently, two randomized phase III studies completed in the TT era questioned the use of CN and brought to light the role of risk stratification while selecting patients for CN. Careful identification of the mRCC patients who are likely to have a rapid progression of the disease is essential, as these patients need prompt systemic therapy. With the continued advancement of systemic therapy using the immune checkpoint inhibitors as a first line therapy, the role of CN will continue to evolve. [ABSTRACT FROM AUTHOR]

Mesenchymal-epithelial transition factor (MET) gene is an important tumor driver gene of non-small cell lung cancer (NSCLC). Drugs targeting MET 14 exon skipping mutation bring new hope to patients. MET inhibitors that are currently on the market or are about to be marketed include: crizotinib, cabozantinib, savolitinib and tepotinib. The objective response rate of MET inhibitors is high, and the safety is good. However, resistance of MET-tyrosine kinase inhibitor (TKI) is inevitable, so it is necessary to pay attention to the study of drug resistance mechanism. In addition, the combined use of hepatocyte growth factor (HGF)/MET inhibitors and other drugs may play an important role in inhibiting and reversing drug resistance. [ABSTRACT FROM AUTHOR]

The activation of C-C chemokine receptor type 1 (CCR1) has been shown to be pro-inflammatory in several animal models of neurological diseases. The objective of this study was to investigate the activation of CCR1 on neuroinflammation in a mouse model of intracerebral hemorrhage (ICH) and the mechanism of CCR1/tetratricopeptide repeat 1 (TPR1)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway in CCR1-mediated neuroinflammation. Adult male CD1 mice (n = 210) were used in the study. The selective CCR1 antagonist Met-RANTES was administered intranasally at 1 h after autologous blood injection. To elucidate potential mechanism, a specific ERK1/2 activator (ceramide C6) was administered prior to Met-RANTES treatment; CCR1 activator (recombinant CCL5, rCCL5) and TPR1 CRISPR were administered in naïve mouse. Neurobehavioral assessments, brain water content, immunofluorescence staining, and western blot were performed. The endogenous expressions of CCR1, CCL5, TPR1, and p-ERK1/2 were increased in the brain after ICH. CCR1 were expressed on microglia, neurons, and astrocytes. The inhibition of CCR1 with Met-RANTES improved neurologic function, decreased brain edema, and suppressed microglia/macrophage activations and neutrophil infiltration after ICH. Met-RANTES treatment decreased expressions of CCR1, TPR1, p-ERK, TNF-α, and IL-1β, which was reversed by ceramide C6. The brain CCR1 activation by rCCL5 injection in naïve mouse resulted in neurological deficits and increased expressions of CCR1, TPR1, p-ERK, TNF-α, and IL-1β. These detrimental effects of rCCL5 were reversed by TPR1 knockdown using TPR1 CRISPR. Our study demonstrated that CCR1 activation promoted neuroinflammation through CCR1/TPR1/ERK1/2 signaling pathway after ICH in mice. CCR1 inhibition with Met-RANTES attenuated neuroinflammation, thereby reducing brain edema and improving neurobehavioral functions. Targeting CCR1 activation may provide a promising therapeutic approach in the management of ICH patients. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor-21 (FGF-21) is a potential cytokine for type II diabetes mellitus. This study aimed to optimize recombinant human FGF-21 (rhFGF-21) production in Escherichia coli BL21 (DE3) employing high cell density fermentation at a 200-L scale and pilot-scale purification. FGF-21 was eventually expressed in E. coli BL21 (DE3) using human FGF-21 synthetic DNA sequence via the introduction of vector pET-3c; the product is used as seed strain during the fermentation of rhFGF-21. Fermentation of rhFGF-21 was performed in a 30-L and 200-L fermenters. rhFGF-21 was primarily expressed in the form of inclusion bodies after IPTG induction. At the 200-L scale, the bacterial production and expression levels of rhFGF-21 were 38.8 ± 0.6 g/L and 30.9 ± 0.7%, respectively. Additionally, the high purification (98%) of rhFGF-21 was tested with HPLC analysis and reducing & non-reducing SDS-PAGE analysis. The final yield of purified rhFGF-21 was 71.1 ± 13.9 mg/L. The activity of rhFGF-21 stock solution reached at 68.67 ± 8.74 IU/mg. Blood glucose controlling and insulin sensitization were improved with treatment of rhFGF-21 in type II diabetic ob/ob mice. Our results showed that the relatively stable and time-saving pilot-scale production process was successfully established, providing an efficient and cost-effective strategy for large-scale and industrial production of rhFGF-21. [ABSTRACT FROM AUTHOR]

