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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]

There have been many recent advances in melanoma therapy. While 50% of melanomas have a BRAF mutation and are a target for BRAF inhibitors, the remaining 50% are BRAF wild-type. Immune checkpoint inhibitors targeting PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and lymphocyte activated gene-3 (Lag-3) are all approved for the treatment of patients with advanced BRAF wild-type melanoma; however, treatment of this patient population following initial immune checkpoint blockade is a current therapeutic challenge given the lack of other efficacious options. Here, we briefly review available US FDA-approved therapies for BRAF wild-type melanoma and focus on developing treatment avenues for this heterogeneous group of patients. We review the basics of genomic features of both BRAF mutant and BRAF wild-type melanoma as well as efforts underway to develop new targeted therapies involving the mitogen-activated protein kinase (MAPK) pathway for patients with BRAF wild-type tumors. We then focus on novel immunotherapies, including developing checkpoint inhibitors and agonists, cytokine therapies, oncolytic viruses and tumor-infiltrating lymphocytes, all of which represent potential therapeutic avenues for patients with BRAF wild-type melanoma who progress on currently approved immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Acne inversa is a chronic, progressive inflammatory skin disease. It is characterized by the occurrence of relapsing, painful, deep-seated nodules, abscesses, fistulae, sinus tracts, and scars in the axilla, inguinal area, submammary folds, and perianal area. The disease significantly affects patients’ quality of life and is often associated with severe, debilitating pain and depression. Pro-inflammatory cytokines such as TNF-α, interleukin 17 (IL-17), IL-23, IL-12, IL-1α, and IL-1β play a significant role in the pathogenesis of hidradenitis suppurativa. Treatment is difficult and often ineffective, based on both surgical and pharmacological methods. Biologic drugs in hidradenitis suppurativa are the subject of many clinical trials and may be effective in patients for whom other therapies have failed. The first biological drug approved by the Food and Drug Administration for the treatment of hidradenitis suppurativa was the TNF-α inhibitor — adalimumab. The advancement of knowledge of immune mechanisms in the pathogenesis of hidradenitis suppurativa has allowed the development of clinical trials of new therapeutic targets. In 2023, the Food and Drug Administration (FDA) approved the IL-17 inhibitor — secukinumab as the second biological drug in hidradenitis suppurativa. The aim of this review is an update of the biological treatment and its effectiveness in hidradenitis suppurativa. [ABSTRACT FROM AUTHOR]

Objective: Periodontitis is an inflammatory disease that involves an imbalance in the oral microbiota, activation of inflammatory and immune responses, and alveolar bone destruction. Macrophage migration inhibitory factor (MIF) is a versatile cytokine involved in several pathological reactions, including inflammatory processes and bone destruction, both of which are characteristics of periodontitis. While the roles of MIF in cancer and other immune diseases have been extensively characterized, its role in periodontitis remains inconclusive. Results: In this review, we describe a comprehensive analysis of the potential roles of MIF in periodontitis from the perspective of immune response and bone regulation at the cellular and molecular levels. Moreover, we discuss its potential reliability as a novel diagnostic and therapeutic target for periodontitis. Conclusion: This review can aid dental researchers and clinicians in understanding the current state of MIF‐related pathogenesis, diagnosis, and treatment of periodontitis. [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]

