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Autoimmune pancreatitis (AIP) is an autoimmune disorder of the pancreas characterized by enhanced IgG4 antibody responses and multiple organ involvement. AIP is a pancreatic manifestation of the systemic IgG4-related disease (IgG4-RD). Although AIP and IgG4-RD predominantly occur in middle-aged and elderly men, the roles of eating habits and lifestyle in the pathogenesis of these conditions are poorly understood. In this study, we examined whether a high-fat diet (HFD), preferred by middle-aged and elderly men, increases sensitivity to experimental AIP. We modeled AIP in MRL/MpJ mice by repeated injections of polyinosinic:polycytidylic acid. HFD exacerbated AIP development and promoted pancreatic accumulation of interferon (IFN)-α-producing plasmacytoid dendritic cells (pDCs). However, HFD did not increase the severity of autoimmune sialadenitis, another disorder associated with AIP and IgG4-RD. Neutralization of type I IFN signaling pathways prevented the development of severe AIP induced by HFD. In contrast, leaky gut was less likely to be associated with the HFD-induced exacerbation of AIP, as was evidenced by the lack of significant alterations in the jejunal or ileal expression of tight junction proteins. These data suggest that HFD exacerbates experimental AIP through the activation of pDCs producing IFN-α.

Chronic hepatitis D (CHD) is the most severe form of viral hepatitis, characterised by the greatest increase in risk of cirrhosis, hepatic decompensation and hepatocellular carcinoma. Pegylated-interferon-α (pegIFNα), the only off-label therapeutic option, has been available for the last 30 years but is associated with suboptimal response rates and poor tolerability. Among the new treatment strategies under clinical evaluation, the entry inhibitor bulevirtide (BLV) is the only one that has received conditional approval from the European Medicines Agency (EMA); approval was granted in July 2020 for the treatment of adult patients with compensated CHD at a dose of 2 mg daily. Phase II studies and the week 24 interim analysis of a phase III study demonstrated the efficacy and safety of this treatment as a monotherapy or combined with pegIFNα. This favourable profile has been confirmed by recent real-world studies performed in Europe. As a long-term monotherapy, BLV has been successfully used to treat patients with advanced compensated cirrhosis. These encouraging yet preliminary findings must be viewed with caution as many critical issues related to this new antiviral strategy are still poorly understood, as summarised in this review. While waiting for new anti-HBV and anti-HDV drugs to become available for combination studies, BLV treatment is currently the only available anti-HDV therapeutic option that might improve the long-term prognosis of difficult-to-manage patients with CHD.

Hepatitis B virus (HBV) can rapidly replicate in the hepatocytes after transmission, leading to chronic hepatitis, liver cirrhosis and eventually hepatocellular carcinoma. Interferon-α (IFN-α) is included in the standard treatment for chronic hepatitis B (CHB). However, this therapy causes serious side effects. Delivering IFN-α selectively to the liver may enhance its efficacy and safety. Imiquimod (IMQ), a Toll-Like Receptor (TLR) 7 agonist, stimulates the release of IFN-α that exhibits potent antiviral activity. However, the poor solubility and tissue selectivity of IMQ limits its clinical use. Here, we demonstrated the use of lipid-based nanoparticles (LNPs) to deliver IMQ and increase the production of IFN-α in the liver. We encapsulated IMQ in two liver-targeted LNP formulations: phospholipid-free small unilamellar vesicles (PFSUVs) and DSPG-liposomes targeting the hepatocytes and the Kupffer cells, respectively. In vitro drug release/retention, in vivo pharmacokinetics, intrahepatic distribution, IFN-α production, and suppression of serum HBV surface antigen (HBsAg) were evaluated and compared for these two formulations. PFSUVs provided95% encapsulation efficiency for IMQ at a drug-to-lipid ratio (D/L) of 1/20 (w/w) and displayed stable drug retention in the presence of serum. DSPG-IMQ showed 79% encapsulation of IMQ at 1/20 (D/L) and exhibited ∼30% burst release when incubated with serum. Within the liver, PFSUVs showed high selectivity for the hepatocytes while DSPG-liposomes targeted the Kupffer cells. Finally, in an experimental HBV mouse model, PFSUVs significantly reduced serum levels of HBsAg by 12-, 6.3- and 2.2-fold compared to the control, IFN-α, and DSPG-IMQ groups, respectively. The results suggest that the hepatocyte-targeted PFSUVs loaded with IMQ exhibit significant potential for enhancing therapy of CHB.