On July 11, 2017, the Food and Drug Administration granted approval for blinatumomab for the treatment of relapsed or refractory (R/R) precursor B‐cell acute lymphoblastic leukemia (ALL). Blinatumomab is a bispecific CD19‐directed CD3 T‐cell engager. The basis for the approval included results from two clinical trials, TOWER and ALCANTARA. TOWER, a randomized trial comparing overall survival in patients with Philadelphia chromosome (Ph)‐negative R/R ALL receiving blinatumomab versus standard‐of‐care (SOC) chemotherapy, demonstrated a hazard ratio of 0.71 favoring blinatumomab (p = .012; median survival, 7.7 months with blinatumomab and 4.0 months with SOC chemotherapy). Complete remission (CR) rates were 34% for patients receiving blinatumomab and 16% for those receiving SOC. Adverse events were consistent with those observed in prior trials, with cytokine release syndrome and some neurologic events, including tremor, encephalopathy, peripheral neuropathy, and depression, observed more frequently in the blinatumomab arm, whereas neutropenia and infection were less common among patients receiving blinatumomab. Depression emerged as a rare but potentially severe neurologic event associated with blinatumomab. In ALCANTARA, a single‐arm trial of blinatumomab in patients with Ph‐positive R/R ALL, the CR rate was 31%, and adverse events were similar to those observed previously in Ph‐negative R/R ALL. These results support conversion from accelerated to regular approval of blinatumomab for R/R ALL and broadening of the intended population to include both Ph‐positive and Ph‐negative precursor B‐cell R/R ALL. Implications for Practice: In TOWER, a randomized trial in patients with relapsed or refractory Philadelphia chromosome (Ph)‐negative precursor B‐cell acute lymphoblastic leukemia (ALL), treatment with blinatumomab showed superiority over conventional chemotherapy for complete remission (CR) rate (34% vs. 16%) and survival (3.7‐month improvement in median; hazard ratio, 0.71). In ALCANTARA, a single‐arm trial of blinatumomab for treatment of relapsed or refractory Ph‐positive precursor B‐cell ALL, the CR rate was 31%. Blinatumomab is now approved for treatment of relapsed or refractory precursor B‐cell ALL that is Ph positive or Ph negative. In 2017, the Food and Drug Administration granted accelerated approval of blinatumomab for the treatment of relapsed or refractory precursor B‐cell acute lymphoblastic leukemia. This article focuses on evidence to support conversion from accelerated to regular approval of blinatumomab. [ABSTRACT FROM AUTHOR]

Objectives: Macrolide therapy is an important conservative therapy for chronic rhinosinusitis, especially in Japan. The mechanism underlying this therapy involves anti-inflammatory and not antimicrobial activity. However, the administration of long-term low-dose macrolides (LTLMs) causes an increase in the number of antibiotic-resistant bacteria. EM900 is a derivative of erythromycin (EM), with anti-inflammatory but not antibacterial effects. It does not induce macrolide-resistant bacteria as shown by LTLM. In the present study, we analyzed the inhibitory effects of EM900 in comparison with those of clarithromycin (CAM) on inflammatory cytokine production in human nasal epithelial cells (HNEpCs). Methods: After HNEpCs were cultured for 4 days, CAM or EM900 was added into the culture, followed by stimulation with tumor necrosis factor (TNF)-α. Interleukin (IL)-8 and vascular endothelial growth factor (VEGF) levels were measured using real-time polymerase chain reaction (RT-PCR) and an enzyme-linked immunosorbent assay (ELISA). Results: Both the ELISA and RT-PCR showed that EM900 and CAM significantly inhibited IL-8 production in HNEpCs. In contrast, EM900 and CAM did not suppress the increased VEGF production when HNEpCs were stimulated with TNF-α. Conclusion: EM900 showed an anti-inflammatory effect, such as that of CAM, due to the inhibitory effect on IL-8 production in HNEpCs. [ABSTRACT FROM AUTHOR]

