Cytokines of the interleukin-1 (IL-1) family, such as IL-1α/β and IL-18, have pleiotropic activities in innate and adaptive immune responses in host defense and diseases. Insight into their ...biological functions helped develop novel therapeutic approaches to treat human inflammatory diseases. IL-33 is an important member of the IL-1 family of cytokines and is a ligand of the ST2 receptor, a member of the IL-1 receptor family. However, the role of the IL-33/ST2 axis in tumor growth and metastasis of breast cancer remains unclear. Here, we demonstrate that IL-33 is a critical tumor promoter during epithelial cell proliferation and tumorigenesis in the breast. IL-33 dose- and time-dependently increased Cancer Osaka Thyroid (COT) phosphorylation via ST2-COT interaction in normal epithelial and breast cancer cells. The IL-33/ST2/COT cascade induced the activation of the MEK-ERK (MEK-extracellular signal-regulated kinase), JNK-cJun (cJun N-terminal kinase-cJun) and STAT3 (signal transducer and activator of transcription 3) signaling pathways, followed by increased AP-1 and stat3 transcriptional activity. When small interfering RNAs of ST2 and COT were introduced into cells, IL-33-induced AP-1 and stat3 activity were significantly decreased, unlike that in the control cells. The inhibition of COT activity resulted in decreased IL-33-induced epithelial cell transformation, and knockdown of IL-33, ST2 and COT in breast cancer cells attenuated tumorigenicity of breast cancer cells. Consistent with these observations, ST2 levels were positively correlated with COT expression in human breast cancer. These findings provide a novel perspective on the role of the IL-33/ST2/COT signaling pathway in supporting cancer-associated inflammation in the tumor microenvironment. Therapeutic approaches that target this pathway may, therefore, effectively inhibit carcinogenesis in the breast.
Retrospective and molecular biologic data suggest that sunitinib may be effective in patients with non-clear cell renal cell carcinoma (nccRCC).
Eligibility criteria included advanced nccRCC except ...for collecting duct carcinoma and sarcomatoid carcinoma without identifiable renal cell carcinoma subtypes. Patients were treated with 50 mg/day oral sunitinib for 4 weeks, followed by 2 weeks of rest. The primary end point was overall response rate (RR).
Thirty-one eligible patients were enrolled. Twenty-four patients (77%) had prior nephrectomy. By Memorial Sloan-Kettering Cancer Center criteria, 8 patients (26%) had poor risk and 14 (45%) had intermediate risk. Twenty-two patients had papillary renal cell carcinoma (RCC), and three had chromophobe RCC. Eleven patients had partial response with a RR of 36% (95% confidence interval (CI) 19% to 52%) and an additional 17 patients (55%) had stable disease. Median duration of response was 12.7 months (95% CI 6.3–19.1 months), and median progression-free survival was 6.4 months (95% CI 4.2–8.6 months). At a median follow-up duration of 18.7 months (95% CI 13.7–23.7 months), 13 patients (42%) had died, resulting in an estimated median survival of 25.6 months (95% CI 8.4–42.9 months). Toxicity profiles were commensurate with prior reports.
Sunitinib has promising activity in patients with nccRCC (NCT01219751).
AIMS: The aim of this study was to evaluate the effects of Bifidobacterium lactis HY8101 on insulin resistance induced using tumour necrosis factor‐α (TNF‐α) in rat L6 skeletal muscle cells and on ...the KK‐AY mouse noninsulin‐dependent diabetes mellitus (NIDDM) model. METHODS AND RESULTS: The treatment using HY8101 improved the insulin‐stimulated glucose uptake and translocation of GLUT4 via the insulin signalling pathways AKT and IRS‐1(Tyr) in TNF‐α‐treated L6 cells. HY8101 increased the mRNA levels of GLUT4 and several insulin sensitivity‐related genes (PPAR‐γ) in TNF‐α‐treated L6 cells. In KK‐AY mice, HY8101 decreased fasting insulin and blood glucose and significantly improved insulin tolerance. HY8101 improved diabetes‐induced plasma total cholesterol and triglyceride (TG) levels and increased the muscle glycogen content. We observed concurrent transcriptional changes in the skeletal muscle tissue and the liver. In the skeletal muscle tissue, the glycogen synthesis‐related gene pp‐1 and GLUT4 were up‐regulated in mice receiving HY8101 treatment. In the liver, the hepatic gluconeogenesis‐regulated genes (PCK1 and G6PC) were down‐regulated in mice receiving HY8101 treatment. CONCLUSIONS: Bifidobacterium lactis HY8101 can be used to moderate glucose metabolism, lipid metabolism and insulin sensitivity in mice and in cells. SIGNIFICANCE AND IMPACT OF THE STUDY: Bifidobacterium lactis HY8101 might have potential as a probiotic candidate for alleviating metabolic syndromes such as diabetes.