Objective: Human leukocyte antigen (HLA)‐DRB1*15:01 has been recently associated with interstitial lung disease (LD), eosinophilia, and drug reactions in systemic juvenile idiopathic arthritis (sJIA). Additionally, genetic variants in IL1RN have been linked to poor response to anakinra. We sought to reproduce these findings in a prospective cohort study of patients with new‐onset sJIA treated with anakinra as first‐line therapy. Methods: HLA and IL1RN risk alleles were identified via whole‐genome sequencing. Treatment responses and complications were compared between carriers versus noncarriers. Results: Seventeen of 65 patients (26%) carried HLA‐DRB1*15:01, comparable with the general population, and there was enrichment for HLA‐DRB1*11:01, a known risk locus for sJIA. The rates of clinical inactive disease (CID) at 6 months, 1 year, and 2 years were generally high, irrespective of HLA‐DRB1 or IL1RN variants, but significantly lower in carriers of an HLA‐DRB1*11:01 allele. One patient, an HLA‐DRB1*15:01 carrier, developed sJIA‐LD. Of the three patients with severe drug reactions to biologics, one carried HLA‐DRB1*15:01. The prevalence of eosinophilia did not significantly differ between HLA‐DRB1*15:01 carriers and noncarriers at disease onset (6.2% vs 14.9%, P = 0.67) nor after the start of anakinra (35.3% vs 37.5% in the first 2 years of disease). Conclusion: We observed high rates of CID using anakinra as first‐line treatment irrespective of HLA‐DRB1 or IL1RN variants. Only one of the 17 HLA‐DRB1*15:01 carriers developed sJIA‐LD, and of the three patients with drug reactions to biologics, only one carried HLA‐DRB1*15:01. Although thorough monitoring for the development of drug hypersensitivity and refractory disease courses in sJIA, including sJIA‐LD, remains important, our data support the early start of biologic therapy in patients with new‐onset sJIA irrespective of HLA‐DRB1 background or IL1RN variants. [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]

Objective: To investigate the single-center experience of the efficacy and safety profile of biologic therapies in patients with juvenile idiopathic arthritis (JIA) and identify risk factors associated with adverse events (AEs). Methods: The medical charts of children with JIA diagnosed between January 2010 and December 2021 were reviewed retrospectively, and patients treated with biological agents were included in the study. Demographic data, clinical features, laboratory results, treatments used, and AEs during the treatment period were collected. Results: From the total JIA cohort (n=814), 237 patients who received biologic therapy for at least 3 months were enrolled in the study. The most frequent subtype was persistent oligoarticular JIA (45.1%) and the most frequently used biologic drug was etanercept (n=118), followed by adalimumab (n=64), tocilizumab (n=31), anti-interleukin-1 (anti-IL-1) agents (n=12; 7 anakinra and 5 canakinumab), infliximab (n=6), abatacept (n=3), secukinumab (n=2) and tofacitinib (n=1). One hundred sixty-four (69.2%) patients received disease-modifying antirheumatic drugs (DMARDs) concomitantly, 10.5% received DMARDs plus corticosteroids and 2.1% received only corticosteroids. The median [interquartile range (IQR)] age and median age at initiation of the biologics were 14.4 (10.7-18) years and 10.9 (6.6-14.5) years, respectively. The median (IQR) follow-up period was 3.9 (2-6.3) years. On biologic therapy, the median (IQR) JADAS-71 decreased from 13 (11-19) at baseline to 0 (0-2) after median 22 (10-40) months of treatment (p<0.001). The most frequent AE was local injection site reactions with biologics administered subcutaneously (n=8), followed by upper respiratory tract infections (n=4) and diffuse erythematous skin rashes (n=4). Serious AEs were observed in 11 (4.6%) patients. To compare the frequency of AEs, patients were divided into three groups according to the biologics administered, as follows: Group 1: Tumor necrosis factor inhibitors, group 2: anti-IL-1 agents, group 3: anti-IL-6 agent. The frequency of AEs was significantly higher in JIA patients on anti-IL-1 therapy than in the other two groups (58.3% vs. 29% and 8.5%, p<0.001). Conclusion: Biological agents are used with increasing frequency in children with JIA, and their off-label use is quite common. Although these agents are considerably effective and quite safe, AEs should not be underestimated. While planning the management of patients with refractory JIA, careful interpretation of benefit-risk balance for every individual patient seems to be reasonable and required. [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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Premature ovarian insufficiency (POI) refers to a dramatic decrease in the number and/or quality of oocytes in the ovaries before the age of 40 years, and is a key cause of female infertility. The prevalence of POI has been increasing annually and tends to be younger. Researches on the etiology of POI and related pathogenesis are still very limited. Herbal medicine can treat many gynecological diseases. And herbal medicine is effective in reproductive health care such as infertility. In recent years, it has been found that immune modulation by cytokines (CK) can prevent or intervene in POI, and herbal medicine can treat POI by regulating CK to improve ovarian function and fertility. This review presents an overview of the molecular mechanisms of regulation of POI related CK, and reports the therapeutic effect of herbal medicine on POI including herbal medicine formulas, single herbal medicine, herbal medicine active components and acupuncture. This review provides theoretical support for clinical prevention and treatment of POI, and provides new ideas for researches on herbal medicine treatment of POI. We performed a collection of relevant scientific articles from different scientific databases regarding the therapeutic effect of herbal medicine on POI by regulating CK, including PubMed, Web of Science, Wanfang Database, CNKI and other publication resources. The search terms used in this review include, 'premature ovarian insufficiency', 'premature ovarian failure (POF)', 'infertility', 'herbal medicine', 'acupuncture', 'cytokine', 'interleukin (IL)', 'tumor necrosis factor-α (TNF-α)', 'interferon-γ (IFN-γ)', 'transforming growth factor-β (TGF-β)', 'vascular endothelial growth factor (VEGF)', 'immune' and 'inflammation'. This review summarized and analyzed the therapeutic effect of herbal medicine according to the existing experimental and clinical researches. The results showed that herbal medicine treats POI through CK (including ILs, TNF-α, INF-γ, VEGF, TGF-β and others) and related signaling pathways, which regulates reproductive hormones disorder, reduces ovarian inflammatory damage, oxidative stress, apoptosis and follicular atresia, improves ovarian pathological damage and ovarian reserve function. This review enriches the theory of POI treatments based on herbal medicine by regulating CK. The specific mechanisms of action and clinical researches on the treatment of POI by herbal medicine should be strengthened in order to promote the application of herbal medicine in the clinic and provide new ideas and better choices for the treatment of POI. Advances in cytokine-based herbal medicine against premature ovarian insufficiency: A review. [Display omitted] • Relationship between POI and CK was mentioned. • The therapeutic effect of herbal medicine on POI was mentioned. • The 'Herbal medicine formula - Single herbal medicine - Ingredient - CK' relationship network was summarized. [ABSTRACT FROM AUTHOR]