The expression of the ubiquitin-like molecule interferon-stimulated gene 15 kDa (ISG15) and post-translational protein modification by ISG15 (ISGylation) are strongly activated by interferons or pathogen infection, suggesting that ISG15 and ISGylation play an important role in innate immune responses. More than 400 proteins have been found to be ISGylated. ISG15 is removed from substrates by interferon-induced ubiquitin-specific peptidase 18 or severe acute respiratory syndrome coronavirus 2‒derived papain-like protease. Therefore, maintaining strong ISGylation may help prevent the spread of coronavirus disease 2019 (COVID-19). However, it is unknown whether nutrients or chemicals affect ISGylation level. Curcumin is the major constituent of turmeric and functions as an immunomodulator. Here, we investigated the effect of curcumin on ISGylation. MCF10A and A549 cells were treated with interferon α and curcumin after which the expression levels of various proteins were determined. The effect of curcumin on ubiquitylation was also determined. Curcumin treatment was found to reduce ISGylation in a dose-dependent manner. The findings suggested that curcumin partly prevents disulfide bond-mediated ISG15 dimerization directly or indirectly, thereby increasing monomer ISG15 levels. Reduced ISGylation may also occur via the prevention of ISG15 activation by ubiquitin-activating enzyme E1-like protein. In conclusion, curcumin treatment was found to reduce ISGylation, suggesting that it may contribute to severe COVID-19. This is the first study to report a relationship between ISGylation and a food component.

editorial research support, non-u.s. gov't 2022 Oct 2022 08 08 imported

Background\ud Systemic inflammation induces acute changes in mood, motivation and cognition that closely resemble those observed in depressed individuals. However, the mechanistic pathways linking peripheral inflammation to depression-like psychopathology via intermediate effects on brain function remain incompletely understood.\ud \ud Methods\ud We combined data from 30 patients initiating interferon-α treatment for Hepatitis-C and 20 anti-tumour necrosis factor (TNF) therapy for inflammatory arthritis and used resting-state functional magnetic resonance imaging to investigate acute effects of each treatment on regional global brain connectivity (GBC). We leveraged transcriptomic data from the Allen Human Brain Atlas to uncover potential biological and cellular pathways underpinning regional vulnerability to GBC changes induced by each treatment.\ud \ud Results\ud Interferon-α and anti-TNF therapies both produced differential small-to-medium sized decreases in regional GBC. However, these were observed within distinct brain regions and the regional patterns of GBC changes induced by each treatment did not correlate suggesting independent underlying processes. Further, the spatial distribution of these differential GBC decreases could be captured by multivariate patterns of constitutive regional expression of genes respectively related to: i) neuroinflammation and glial cells; and ii) glutamatergic neurotransmission and neurons. The extent to which each participant expressed patterns of GBC changes aligning with these patterns of transcriptomic vulnerability also correlated with both acute treatment-induced changes in interleukin-6 (IL-6) and, for Interferon-α, longer-term treatment-associated changes in depressive symptoms.\ud \ud Conclusions\ud Together, we present two transcriptomic models separately linking regional vulnerability to the acute effects of interferon-α and anti-TNF treatments on brain function to glial neuroinflammation and glutamatergic neurotransmission. These findings generate hypotheses about two potential brain mechanisms through which bidirectional changes in peripheral inflammation may contribute to the development/resolution of psychopathology.