Stress-related changes in β-cell mRNA levels result from a balance between gene transcription and mRNA decay. The regulation of RNA decay pathways has not been investigated in pancreatic β-cells. We found that no-go and nonsense-mediated RNA decay pathway components (RDPCs) and exoribonuclease complexes were expressed in INS-1 cells and human islets. Pelo, Dcp2, Dis3L2, Upf2, and Smg1/5/6/7 were upregulated by inflammatory cytokines in INS-1 cells under conditions where central β-cell mRNAs were downregulated. These changes in RDPC mRNA or corresponding protein levels were largely confirmed in INS-1 cells and rat/human islets. Cytokine-induced upregulation of Pelo, Xrn1, Dis3L2, Upf2, and Smg1/6 was reduced by inducible nitric oxide synthase inhibition, as were endoplasmic reticulum (ER) stress, inhibition of Ins1/2 mRNA, and accumulated insulin secretion. Reactive oxygen species inhibition or iron chelation did not affect RDPC expression. Pelo or Xrn1 knockdown (KD) aggravated, whereas Smg6 KD ameliorated, cytokine-induced INS-1 cell death without affecting ER stress; both increased insulin biosynthesis and medium accumulation but not glucose-stimulated insulin secretion in cytokine-exposed INS-1 cells. In conclusion, RDPCs are regulated by inflammatory stress in β-cells. RDPC KD improved insulin biosynthesis, likely by preventing Ins1/2 mRNA clearance. Pelo/Xrn1 KD aggravated, but Smg6 KD ameliorated, cytokine-mediated β-cell death, possibly through prevention of proapoptotic and antiapoptotic mRNA degradation, respectively. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) patients with concomitant peripheral artery disease (PAD) experience more extensive and calcified atherosclerosis, greater lesion progression and more common coronary events compared to patients with CAD only. To characterize the distinct features of this aggressive atherosclerotic disease, we studied novel cytokines that code different stages of atherogenesis. One hundred and eighty consecutive subjects (60 patients into each group of CAD+PAD, CAD and controls) were recruited among patients with stable angina pectoris scheduled for coronary angiography. An ankle–brachial index (ABI) ≤0.9 was determined as occlusive PAD. Fasting serum tumor necrosis factor (TNF)-like antigen 1A (TL1A) and its receptor death receptor 3 (DR3), NOGO-B (reticulon 4B) and its receptor NUS1, high-sensitivity C-reactive protein (hsCRP), A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 1, 4, 5 and interleukin (IL) 6 levels were determined. Serum hsCRP and DR3/TL1A concentrations were similar and higher than controls in the CAD and CAD+PAD groups. Levels of NOGO-B and its receptor NUS1 were increased and ADAMTS-5 was decreased in patients with CAD+PAD. Independent predictors of ABI in multivariate analysis were smoking (B = −0.13, p = 0.04), NUS1 (B = −0.88, p < 0.001), ADAMTS-5 (B = 0.63, p < 0.001) and SYNTAX score (B = −0.26, p < 0.001). Similarly, smoking (OR = 5.5, p = 0.019), SYNTAX score (OR = 1.2, p < 0.001), NUS1 (OR = 14.4, p < 0.001), ADAMTS-5 (OR = 1.1, p < 0.001) and age (OR = 1.1, p = 0.042) independently predicted the involvement of peripheral vasculature in logistic regression. The diagnostic performance of these cytokines to discriminate CAD+PAD were AUC 0.79 (p < 0.001) for NUS1 and 0.37 (p = 0.013) for ADAMTS-5. We report herein that circulating cytokines can give clues to the ongoing atherosclerotic process and the extent of vascular involvement in which distinct features of ADAMTS-5 and NUS1 make them promising cytokines for future research. [ABSTRACT FROM AUTHOR]