Bretherton et al. (2004) used the Special Sensor Microwave Imager (SSM/I) version 5 product to derive an exponential curve that describes the relationship between precipitation and column relative ...humidity (CRH) over the tropical oceans. The curve, which features a precipitation pickup at a CRH of about 0.75 and a rapid increase of precipitation with CRH after the pickup, has been widely used in the studies of the tropical atmosphere. This study reexamines the moisture‐precipitation relationship by using the version 7 SSM/I data, in which several biases in the previous version are corrected, and evaluates the relationship in the Coupled Model Intercomparison Project phase 5 (CMIP5) models. In the revised exponential curve derived using the updated satellite data, the precipitation pickup occurs at a higher CRH (~0.8), and precipitation increases more slowly with CRH than in the previous curve. In most CMIP5 models, the precipitation pickup is too early due to the common model bias of overestimated (underestimated) precipitation in the dry (wet) regime.
Key Points
A revised exponential relationship between column relative humidity (CRH) and precipitation is obtained
The precipitation pickup occurs at a higher CRH, and precipitation increases with CRH at a lower rate in the new relationship
Most CMIP5 models exhibit a too early precipitation pickup bias
To cite this article: Kim YH, Yang TY, Park C‐S, Ahn S‐H, Son BK, Kim JH, Lim DH, Jang TY. Anti‐IL‐33 antibody has a therapeutic effect in a murine model of allergic rhinitis. Allergy 2012; 67: ...183–190.
Background: Interleukin (IL)‐33 is involved in the Th2 immune response and could play an essential role in nasal allergy. Therefore, we aimed to investigate the therapeutic potential of anti‐IL‐33 for allergic rhinitis (AR).
Methods: Twenty‐four BALB/c mice were used. In group A (control group, n = 6), mice were sensitized and challenged with saline. Group B ovalbumin (OVA) group, n = 6 mice received intraperitoneal and intranasal OVA challenge. In group C (control IgG group, n = 6), mice were injected intraperitoneally with rabbit control IgG before OVA challenge. In group D (anti‐IL‐33 group, n = 6), anti‐IL‐33 was injected before challenge. We evaluated the number of nose‐scratching events and external morphology; serum total and OVA‐specific IgE; number of eosinophils, neutrophils, and lymphocytes in bronchoalveolar lavage (BAL) fluid; histopathologic examination of nasal cavity; and IL‐4, IL‐5, and IL‐13 in BAL fluid.
Results: Anti‐IL‐33 treatment significantly reduced the nose‐scratching events and ameliorated skin denudation. Serum total and OVA‐specific IgE was significantly decreased in group D. The number of eosinophils in BAL fluid was also significantly decreased. Eosinophilic infiltration in the nasal cavity was significantly decreased in group D. IL‐4, IL‐5, and IL‐13 in BAL fluid were also significantly decreased after treatment.
Conclusions: Anti‐IL‐33 antibody has a therapeutic potential for experimental AR.
ABO incompatibility is no longer considered a contraindication for adult living donor liver transplantation (ALDLT) due to various strategies to overcome the ABO blood group barrier. We report the ...largest single‐center experience of ABO‐incompatible (ABOi) ALDLT in 235 adult patients. The desensitization protocol included a single dose of rituximab and total plasma exchange. In addition, local graft infusion therapy, cyclophosphamide, or splenectomy was used for a certain time period, but these treatments were eventually discontinued due to adverse events. There were three cases (1.3%) of in‐hospital mortality. The cumulative 3‐year graft and patient survival rates were 89.2% and 92.3%, respectively, and were comparable to those of the ABO‐compatible group (n = 1301). Despite promising survival outcomes, 17 patients (7.2%) experienced antibody‐mediated rejection that manifested as diffuse intrahepatic biliary stricture; six cases required retransplantation, and three patients died. ABOi ALDLT is a feasible method for expanding a living liver donor pool, but the efficacy of the desensitization protocol in targeting B cell immunity should be optimized.
This article presents the clinical results of ABO‐incompatible adult living donor liver transplantation in a single institution.
Summary
Background Skin ageing is influenced by environmental factors such as ultraviolet (UV) radiation. The effects of UV radiation on skin functions should be investigated using human in vitro ...models to understand the mechanisms of skin ageing. Additionally, marine algae provide a valuable source for identifying and extracting biologically active substances.
Objectives In this study, sargachromanol E was isolated from a marine brown alga, Sargassum horneri, and its inhibitory effect on skin ageing was investigated using UVA‐irradiated dermal fibroblasts.
Methods Formation of intracellular reactive oxygen species (ROS), lipid peroxidation and protein oxidation induced by UVA irradiation were investigated in UVA‐irradiated human dermal fibroblasts. The levels of matrix metalloproteinases (MMPs) were determined by reverse‐transcriptase polymerase chain reaction and Western blot analysis.