The optimal therapeutic strategy in nucleoside analogue (NA) experienced chronic hepatitis B (CHB) using peginterferon is still unclear; hence we explored a switch to or add-on peginterferon strategy versus continued NA.We conducted a randomized controlled trial of CHB patients on NA12 months with HBV DNA(-) randomized to switch or add-on peginterferon-alpha2b (1.5 μg/kg/weekly) for 48 weeks versus continuing NA (controls) (allocation 2:2:1; Clinicaltrial.gov: NCT01928511) in tertiary Singapore hospitals. The primary composite endpoint at week 72 was hepatitis B e antigen (HBeAg) loss or quantitative HBsAg (qHBsAg)1 log IU/mL reduction, and secondary endpoints were HBsAg loss, HBsAg seroconversion, qHBsAg200 IU/mL, qHBsAg100 IU/mL, HBV DNA(-), viral relapse, and safety. Analysis was by intention-to-treat (ITT).A total of 253 patients (controls 51, switch 103, add-on 99) were randomized. The primary ITT endpoint was achieved in 3.9% of controls, 33.3% of switch, and 26.7% of add-on (P.0001, switch/add-on versus controls). HBsAg loss occurred in 0% of controls, 7.8% of switch, and 10.1% of add-on (ITT, P.001, switch/add-on versus controls). HBeAg(+) patients on peginterferon had higher HBeAg loss than controls but poor HBsAg responses, whereas HBeAg(-) patients on peginterferon achieved better HBsAg responses than controls. Reduction in qHBsAg in HBeAg(+) was 0.14 log IU/mL versus 0.51 log IU/mL in HBeAg(-) (P.0001) in peginterferon-treated patients. Clinical relapse was higher in switch (13.6% overall, 27% in HBeAg(+)) versus 1% add-on and 0% controls. Adverse events were typically interferon-related symptoms, with one death (myocardial infarction unrelated to therapy).ITT analysis showed that either peginterferon strategies were superior to NA for the primary endpoint and HBsAg loss, but add-on peginterferon is preferred to switch due to improved safety and similar efficacy. ClincialTrials.gov number: NCT01928511.

Recent studies have identified an association between perturbed type I interferon (IFN) responses and the severity of coronavirus disease 2019 (COVID-19). IFNα intervention may normalize the dysregulated innate immunity of COVID-19. However, details regarding its utilization and therapeutic evidence have yet to be systematically evaluated. The aim of this comprehensive review was to summarize the current utilization of IFNα for COVID-19 treatment and to explore the evidence on safety and efficacy. A comprehensive review of clinical studies in the literature prior to December 1st, 2021, was performed to identify the current utilization of IFNα, which included details on the route of administration, the number of patients who received the treatment, the severity at the initiation of treatment, age range, the time from the onset of symptoms to treatment, dose, frequency, and duration as well as safety and efficacy. Encouragingly, no evidence was found against the safety of IFNα treatment for COVID-19. Early intervention, either within five days from the onset of symptoms or at hospital admission, confers better clinical outcomes, whereas late intervention may result in prolonged hospitalization.

Objective BCG can improve the response to vaccines directed against viral infections, and also, BCG vaccination reduces all-cause mortality, most likely by protecting against unrelated infections. However, the effect of BCG vaccination on dendritic cell (DC) subsets is not well characterized. Methods We investigated the impact of BCG vaccination on the frequencies of DC subsets and type I and III interferons (IFNs) using whole blood and plasma samples in a group of elderly individuals (age 60-80 years) at one-month post-vaccination as part of our clinical study to examine the effect of BCG on COVID-19. Results Our results demonstrate that BCG vaccination induced enhanced frequencies of plasmacytoid DC (pDC) and myeloid DC (mDC). BCG vaccination also induced diminished plasma levels of type I IFNs, IFNα and IFNβ but increased levels of type III IFNs, IL-28A and IL-29. Conclusions Thus, BCG vaccination was associated with enhanced DC subsets and IL-28A/IL-29 in elderly individuals, suggesting its ability to induce non-specific innate immune responses.