Acute rejection (AR) and spontaneous tolerance may occur after allograft orthotopic liver transplants (OLT) performed in certain combinations of donor and recipient rat strains, yet the underlying molecular cascades involved in these conditions remain poorly understood. Comprehensive analysis with proteomic tools revealed that ceruloplasmin was highly expressed during the tolerant period on day 63 post-OLT (POD 63) compared to the rejected samples on POD 14. Meanwhile, cytokine expression profiles implied that the inflammation was significantly stimulated in the AR subjects. Again, protein carbonylation was dramatically upregulated in the rejected subject within the tolerant group. Knockdown of ceruloplasmin would elicit more severe ROS damage, leading to cell death in the presence of H2O2, which induced Nrf2 cascade and the recovery of ceruloplasmin to mediate spontaneous tolerance. In summary, ceruloplasmin may contribute to amending the oxidative stress that eventually causes cell apoptosis and to maintaining the survival of hepatocytes in a drug-free tolerance OLT model. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory arthropathy associated with articular damage and attendant comorbidities. Even although RA treatment has advanced remarkably over the last decade, a significant proportion of patients still do not achieve sustained remission. The cause of RA is not yet known despite the many potential mechanisms proposed. It has been confirmed that RA is associated with dysregulated immune system and persistent inflammation. Therefore, management of inflammation is always the target of therapy. Sinomenine (SIN) is the prescription drug approved by the Chinese government for RA treatment. A previous study found that SIN was a robust anti-inflammation drug. In this study, we screened the different secretory cytokines using inflammation antibody arrays and qRT-PCR in both LPS-induced and SIN-treated RAW264.7 cells followed by evaluation of the ability of SIN to modulate cytokine secretion in a cell model, collagen-induced arthritis (CIA) mouse model, and RA patients. Several clinical indexes affecting the 28-joint disease activity score (DAS28) were determined before and after SIN treatment. Clinical indexes, inflammatory cytokine secretion, and DAS28 were compared among RA patients treated with either SIN or methotrexate (MTX). To explore the mechanism of SIN anti-inflammatory function, RA-associated monocyte/macrophage subsets were determined using flow cytometry in CIA mouse model and RA patients, both treated with SIN. The results demonstrated that SIN regulated IL-6, GM-CSF, IL-12 p40, IL-1α, TNF-α, IL-1β, KC (CXCL1), Eotaxin-2, IL-10, M-CSF, RANTES, and MCP-1 secretion in vivo and in vitro and reduced RA activity and DAS28 in a clinical setting. Furthermore, SIN attenuated CD11b+F4/80+CD64+ resident macrophages in the synovial tissue, CD11b+Ly6C+CD43+ macrophages in the spleen and draining lymph nodes of CIA mice. The percentage of CD14+CD16+ peripheral blood mononuclear cells was reduced by SIN in RA patients. These data indicated that SIN regulates the secretion of multiple inflammatory cytokines and monocyte/macrophage subsets, thereby suppressing RA progression. Therefore, along with MTX, SIN could be an alternative cost-effective anti-inflammatory agent for treating RA. [ABSTRACT FROM AUTHOR]

One strategy to control leishmaniasis is vaccination with potent antigens alongside suitable adjuvants. The use of toll-like receptor (TLR) agonists as adjuvants is a promising approach in Leishmania vaccine research. Leishmania (L.) tropica is among the less-investigated Leishmania species and a causative agent of cutaneous and sometimes visceral leishmaniasis with no approved vaccine against it. In the present study, we assessed the adjuvant effects of a TLR4 agonist, monophosphoryl lipid A (MPL) and a TLR7/8 agonist, R848 beside two different types of Leishmania vaccine candidates; namely, whole-cell soluble L. tropica antigen (SLA) and recombinant L. tropica stress-inducible protein-1 (LtSTI1). BALB/c mice were vaccinated three times by the antigens (SLA or LtSTI1) with MPL or R848 and then were challenged by L. tropica. Delayed-type hypersensitivity (DTH), parasite load, disease progression and cytokines (IL-10 and IFN-γ) responses were assessed. In general compared to SLA, application of LtSTI1 resulted in higher DTH, higher IFN-γ response and lower lymph node parasite load. Also compared to R848, MPL as an adjuvant resulted in higher DTH and lower lymph node parasite load. Although, no outstanding ability for SLA and R848 in evoking immune responses of BALB/c mice against L. tropica infection could be observed, our data suggest that LtSTI1 and MPL have a better potential to control L. tropica infection and could be pursued for the development of effective vaccination strategies. [ABSTRACT FROM AUTHOR]

The overpowering effect of trauma on the immune system is undisputed. Severe trauma is characterized by systemic cytokine generation, activation and dysregulation of systemic inflammatory response complementopathy and coagulopathy, has been immensely instrumental in understanding the underlying mechanisms of the innate immune system during systemic inflammation. The compartmentalized functions of the innate and adaptive immune systems are being gradually recognized as an overlapping, interactive and dynamic system of responsive elements. Nonetheless the current knowledge of the complement cascade and its interaction with adaptive immune response mediators and cells, including T- and B-cells, is limited. In this review, we discuss what is known about the bridging effects of the complement system on the adaptive immune system and which unexplored areas could be crucial in understanding how the complement and adaptive immune systems interact following trauma. [ABSTRACT FROM AUTHOR]