Peucedanum japonicum Thunberg has been used to treat cold, cough, and inflammatory diseases in Southern and Eastern Asia. The effects of P. japonicum root aqueous extract (PJ) on lipopolysaccharide (LPS)-induced inflammation were investigated in RAW264.7 macrophages and an animal model of septic shock. Lipopolysaccharides are endotoxins that trigger excessive inflammatory responses, similar to those elicited by gram-negative bacteria. Inflammation is characterized by a primary defense system against pathogens and the onset of sundry diseases or illnesses, and macrophages are important components of the phagocytic system during inflammatory processes. The present study evaluated the effects of PJ on the production of pro-inflammatory mediators, such as nitric oxide and prostaglandin E2, and assessed the expression of enzymes that induce the production of pro-inflammatory mediators using western blotting. We also evaluated the production and mRNA expression of pro-inflammatory cytokines using enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction, respectively. Using western blotting, we determined whether nuclear factor-kappa B (NF- κ B) and c-Jun N-terminal kinase (JNK) are involved in the molecular mechanisms induced by PJ that suppressed LPS-induced inflammatory responses. We also found that PJ inhibited NF- κ B and JNK pathways in macrophages and reduced LPS-induced mortality in the mouse model of septic shock by inhibiting the activation of NF- κ B and JNK pathways that downregulated the expression of inflammatory mediators. These results indicated that PJ is an effective inflammatory suppressor. [ABSTRACT FROM AUTHOR]

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]