Overexpression of interferon induced transmembrane protein-1 (IFITM1) enhances tumor progression in multiple cancers, but its role in triple-negative breast cancer (TNBC) is unknown. Here, we explore the functional significance and regulation of IFITM1 in TNBC and strategies to target its expression. Immunohistochemistry staining of a tissue microarray demonstrates that IFITM1 is overexpressed in TNBC samples which is confirmed by TCGA analysis. Targeting IFITM1 by siRNA or CRISPR/Cas9 in TNBC cell lines significantly inhibits proliferation, colony formation, and wound healing in vitro. Orthotopic mammary fat pad and mammary intraductal studies reveal that loss of IFITM1 reduces TNBC tumor growth and invasion in vivo. RNA-seq analysis of IFITM1/KO cells reveals significant downregulation of several genes involved in proliferation, migration, and invasion and functional studies identified NF-κB as an important downstream target of IFITM1. Notably, siRNA knockdown of p65 reduces IFITM1 expression and a drug-repurposing screen of FDA approved compounds identified parthenolide, an NFκB inhibitor, as a cytotoxic agent for TNBC and an inhibitor of IFITM1 in vitro and in vivo. Overall, our findings suggest that targeting IFITM1 by suppressing interferon-alpha/NFκB signaling represents a novel therapeutic strategy for TNBC treatment.

Background The progress of liver diseases may not stop after viral eradication. This study aimed to provide data on long-term prognosis of patients with hepatitis C virus (HCV) infection who underwent pegylated interferon plus ribavirin (PR) regimen and achieved a sustained virological response 24 weeks post-treatment (SVR24). Methods Responders to the PR regimen in our hospital from January 2011 to June 2014 were enrolled and prospectively followed up. Baseline characteristics were profiled. The incidence of hepatocellular carcinoma (HCC), progression of liver disease (increase in liver stiffness or occurrence of decompensated complication), and HCV recurrence was all monitored. The accumulative and annualized incidence rates (AIRs) of these adverse events were analyzed, and the risk factors were also examined. Results In total, 151 patients reached a median follow-up time of 103 weeks. Among them, two had an incidence of HCC during the surveillance with AIR of 0.68% (95% CI: 0.00-1.63%). Six patients showed progression of liver disease with AIR of 2.05% (95% CI: 0.42%-3.68%). Three patients who had risky behaviors encountered HCV reinfection. The cirrhotic patients faced higher risk of poor prognosis than non-cirrhotic patients, including HCC and progression of liver disease (AIR: 6.17% vs. 1.42%, P = 0.039). Conclusions The incidence of HCC and progression of liver disease was evident in PR responders during the long-term follow-up period, but the risk level was low. Cirrhotic responders were more vulnerable to develop HCC post SVR24 compared with non-cirrhotic ones. HCV recurrence was rare in responders with SVR24 who had corrected their risky behaviors.

