Disease-Association Analysis of an Inflammation-Related Feedback Loop

SummaryThe IL-6-triggered positive feedback loop for NFκB signaling (or the IL-6 amplifier/Inflammation amplifier) was originally discovered as a synergistic-activation signal that follows IL-17/IL-6 stimulation in nonimmune cells. Subsequent results from animal models have shown that the amplifier is activated by stimulation of NFκB and STAT3 and induces chemokines and inflammation via an NFκB loop. However, its role in human diseases is unclear. Here, we combined two genome-wide mouse screens with SNP-based disease association studies, revealing 1,700 genes related to the IL-6 amplifier, 202 of which showed 492 indications of association with ailments beyond autoimmune diseases. We followed up on ErbB1 from our list. Blocking ErbB1 signaling suppressed the IL-6 amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. These results indicate that the IL-6 amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets

Disease-Association Analysis of an Inflammation-Related Feedback Loop

SummaryThe IL-6-triggered positive feedback loop for NFκB signaling (or the IL-6 amplifier/Inflammation amplifier) was originally discovered as a synergistic-activation signal that follows IL-17/IL-6 stimulation in nonimmune cells. Subsequent results from animal models have shown that the amplifier is activated by stimulation of NFκB and STAT3 and induces chemokines and inflammation via an NFκB loop. However, its role in human diseases is unclear. Here, we combined two genome-wide mouse screens with SNP-based disease association studies, revealing 1,700 genes related to the IL-6 amplifier, 202 of which showed 492 indications of association with ailments beyond autoimmune diseases. We followed up on ErbB1 from our list. Blocking ErbB1 signaling suppressed the IL-6 amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. These results indicate that the IL-6 amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets

Intratumoral expression levels of PD-L1, GZMA, and HLA-A along with oligoclonal T cell expansion associate with response to nivolumab in metastatic melanoma

Immune checkpoint inhibitors blocking the interaction between programmed death-1 (PD-1) and PD-1 ligand-1 (PD-L1) are revolutionizing the cancer immunotherapies with durable clinical responses. Although high expression of PD-L1 in tumor tissues has been implicated to correlate with the better response to the anti-PD-1 therapies, this association has been controversial. In this study, to characterize immune microenvironment in tumors, we examined mRNA levels of immune-related genes and characterized T cell repertoire in the tumors of 13 melanoma patients before and after nivolumab treatment. We found that, in addition to the PD-L1 (p = 0.03), expression levels of PD-1 ligand-2 (PD-L2), granzyme A (GZMA) and human leukocyte antigen-A (HLA-A) in the pre-treatment tumors were significantly higher (p = 0.04, p = 0.01 and p = 0.006, respectively) in responders (n = 5) than in non-responders (n = 8). With nivolumab treatment, tumors in responders exhibited a substantial increase of CD8, GZMA and perforin 1 (PRF1) expression levels as well as increased ratio of TBX21/GATA3, suggesting dominancy of helper T cell type 1 (Th1) response to type 2 (Th2) response. T cell receptor β (TCR-β) repertoire analysis revealed oligoclonal expansion of tumor-infiltrating T lymphocytes (TILs) in the tumor tissues of the responders. Our findings suggest that melanoma harboring high PD-1 ligands (PD-L1 and PD-L2), GZMA and HLA-A expression may respond preferentially to nivolumab treatment, which can enhance Th1-skewed cellular immunity with oligoclonal expansion of TILs.ArticleONCOIMMUNOLOGY.5(9):e1204507(2016)journal articl

Aortic Annular Sizing for Transcatheter Aortic Valve Replacement Using Cross-Sectional 3-Dimensional Transesophageal Echocardiography

ObjectivesThis study compared cross-sectional three-dimensional (3D) transesophageal echocardiography (TEE) to two-dimensional (2D) TEE as methods for predicting aortic regurgitation after transcatheter aortic valve replacement (TAVR).BackgroundData have shown that TAVR sizing using cross-sectional contrast computed tomography (CT) parameters is superior to 2D-TEE for the prediction of paravalvular aortic regurgitation (AR). Three-dimensional TEE can offer cross-sectional assessment of the aortic annulus but its role for TAVR sizing has been poorly elucidated.MethodsAll patients had severe symptomatic aortic stenosis and were treated with balloon-expandable TAVR in a single center. Patients studied had both 2D-TEE and 3D imaging (contrast CT and/or 3D-TEE) of the aortic annulus at baseline. Receiver-operating characteristic curves were generated for each measurement parameter using post-TAVR paravalvular AR moderate or greater as the state variable.ResultsFor the 256 patients studied, paravalvular AR moderate or greater occurred in 26 of 256 (10.2%) of patients. Prospectively recorded 2D-TEE measurements had a low discriminatory value (area under the curve = 0.52, 95% confidence interval: 0.40 to 0.63, p = 0.75). Average cross-sectional diameter by CT offered a high degree of discrimination (area under the curve = 0.82, 95% confidence interval: 0.73 to 0.90, p < 0.0001) and mean cross-sectional diameter by 3D-TEE was of intermediate value (area under the curve = 0.68, 95% confidence interval: 0.54 to 0.81, p = 0.036).ConclusionsCross-sectional 3D echocardiographic sizing of the aortic annulus dimension offers discrimination of post-TAVR paravalvular AR that is significantly superior to that of 2D-TEE. Cross-sectional data should be sought from 3D-TEE if good CT data are unavailable for TAVR sizing

Albumin fusion prolongs the antioxidant and anti-inflammatory activities of thioredoxin in mice with acetaminophen-induced hepatitis

Overdoses of acetaminophen (APAP) are a major cause of acute liver failure. N-acetylcysteine (NAC) is the standard therapy for the patients with such an overdose because oxidative stress plays an important role in the pathogenesis of APAP-induced hepatitis. However, NAC is not sufficiently efficacious. We previously developed a recombinant human serum albumin (HSA)-thioredoxin 1 (Trx) fusion protein (HSA-Trx), designed to overcome the unfavorable pharmacokinetic and short pharmacological properties of Trx, an endogenous protein with anti-oxidative and anti-inflammatory properties. In this study, we investigated the therapeutic impact of HSA-Trx in mice with APAP-induced hepatitis. The systemic administration of HSA-Trx significantly improved the survival rate of mice treated with a lethal dose of APAP compared with saline. HSA-Trx strongly attenuated plasma transaminases in APAP-induced hepatitis mice compared with HSA or Trx, components of the fusion protein. HSA-Trx also markedly caused a diminution in the histopathological features of hepatic injuries and the number of apoptosis-positive hepatic cells. In addition, an evaluation of oxidative stress markers and plasma cytokine and chemokine levels clearly showed that HSA-Trx significantly improved the breakdown of hepatic redox conditions and inflammation caused by the APAP treatment. HSA-Trx also significantly decreased oxidative and nitrosative/nitrative stress induced by SIN-1 in vitro. Finally, HSA-Trx, but not the NAC treatment at 4 hours after APAP injection, significantly inhibited the elevation in plasma transaminases levels. In conclusion, the findings suggest that HSA-Trx has considerable potential for use as a novel therapeutic agent for APAP-induced hepatitis, due to its long-lasting anti-oxidative and anti-inflammatory effects