Background: Fosgonimeton (ATH-1017) is being developed as a first-in-class regenerative therapy for people with Alzheimer's disease (AD) and dementia; potentially improving dementia symptoms and altering disease progression by reversing synaptic disconnection and neuronal loss.Objective: This randomized, double-blind, placebo-controlled phase I trial (NCT03298672) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of fosgonimeton.Methods: Fosgonimeton was administered once daily via subcutaneous injection to 88 subjects. The single ascending dose study enrolled healthy young male subjects (n = 48; age, 33.4±6.3 years; dose, 2, 6, 20, 40, 60, or 90 mg); the multiple ascending dose study enrolled healthy elderly subjects (n = 29; age, 63.8±4.0 years; dose, 20, 40, 60, or 80 mg; 9-day duration); and the fixed-dose study enrolled AD subjects (n = 11; age, 69.2±7.1 years; dose, 40 mg; 9-day duration). Quantitative electroencephalogram (qEEG) and event-related potential (ERP) P300 measured neurophysiological signals following fosgonimeton treatment, supporting brain penetration and target engagement.Results: Fosgonimeton and placebo were shown to be safe and well-tolerated across all doses. Pharmacokinetic results for fosgonimeton were dose-proportional, with no sex effect or accumulation over 9 days. The main effect of fosgonimeton on qEEG was acute and sustained gamma power induction. In AD subjects, there was a significant effect toward ERP P300 latency normalization compared with placebo (p = 0.027; n = 7 at 40 mg fosgonimeton versus n = 4 placebo).Conclusion: These results support the continued development of fosgonimeton as a novel therapeutic for people with AD and dementia. The fast-onset normalization of ERP P300 latency in AD subjects suggests enhancement of synaptic function and potential procognitive effects. [ABSTRACT FROM AUTHOR]

Aim: Cetuximab is an essential drug for the treatment of wild-type K-RAS colorectal cancer (CRC). It improves the overall survival of patients. However, acquired resistance prevents its clinical efficacy. Tumor heterogeneity may be a nonnegligible reason for cetuximab resistance. We attempted to explore the corresponding molecular mechanism.Methods: Cetuximab-resistant CRC cell RKO and cetuximab-sensitive CRC cell Caco-2 were applied in this study. Cells were centrifuged to determine the concentration in the culture supernatant (CS). MTT, EdU, and colony formation assays were utilized to evaluate cell survival and proliferation. Chromatin immunoprecipitation (ChIP) and promoter-luciferase reporter assays were employed to confirm the direct binding of transcription factors. Western blot and reverse transcription-polymerase chain reaction (RT-PCR) assays were used to detect the expression of molecular markers in the pathway.Results: Hepatocyte growth factor (HGF) was up-regulated in RKO cell culture supernatant and induced cetuximab resistance in Caco-2 cells. SRY-Box Transcription Factor 8 (SOX8) bound to the promoter sequence of HGF. HGF activated the HGF/MET bypass pathway and induced cetuximab resistance in Caco-2 cells.Conclusion: The SOX8/HGF/MET axis played a crucial role in the communication between cetuximab-resistant cells and cetuximab-sensitive cells, inducing treatment resistance. [ABSTRACT FROM AUTHOR]

The article presents a case study of eight pediatric cases initially diagnosed with Kawasaki disease (KD) but later confirmed to have underlying autoinflammatory diseases (AIDs). It is reported that the patients exhibited recurrent febrile episodes, posing a diagnostic challenge. It further underscores the importance of considering AIDs in fevers of unknown origin.

Copyright of Chinese Journal of Cancer Biotherapy is the property of Editorial Office of Chinese Journal of Cancer Biotherapy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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]

Cytokines play an important role in the pathological process of atherosclerosis (AS), affecting the progression and prognosis of cerebrovascular diseases concerned with AS. Cytokines mainly include C-reactive protein, interleukin, tumor necrosis factor, chemotactic cytokines, matrix metalloproteinases, etc. These These cytokines promote or inhibit the inflammatory response and plaque formation during AS process through different targets and mechanisms. A comprehensive understanding of the cytokines in the occurrence and development of AS is conducive to search for new therapeutic targets and drugs. [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]

In severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, viral load peaks early and declines quickly after symptom onset. Severe coronavirus disease 2019 (COVID-19) is marked by aberrant innate and adaptive immune responses with an abnormal cytokine profile and multiorgan system dysfunction that persists well after viral clearance. A purely antiviral treatment strategy may therefore be insufficient, and antiviral agents have not shown a benefit later in the illness course. A number of immunomodulatory strategies are being tested, including corticosteroids, cytokine and anticytokine therapies, small molecule inhibitors, and cellular therapeutics. To date, the only drug to show a mortality benefit for COVID-19 in a randomized, controlled trial is dexamethasone. However, there remains uncertainty about which patients may benefit most and about longer-term complications, including secondary infections. Here, we review the immune dysregulation of severe COVID-19 and the existing data behind various immunomodulatory strategies, and we consider future directions of study. [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]

To evaluate the influence of irisin on the experimental paradigm of non-alcoholic fatty liver (NAFL) as a part of MetS cluster. Forty male albino rats were divided into four groups; normal control, standard diet + irisin, high carbohydrate and fat diet (HCHF), and HCHF + irisin. After the experimental period, levels of fasting blood sugar (FBS), insulin, lipid profile, kidney functions, salusin-alpha (Sal-α), adropin, and retinol-binding protein-4 (RBP-4) were evaluated. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) expression in skeletal muscle was evaluated by quantitative real-time PCR. Aorta, liver, pancreas, and skeletal muscle tissue samples were prepared for histopathological examination. Rats administrated HCHF showed elevated levels of FBS, lipid profile, kidney functions, RBP-4, and downregulation of PGC-1α expression along with a decline in levels of insulin, Sal-α, and adropin while administration of irisin significantly attenuated these levels. Irisin as based therapy could emerge as a new line of treatment against MetS and its related diseases. [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]

Hydroxytyrosol (HT) and oleuropein (OL), the most abundant of the phenolic compounds in olives, have anticancer properties against breast cancer (BC). However, little attention has been paid to the mechanism of HT or OL in BC cells. The objective of this study was to identify the underlying molecular mechanisms of these compounds. ER-positive BC MCF7 and T47D cells were treated with HT and OL in combination with hepatocyte growth factor (HGF), rapamycin (Rapa, an agonist of autophagy) or 3-methyladenine (3-MA, an inhibitor of autophagy). Cell viability, metastasis capability and autophagy-related proteins were evaluated by wound healing assays, Transwell assays and Western blot. HT and OL reduced the cell viability of MCF-7 and T47D cells in a dose-dependent manner. Both cells were more sensitive to HT than OL. In addition, Rapa significantly inhibited HGF-induced migration and invasion, indicating that metastases of both BC cells could be inhibited by suppression of autophagy. Moreover, HT and OL significantly blocked HGF- or 3-MA-induced cell migration and invasion by reversing LC3II/LC3I and Beclin-1 downregulation and p62 upregulation. These findings revealed that HT and OL could suppress migration and invasion by activating autophagy in ER-positive BC cells, which might be a promising therapeutic strategy. [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]

Present work aimstodetect the effect of anti-tuberculosis therapy on the immunity of pTB (pulmonary tuberculosis) patients among populations from Babylon, Iraq. The study was applied on (250) TB patients admitted to respiratory diseases consultant clinic in Al-Hilla city during the period from July 2017 to February 2018. pTB patients comprised of (100) females and (150) males, age ranging from 15-65 years. The diagnosis of active pTB cases were established by AFB smear of sputum samples while blood samples were collected for estimating gamma interferon (IFN-ã) and interleukin 10 (IL-10). Also, the level of copper and zinc were estimated by spectrophotometer. The cell mediated parameters showing increased in IFN-ã level during TB therapy and then decreased during (8) months when complete the course of anti-tuberculosis therapy. While, IL-10 level decreased gradually during anti-TB therapy till lowest level during (8) months after complete course of anti-tuberculosis therapy. The zinc level in serum was increased during anti-TB therapy, while copper level was decreased during the course of anti-TB. These parameters could be used in follow-up as indicators of the success of pTB therapy. [ABSTRACT FROM AUTHOR]