Essential thrombocytopenia (ET), polycythemia vera (PV), and myelofibrosis (MF) are heterogeneous groups of clonal hematopoietic cells the major subgroups within MPNs. MPNs can be critical, mainly due to the risk of thrombosis. ET is mainly concerned with increased risk of thrombosis with preserved quality of life, PV affecting both morbidity and also life expectancy; elevated total leucocytic count enhances the TTT with Interferon Alpha due to cytogenetic remission in case of JAKV617F and so pregnancy with MPNs has been reported to be associated with maternal thrombosis, hemorrhage, and placental dysfunction, leading to fetal growth restriction or loss.A retrospective study was held at Ain Shams University (outpatient clinic) and the prenatal care of El Sheik Zayed Al Nahian (MOH). 25 patients aged (18-55) were included 14 patients with ET (56%), 8 patients with PV (32%), 3 patients with MF 12%; those with MF didn't meet the inclusion criteria.Recorded total 118 pregnancies with live birth represented 70% in ET and 62% in PV, 56% spontaneous losses occurred in the first trimester, 24% in the second trimester, and 11% in the third trimester. The aspirin dose was described in all patients with ET and PV with dose 75 mg and was correlated with the pregnancy outcome to show a significant correlation with P0.5. Low molecular weight (LMWT) heparin was added as a second line in 64% of patients with a significant correlation with pregnancy outcome as regard live birth, P0.5. Interferon was added in the second trimester in two patients with PV with no impact on the outcome of live birth. Patients with PV continue on aspirin and LMWT heparin (Clexan) postpartum till the end of the puerperium in 4 patients with PV. Incidence of bleeding or thrombosis in patients treated with LMWH vs Aspirin only in the postpartum period showed no significant difference. Preeclampsia was reported in 2 patients 8% and ended in a live birth.To improve outcomes and reduce complications, several strategies have been attempted, including aspirin, heparin, and cytoreductions with interferon.

Importance The most supportive evidence of the inflammation theory of depression is that up to one-third of patients with Hepatitis C virus infection (HCV) develop clinical depressive episodes during interferon-α (IFN-α) therapy. As glutamate-mediated excitotoxicity has been found to be a consequence of excessive inflammation and a pathogenic mechanism of depression, it is plausible to investigate genes on ionotropic glutamate receptor pathways. Objective To identify the at-risk genetic variations on ionotropic glutamate receptor pathways for interferon-α-induced depression. Method We assessed 291 patients with chronic HCV undergoing IFN-α therapy and analyzed the single nucleotide polymorphisms (SNPs) in genes related to ionotropic glutamate receptors in this prospective case-control study. Patients who developed IFN-α-induced depression anytime during the treatment were defined as the case group, while those who did not were defined as the control group. Genomic DNA was extracted from peripheral blood and analyzed by Affymetrix TWB array. Allelic and haplotype association tests were conducted using χ2 tests to assess the difference in allele and haplotype frequencies between cases and controls. Additionally, we performed 5000 permutations to control gene-wide family-wise error rates and create empirical p-values. Stratified analyses were then done to control for confounders and adjust odds ratios for our significant SNPs. We also did an additional stratified analysis to re-assess genes with near-significant SNPs (empirical p-value=0.05-0.10), employing Bonferroni correction with the effective number of independent tests to control gene-wide family-wise error rates. Results The minor and major allele frequencies of rs7542 (empirical p-value=0.0310) in MAPK3, rs3026685 (empirical p-value=0.0378) in PICK1, rs56005409 (empirical p-value=0.0332) in PRKCA, rs12914792 (empirical p-value=0.0096), rs17245773 (empirical p-value=0.0340) in RASGRF1, and rs78387863 (empirical p-value=0.0086), rs74365480 (empirical p-value=0.0200) in RASGRF2 were found significantly different between cases and controls. Haplotype association tests also revealed one significant haplotype in PRKCA (empirical p-value=0.0200) and one in RASGRF1 (empirical p-value=0.0048). Stratified analyses showed no signs of confounders for most of our significant SNPs, except for rs78387863 in RASGRF2. After a re-assessment of our near-significant genes by stratified analyses, two SNPs in GRIN2B turned significant. Conclusions This study provided supportive evidence of the involvement of the RAS/RAF/mitogen-activated protein kinase (MAPK) signaling pathway and glutamate ionotropic receptor AMPA type subunit 2(GluR2) transportation in the pathogenesis of IFN-α-induced depression.