As HER2 is frequently overexpressed in various malignancies, targeting HER2 is considered an efficient, highly selective antitumor therapy. HER2-targeted immunoconjugates are being developed and result in persistent remission of HER2-overexpressing tumors. However, many of the antibodies used as the targeting moiety are of murine origin and exhibit risk of inducing immunogenicity, limiting their antitumor therapeutic efficacy. Here, we humanized e23sFv, an HER2-targeting murine scFv with excellent affinity and specificity, using a human antibody consensus sequence engraftment strategy. The affinity of the initially humanized e23sFv was then rescued and improved by selective mutagenesis followed by phage-display-based affinity panning of the mutant pool. The resulting humanized e23sFv candidates (husFvs) exhibited up-to-94-fold increased affinity to recombinant HER2. The immunogenicity of e23sFv was dramatically alleviated after humanization, as indicated by the impaired production of cytokines by husFv-stimulated human PBMCs. Two internalizable husFvs with optimal affinity were applied to generate humanized immunoapoptotins by infusion with the translocation domain Fdt and the proapoptotic domain truncated Bid. The husFv-immunoapoptotins demonstrated improved HER2-targeting and tumor-killing capacities in vitro and in vivo compared with the e23sFv-immunoapoptotins and would enable the administration of multiple treatment cycles to patients, resulting in improved antitumor efficacy. Furthermore, the husFvs recognized distinct HER2 epitopes and could thus be used in combination with trastuzumab or pertuzumab to achieve robust synergistic antitumor effects in HER2-positive malignancies. [ABSTRACT FROM AUTHOR]

It has been suggested that cytokine-mediated inflammation plays a key role for the onset and/or development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). However, clinical studies have yielded inconsistent results for the aberrant cytokine levels in circulation of patients with AD, PD, and ALS. Previous studies have used meta-analysis to address the inconsistent data for blood cytokine levels in the patients with AD, PD, and ALS. Here, we performed a systemic review of cerebrospinal fluid inflammatory cytokine data in patients with AD, PD and ALS, and sought to quantitatively summarize the CSF inflammatory cytokine data with a meta-analytical technique. The systematic search from Pubmed and Web of Science identified 71 articles with 2629 patients and 2049 controls for the meta-analysis. Random-effects meta-analysis demonstrated that CSF TGF-β, MCP-1, and YKL-40 levels were significantly elevated in AD patients when compared with controls. In addition, patients with PD had heightened levels of TGF-β1, IL-6, and IL-1β in CSF. Furthermore, G-CSF, IL-2, IL-15, IL-17, MCP-1, MIP-1α, TNF-α, and VEGF levels were significantly increased in patients with ALS as compared with controls. Taken together, these results not only strengthen the clinical evidence that neurodegenerative diseases are accompanied by the increased inflammatory response, but also reveal the unique inflammatory response profile in the central nervous system of patients with AD, PD and ALS. Given the robust associations between some cytokines and neurodegenerative diseases found in this meta-analysis, CSF inflammatory cytokines may be used as biomarkers for these diseases in the future. [ABSTRACT FROM AUTHOR]

Background. Kudiezi injection is a traditional Chinese medicine for acute cerebral infarction, but the exact mechanisms are poorly understood. Objective. To investigate the mechanisms of Kudiezi injection on the inflammatory response in the treatment of acute cerebral infarction. Methods. This was a prospective study of patients with acute cerebral infarction within 48 h of onset and treated between July 2012 and July 2016 at three hospitals in China. The patients were randomized to routine treatments (control group) versus routine treatments and Kudiezi injection (Kudiezi group). The National Institutes of Health Stroke Score was assessed on days 1, 3, 5, 7, and 14. The patients were tested for serum levels of pro- and anti-inflammatory cytokines (S100 calcium-binding protein B, neuron-specific enolase, interleukin-6, interleukin-10, interleukin-18, and matrix metaloproteinase-9; by enzyme-linked immunosorbent assay) immediately after admission and on days 3, 5, and 14. Results. Stroke scores were improved in both groups from days 1 to 14. On days 5 and 7, stroke scores in the Kudiezi group were lower than in the control group (P<0.05). Compared with controls, the Kudiezi group had lower serum S100 calcium-binding protein B on day 14; higher interleukin-6 and interleukin-10 on day 3; lower interleukin-6 and interleukin-18 on day 5; and lower interleukin-18 and matrix metaloproteinase-9 on day 14. Conclusion. Kudiezi injection could lead to early reduction of interleukin-6, interleukin-18, matrix metaloproteinase-9, neuron-specific enolase, and S100 calcium-binding protein B levels and increases of interleukin-10 levels in patients with acute ischemic stroke. This trial is registered with ClinicalTrials.gov NCT01636154. [ABSTRACT FROM AUTHOR]