The current challenge of the COVID-19 pandemic is complicated by the limited therapeutic options against the virus, with many being anecdotal or still undergoing confirmatory trials, underlining the urgent need for novel strategies targeting the virus. The pulmotropic virus causes loss of oxygenation in severe cases with acute respiratory distress syndrome (ARDS) and need for mechanical ventilation. This work seeks to introduce placental extract-derived biologically active components as a therapeutic option and highlights their mechanism of action relevant to COVID-19 virus. Human placenta has been used in clinical practice for over a century and there is substantial experience in clinical applications of placental extract for different indications. Aqueous extract of human placentacontains growth factors, cytokines/chemokines, natural metabolic and other compounds, anti-oxidants, amino acids, vitamins, trace elements and biomolecules, which individually or in combination show accelerated cellular metabolism, immunomodulatory and anti-inflammatory effects, cellular proliferation and stimulation of tissue regeneration processes. Placental extract treatment is proposed as a suitable therapeutic approach consideringthe above properties which could protect against initial viral entry and acute inflammation of alveolar epithelial cells, reconstitute pulmonary microenvironment and regenerate the lung. We reviewed useful therapeutic information of placental biomolecules in relation to COVID-19 treatment. We propose the new approach of using placental growth factors, chemokines and cytokine which will execute antiviral activity in coordination with innate and humoral immunity and improve patient's immunological responses to COVID-19. Executing a clinical trial using placental extract as preventive, protective and/or therapeutic approach for COVID-19treatment could advance the development of a most promising therapeutic candidate that can join the armamentaria against the COVID-19 virus. [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]

Purpose: To update the clinical practice guidelines for the use of growth factors and cytokines for the prevention and/or treatment of oral mucositis (OM).Methods: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. The findings were added to the database used to develop the 2014 MASCC/ISOO clinical practice guidelines. Based on the evidence level, the following guidelines were determined: recommendation, suggestion, and no guideline possible.Results: A total of 15 new papers were identified within the scope of this section and were merged with 51 papers that were reviewed in the previous guidelines update. Of these, 14, 5, 13, 2, and 1 were randomized controlled trials about KGF-1, G-CSF, GM-CSF, EGF, and erythropoietin, respectively. For the remaining agents there were no new RCTs. The previous recommendation for intravenous KGF-1 in patients undergoing autologous hematopoietic stem cell transplantation (HSCT) conditioned with high-dose chemotherapy and TBI-based regimens is confirmed. The previous suggestion against the use of topical GM-CSF for the prevention of OM in the setting of high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation remains unchanged.Conclusions: Of the growth factors and cytokines studied for the management of OM, the evidence supports a recommendation in favor of KGF-1 and a suggestion against GM-CSF in certain clinical settings. [ABSTRACT FROM AUTHOR]

Peritoneal adhesion occurs frequently after gastrointestinal/gynecological surgery. Tissue repair and regeneration are very important during this process. IL‐22 is an important cytokine that is secreted from immune cells but functions on mesenchymal cells, such as mesothelial cells. The objective of this study was to investigate the roles of IL‐22 and its regulators during adhesion formation. Postsurgical peritoneal drainage fluid from patients and rodent models was examined by enzyme‐linked immunosorbent assay and fluorescence‐activated cell sorting. It was observed that IL‐22 expression in the abdominal cavity was rapidly induced 12 hours after surgery and then slowly decreased to a lower, steady level for up to 7 days after surgery. However, neutralizing IL‐22 at the time point at which the highest level of expression was observed failed to reduce adhesion, but neutralizing IL‐22 at a later time point, i.e., 3 days after surgery, prevented adhesion significantly. The IL‐22 receptor was induced on the mesothelial membrane, and IL‐22BP, an inhibitor of IL‐22, was reduced 3 days after surgery. Furthermore, IFN‐γ was identified to have the ability to induce IL‐22R, and IL‐18, which was induced by the infiltrating macrophages, was found to inhibit IL‐22BP expression both in vivo and in vitro. Together, these data suggest that IL‐22 may promote adhesion formation and that the regulation of IL‐22, IL‐22R, and IL‐22BP may have therapeutic potential to prevent adhesion formation after surgery without disturbing the normal immune process. [ABSTRACT FROM AUTHOR]