The partial response of chronic hepatitis B virus (CHB) patients to interferon-α (IFN-α) therapy remains elusive, which requires a better understanding of the involved molecular mechanism. In our study, bioinformatics analysis was applied to relate IFN-α regulated candidate genes and RNA editing sites by RNA sequencing. Mitochondrial antiviral signaling protein (MAVS) antiviral effect was confirmed in HepG2.2.15 cells and in two mouse models. The associations between polymorphisms in MAVS gene and response to IFN-α therapy were confirmed in CHB patients. We found that IFN-α downregulates MAVS via RNA editing that was mediated by adenosine deaminase acting on RNA (ADAR1). ADAR1 inhibited MAVS expression via a human antigen R (HuR)-mediated post-transcriptional regulation. MAVS exerted an antiviral activity and reduced the level of hepatitis B virus (HBV) markers in vitro and in vivo. IFN-α antiviral effects were significantly enhanced by MAVS co-transfection. Hepatitis B core protein (HBc) interacted with SP1 to inhibit the promoter activity of MAVS that regulates its expression. CHB patients with a rs3746662A allele had higher MAVS expression and thus were more responsive to IFN-α treatment. In this work, we demonstrated that the decrease of MAVS expression is mediated by the IFN-α-ADAR1 axis. This study also highlighted the potential for the clinical application of MAVS in combination with IFN-α for the treatment of HBV infection.

Background & Aims During treatment of chronic HBV infections, loss or seroconversion of the HBV surface antigen (HBsAg) is considered a functional cure. HBsAg consists of the large (LHBs), middle (MHBs), and small surface protein (SHBs) and their relative proportions correlate strongly with disease stage. Our aim was to assess the association between HBsAg composition and functional cure during treatment. Methods A total of 83 patients were retrospectively analyzed. HBsAg loss was achieved by 17/64 patients during nucleos(t)ide analogue (NA) treatment and 3/19 patients following treatment with pegylated interferon-alfa2a (PEG-IFN) for 48 weeks. Sixty-three patients without HBsAg loss were matched as controls. LHBs, MHBs and SHBs were quantified in sera collected before and during treatment. Results Before treatment, median MHBs levels were significantly lower in patients with subsequent HBsAg loss than in those without (p = 0.005). During treatment, MHBs and LHBs proportions showed a fast decline in patients with HBsAg loss, but not in patients with HBV e antigen seroconversion only or patients without serologic response. MHBs became undetectable by month 6 of NA treatment in all patients with HBsAg loss, which occurred on average 12.8 ± 8.7 (0–52) months before loss of total HBsAg. Receiver-operating characteristic analyses revealed that the proportion of MHBs was the best early predictor of HBsAg loss before NA treatment (AUC = 0.726, p = 0.019). In patients achieving HBsAg loss with PEG-IFN, the proportions of MHBs and LHBs showed similar kinetics. Conclusion Quantification of HBsAg proteins shows promise as a novel tool to predict early treatment response. These assessments may help optimize individual antiviral treatment, increasing the rates of functional cure in chronically HBV-infected patients. Lay summary The hepatitis B surface antigen (HBsAg) is a key serum marker for viral replication. Loss of HBsAg is considered stable remission, which can be achieved with antiviral treatments. We have investigated whether the ratios of the different components of HBsAg, namely the large (LHBs) and medium (MHBs) HBsAg during different treatments are associated with the occurrence of HBsAg loss. We found that LHBs and MHBs decrease earlier than total HBsAg before HBsAg loss and we propose LHBs and MHBs as promising novel biomarker candidates for predicting cure of HBV infection.