Results Sargachromanol E did not exhibit any significant cytotoxicity or phototoxicity in UVA‐exposed dermal fibroblasts. Additionally, sargachromanol E suppressed intracellular formation of ROS, membrane protein oxidation, lipid peroxidation and expression of collagenases such as MMP‐1, MMP‐2 and MMP‐9, all of which are caused by UVA exposure. It was further found that these inhibitions were related to an increase in the expression of the tissue inhibitor of metalloproteinase (TIMP) genes, TIMP1 and TIMP2. Moreover, we have shown that the transcriptional activation of activator protein 1 (AP‐1) signalling caused by UVA irradiation was inhibited by treatment with sargachromanol E.
Conclusions This study suggests that UVA irradiation modulates MMP expression via the transcriptional activation of AP‐1 signalling, whereas treatment with sargachromanol E protected cell damage caused by UVA irradiation.
What’s already known about this topic?
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Sargachromanol E isolated from Sargassum horneri prevents photoageing of skin.
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Skin photoageing can result from extrinsic factors such as ultraviolet (UV)A, which weakens collagen fibres.
What does this study add?
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Photoageing studies indicate that UVA‐induced expression of matrix metalloproteinases is associated with matrix degradation in dermal fibroblasts.
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Sargassum horneri is a valuable source for the isolation of skin‐protective chemicals.
Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis. The phase III KESTREL study evaluated the efficacy of durvalumab programmed death-ligand ...1 (PD-L1) antibody with or without tremelimumab cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, versus the EXTREME regimen in patients with R/M HNSCC.
Patients with HNSCC who had not received prior systemic treatment for R/M disease were randomized (2 : 1 : 1) to receive durvalumab 1500 mg every 4 weeks (Q4W) plus tremelimumab 75 mg Q4W (up to four doses), durvalumab monotherapy 1500 mg Q4W, or the EXTREME regimen (platinum, 5-fluorouracil, and cetuximab) until disease progression. Durvalumab efficacy, with or without tremelimumab, versus the EXTREME regimen in patients with PD-L1-high tumors and in all randomized patients was assessed. Safety was also assessed.
Durvalumab and durvalumab plus tremelimumab were not superior to EXTREME for overall survival (OS) in patients with PD-L1-high expression median, 10.9 and 11.2 versus 10.9 months, respectively; hazard ratio (HR) = 0.96; 95% confidence interval (CI) 0.69-1.32; P = 0.787 and HR = 1.05; 95% CI 0.80-1.39, respectively. Durvalumab and durvalumab plus tremelimumab prolonged duration of response versus EXTREME (49.3% and 48.1% versus 9.8% of patients remaining in response at 12 months), correlating with long-term OS for responding patients; however, median progression-free survival was longer with EXTREME (2.8 and 2.8 versus 5.4 months). Exploratory analyses suggested that subsequent immunotherapy use by 24.3% of patients in the EXTREME regimen arm contributed to the similar OS outcomes between arms. Grade 3/4 treatment-related adverse events (TRAEs) for durvalumab, durvalumab plus tremelimumab, and EXTREME were 8.9%, 19.1%, and 53.1%, respectively.
In patients with PD-L1-high expression, OS was comparable between durvalumab and the EXTREME regimen. Durvalumab alone, and with tremelimumab, demonstrated durable responses and reduced TRAEs versus the EXTREME regimen in R/M HNSCC.
•KESTREL assessed first-line durvalumab with or without tremelimumab versus the EXTREME regimen in patients with R/M HNSCC.•Durvalumab ± tremelimumab was not superior to the EXTREME regimen for OS in patients with PD-L1-high expression.•Durvalumab ± tremelimumab produced durable responses and fewer TRAEs versus EXTREME in patients with R/M HNSCC.•Subsequent immunotherapy use may have contributed to longer-than-expected OS in the EXTREME regimen arm.
STING (stimulator of interferon genes) is a cytosolic sensor for cyclic dinucleotides and also an adaptor molecule for intracellular DNA receptors. Although STING has important functions in the host ...defense against pathogens and in autoimmune diseases, its physiological relevance in intestinal homeostasis is largely unknown. In this study, we show that STING
mice presented defective protective mechanisms of intestinal mucosa, including decreased number of goblet cells, diminished mucus production, and lower levels of secretory IgA, when compared with wild-type (WT) mice. Fecal content and microbiota DNA could activate STING, indicating a role of this molecule in gut. Microbiota composition was altered in STING
mice toward a more inflammatory profile, evidencing a reduction in the Allobacolum and Bifidobacterium groups along with increase in Disulfovibrio bacteria. Absence of STING lead to decrease in induced intraepithelial lymphocytes (IEL) and to increase in group 1 innate lymphoid cell (ILC1) as well as ILC3 frequencies and decrease in ILC2 in the colon. Development and function of Foxp3+ and LAP+ regulatory T cells were also compromised in STING
mice. Moreover, these mice were highly susceptible to dextran sodium sulfate-induced colitis, T-cell-induced colitis, and enteric Salmonella typhimurium infection when compared with WT animals. Therefore, our results identify an important role of STING in maintaining gut homeostasis and also a protective effect in controlling gut inflammation.
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