Abstract: In dairy cows, retained fetal membranes (RFM) affect reproductive performance. The aim of this study was to examine the leukocyte counts and the gene expression of tumour necrosis factor α (TNFα), interleukin 1β (IL‐1β), IL‐8, and IL‐10 in polymorphonuclear leukocytes (PMNs) and peripheral blood mononuclear cells (PBMCs) in cows with (n = 5) or without (n = 5) RFM during the peripartum period. The lymphocyte counts in RFM cows were higher than those in control cows throughout the experiment (p < .05). The expression of IL‐8 in PMNs of control cows was higher (p < .05) compared with that of RFM cows postpartum. In cows with RFM, IL‐1β expression was higher (p < .05) in PMNs at 6 weeks postpartum whereas the expression of IL‐1β was lower (p < .05) in PBMCs at 4 weeks postpartum. The expression of IL‐10 in PBMCs of control cows was higher (p < .05) than that of RFM cows at 2 weeks prepartum and 4 weeks postpartum. Taken together, our data indicate that changes of gene expression of pro‐ and anti‐inflammatory cytokines in RFM cows might be associated with the delayed placental separation and development of uterine inflammation in RFM cows. [ABSTRACT FROM AUTHOR]

Over 350 million individuals suffer from depression, a psychiatric illness classified as major depressive disorder (MDD) with symptoms that include a loss of interest or pleasure in life accompanied by depressed mood. The present understanding of major depressive disorder does not encompass a systematic characterization of the neurobiological processes that drive the behavioral physiology in patients diagnosed with major depressive disorder. Psychiatric illness is a complex intersection between genetics, physiology, immunology and environmental stress. The increased attention to the relevance of depression has led to new discoveries that highlight the biological significance of 'neuroinflammation' and immunity underlying a spectrum of psychiatric illnesses. The process of neuroinflammation involves sentinel immune cells in the central nervous system (CNS). The activation and polarization of microglia, CNS-resident macrophages, modulates the production and secretion of pro-inflammatory cytokines implicated in the etiology of major depressive disorder, and this phenomenon has been aptly titled the 'macrophage theory of depression'. Of particular interest are three hallmark cytokines, IL-6, TNFα and IL-1β, which have been studied extensively in basic research, cell-receptor signaling and drug development. The field of inflammasome-mediated neuroinflammation is an emerging area of MDD research that is providing new cellular insight into how macrophages mechanistically support cytokine-associated neuropathology, particularly in the case of IL-1β-associated inflammation in MDD. With the increasing number of individuals identified with depression, a comprehensive understanding of macrophage-cytokine signaling pathways in the CNS in depression is necessary for developing effective anti-depressant therapeutics. [ABSTRACT FROM AUTHOR]

It is well known that unmethylated 20-deoxycytidine-phosphate-20-guanine (CpG) sequences alone or in longer DNA and RNA oligonucleotides can act like pathogen-associated molecular patterns (PAMPs) and trigger the innate immune response leading to deleterious cytokine production via Toll-like receptors (TLRs). Clearly, such CpG or CpG-containing sequences in aptamers intended for therapy could present very damaging side effects to patients. Previous antisense oligonucleotide developers were faced with the same basic CpG dilemma and devised not only avoidance, but other effective strategies from which current aptamer developers can learn to ameliorate or eliminate damaging CpG effects. These strategies include obvious methylation of cytosines in the aptamer structure, as long as it does not affect aptamer binding in vivo, truncation of the aptamer to its essential binding site, backbone modifications, co-administration of antagonistic or suppressive oligonucleotides, or other novel drugs under development to lessen the toxic CpG effect on innate immunity. [ABSTRACT FROM AUTHOR]