Background & Aims Despite recent advances in antiviral therapy for hepatitis C virus (HCV), a proportion of patients with genotype 3 (G3) HCV infection do not respond to current all oral treatment regimens. Genomic analyses have identified key polymorphisms correlating with increased resistance to direct-acting antivirals. We previously reported that amino acid polymorphisms (A150V and K206E) in the polymerase (NS5B) of G3 HCV reduce response to sofosbuvir. We now demonstrate that these polymorphisms alter the response to interferon alpha. Methods Quantitative polymerase chain reaction, immunofluorescence, luciferase activity assay, immunoblotting, and flow cytometry were used to study the antiviral effect of interferon (IFN) on DBN G3 HCV-infected cells and G3 HCV replicons. Results We show the presence of the A150V polymorphism markedly reduces the response to IFN alpha (IC50 of S52_WT = 1.162 IU/mL and IC50 of S52_A150V = 14.45 IU/mL, 12.4-fold difference). The induction of IFN-stimulated genes in A150V replicon cells is unaffected, but nuclear localization of active protein kinase R (PKR) is reduced. Blockade of PKR activity reduced the antiviral effect of IFN on wild-type replicons, whereas augmented PKR activation promoted the antiviral effect of IFN on A150V replicons. Furthermore, we show that impaired activation of PKR in A150V replicon cells diminishes cellular apoptosis. Conclusions These results demonstrate that polymorphisms reducing response rates to direct-acting antivirals may function beyond conferring drug resistance by modulating the intrinsic cellular antiviral response.

Intestinal inflammation in poultry is a complex response that involves immune and intestinal cells which is still not fully understood. Thus, to better understand the mechanisms that drive the chronic intestinal inflammation in fowl we conducted an experiment applying a previously established nutritional model of low-grade chronic intestinal inflammation to evaluate cytokine and chemokine profiles in the chicken intestine. For this, we placed 90 one-day chickens into two treatments: (1) a control group (CNT) fed a corn-soybean diet, and (2) a group fed a diet high in non-starch polysaccharides (NSP). At days 14, 22, 28 and 36 of age, 6 birds from each treatment were euthanized, jejunal and ileal samples were collected for histological examination and cytokine measurements. The cytokines interferon-alpha (IFN-α), IFN-γ, interleukin-16 (IL-16), IL-10, IL-21, IL-6, macrophage-colony stimulating factor (M-CSF), chemokine C-C motif ligand 20 (CCL20), CCL4, CCL5 and vascular endothelial growth factor (VEGF) were quantified in the intestinal tissue. Histologically, both jejunum and ileum of broilers fed NSP diet showed marked infiltration of mononuclear immune cells into the villi. Further, these birds exhibited a significant (P 0.05) increase in CCL20 concentration in the jejunum at 14d, but a dramatic reduction of M-CSF at 14 and 21d. Later at 28d and 36d, birds fed the NSP diet exhibited increased IL-16 concentration in the jejunum. Since M-CSF is a monocyte stimulatory cytokine and CCL20 a chemokine of T-cells, the reduced M-CSF and increased production of CCL20 may indicate the involvement of the adaptive immune response, specifically driven by T-cells, occurring around the third week of age in the NSP model. Lastly, as a result of the mononuclear cell infiltration and activation of T-cells, IL-16, a pro-inflammatory T-cell cytokine, increased. Therefore, the current work indicates the importance of adaptive immune cells, especially T-cells, in the chronic intestinal inflammation in broiler chicken.

Objective Acute myocardial infarction (AMI) initiates pathological inflammation which aggravates tissue damage and causes heart failure. Lysophosphatidic acid (LPA), produced by autotaxin (ATX), promotes inflammation and the development of atherosclerosis. The role of ATX/LPA signaling nexus in cardiac inflammation and resulting adverse cardiac remodeling is poorly understood. Approach and results We assessed autotaxin activity and LPA levels in relation to cardiac and systemic inflammation in AMI patients and C57BL/6 (WT) mice. Human and murine peripheral blood and cardiac tissue samples showed elevated levels of ATX activity, LPA, and inflammatory cells following AMI and there was strong correlation between LPA levels and circulating inflammatory cells. In a gain of function model, lipid phosphate phosphatase-3 (LPP3) specific inducible knock out (Mx1-Plpp3Δ) showed higher systemic and cardiac inflammation after AMI compared to littermate controls (Mx1-Plpp3fl/fl); and a corresponding increase in bone marrow progenitor cell count and proliferation. Moreover, in Mx1- Plpp3Δ mice, cardiac functional recovery was reduced with corresponding increases in adverse cardiac remodeling and scar size (as assessed by echocardiography and Masson's Trichrome staining). To examine the effect of ATX/LPA nexus inhibition, we treated WT mice with the specific pharmacological inhibitor, PF8380, twice a day for 7 days post AMI. Inhibition of the ATX/LPA signaling nexus resulted in significant reduction in post-AMI inflammatory response, leading to favorable cardiac functional recovery, reduced scar size and enhanced angiogenesis. Conclusion ATX/LPA signaling nexus plays an important role in modulating inflammation after AMI and targeting this mechanism represents a novel therapeutic target for patients presenting with acute myocardial injury.