Therapeutic resistance leading to tumor relapse is a major challenge in breast cancer (BCa) treatment. Numerous factors involved in multiple mechanisms promote the development of tumor chemo/radio-resistance. Cytokines/chemokines are important inflammatory factors and highly related to tumorigenesis, metastasis and tumors responses to treatment. A large number of studies have demonstrated that the network of cytokines activates multiple cell signaling pathways to promote tumor cell survival, proliferation, invasion, and migration. Particularly in BCa, cytokines-enhanced the epithelial-mesenchymal transition (EMT) process plays a pivotal role in the progression of metastatic phenotypes and resistance to the traditional chemo/radio-therapy. Virtually, therapeutic resistance is not entirely determined by tumor cell intrinsic characteristics but also dependent upon synchronized effects by numerous of local microenvironmental factors. Emerging evidence highlighted that exosomes secreted from various types of cells promote intercellular communication by transferring bioactive molecules including miRNAs and cytokines, suggesting that exosomes are essential for sustentation of tumor progression and therapeutic resistance within the tumor microenvironment. In this review, we discuss the mechanisms by which cytokines promote therapeutic resistance of BCa and suggest a potential approach for improving BCa therapeutics by inhibition of exosome function. [ABSTRACT FROM AUTHOR]

Background. Progress in breast cancer surgery results in a decreased frequency of mastectomy, in the early phases of cancer replaced by breast conserving therapy (lumpectomy). Increased popularity of breast reconstruction by fat or adipose stem cells (ASC)-enriched fat transfer raised uncertainty about the possible risk of increased cancer recurrence. In vitro studies suggest that locally secreted cytokines and reconstructed local blood vessels may stimulate cancer expansion or cancer de novo induction from glandular tissue remaining after lumpectomy. Objectives. The purpose of the study was to evaluate the risk of cancer recurrence in breast cancer patients related to the stromal vascular fraction (SVF) augmentation during autologous fat grafting for breast reconstruction. Material and methods. The tumor recurrence ratio in 56 patients having the breast reconstructed with autologous ASC (transplanted as the subpopulation present in SVF) was compared with the frequency of tumor recurrence in 252 matched patients treated in clinics without subsequent breast reconstruction. Adipose tissue was collected by the Coleman technique and split into 2 portions: one was used for breast reconstruction, the other was enzymatically digested, and isolated cells were used for the augmentation of fat implanted into the breast area. Cancer recurrence in the experimental and matched control group was evaluated following 3-year-long observation time, and the statistical significance of difference in cancer recurrence between the experimental and control group was evaluated. Results. Cancer recurrence in the group of patients treated with ASC-enriched fat for breast reconstruction was 3.7% and did not differ significantly from the control group data (4.13%). No adverse effects of therapy were observed. Conclusions. Our study does not produce any data suggesting increased cancer risk following breast reconstruction after a mastectomy or a lumpectomy combined with local radiotherapy. It may be concluded that an autologous transplantation of fat augmented with ASC is a safe and efficient procedure. Longer observation time and the observation of larger numbers of patients would be useful for strengthening the conclusion. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) caused by contrast exposure is a common problem, which may cause a significant increase in patients in-hospital stay and therefore the cost of treatment. This study was conducted to evaluate the role of inflammation, inflammatory markers in predicting contrast induced nephropathy (CIN). This is a prospective study that was carried out in a major tertiary referral hospital in Jordan.  Methods: Clinical data, blood and urine samples were collected from all patients admitted to the cardiology unit. All patients who agreed to participate in the study had creatinine level analysis 48–72 hours after the procedure. The CIN was defined as an increase in serum creatinine by 25% or 44 μmol/L from the baseline within 48–72 hours after the contrast administration. Patients with stage 4, 5 renal failure, patients on dialysis, and patients with recent intravenous contrast use, active infection or cancer were excluded from the study. Results: Of the total 202 patients, 30 (14.8%) developed CIN. The incidence rate was 21.1% among females and 12.4% among males. In the multivariate analysis, beside eGFR, diuretics, and alkaline phosphatase, IL-33 was significantly associated with CIN, while the other cytokines did not to show this an association. Conclusion: Serum level of IL-33 was a significant predictor for development of CIN. Good clinical judgment and high serum levels of IL-33 may stratify patients into low and high risk for CIN. [ABSTRACT FROM AUTHOR]