Background Recent studies report incongruent finds regarding the addition of pegylated interferon -alpha (Peg- IFNα) to nucleos(t)ide analogues. This study was designed to compare the efficacy of Peg- IFNα and tenofovir disoproxil fumarate (TDF) combination therapy with each of the treatments separately. Methods In this open-label, randomized clinical trial, treatment-naive hepatitis B e antigen (HBeAg)-negative patients were randomly assigned to three treatment groups: Group A: Peg- IFNα (180 mcg/week) with TDF (300 mg/day); Group B: TDF (300 mg/day); and Group C: Peg- IFNα (180 mcg/week). The intervention spanned 48 weeks and patients were followed up every 12 weeks. The primary end-point was HBV DNA load Results Groups A, B and C each comprised of 22, 23 and 22 patients, respectively. The number of patients with HBV DNA suppression in group A was significantly higher compared to groups B and C (P = 0.034). No significant difference was observed in the normalization trends of serum ALT levels between the three groups (P = 0.082). At week 48, combination therapy was significantly more effective in suppressing HBV DNA concentration to below the level of detection than TDF monotherapy (OR = 2.1, 95%CI: 1.18–4.15; P = 0.034). Furthermore, a comparison between monotherapy arms revealed that both interventions had similar effects on the overall outcome (OR = 1.24, 95%CI: 1.02–5.8; P = 0.062). Conclusion A Peg- IFNα and TDF combination therapy resulted in improved virologic response and was safe in HBeAg negative patients. Monotherapy with Peg-IFNα or TDF procured limited benefits in comparison. Trial registration This study was registered in the Iranian Registry of Clinical Trials (IRCT20181113041635N1).

Background Myelofibrosis (MF) is a Philadelphia chromosome–negative myeloproliferative neoplasm characterized by progressive bone marrow failure, increased risk of progression to acute myeloid leukemia, and constitutional symptoms. For over 3 decades, various formulations of interferon (IFN) have been used for the treatment of MF, with variable results, and the role of IFN in the treatment of MF is evolving. Patients and Methods For this systematic review and meta-analysis, Medline and Embase via Ovid, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science were searched from inception through March 2019 for studies of pegylated IFN (peg-IFN) and non–peg-IFN in MF patients. The primary outcome of overall response rate was defined as a composite of complete response, partial response, complete hematologic response, and partial hematologic response. Random-effects models were used to pool overall response rate, and metaregression analyses were performed to compare peg-IFN and non-–peg-IFN formulations. Results Among the 10 studies with 141 MF patients included, the overall response rate was 49.9% (95% confidence interval [CI], 30.4-69.3), and there was no statistically significant difference (P = .99) between peg-IFN (50.0%; 95% CI, 26.2-73.9; I2 = 76.9%) and non–peg-IFN (49.6%; 95% CI, 20.5-79.0; I2 = 56.7%). Treatment discontinuation resulting from adverse events was common with non–peg-IFN at 35.8% (95% CI, 3.5-68.1) per year, and less in the one study on peg-IFN (0.5% per year). Conclusion IFN can lead to hematologic improvements in a subset of MF patients, but study quality is limited and heterogenous. Biomarkers predicting response to IFN and formulations with improved tolerability are needed.

Objectives: The purpose of this study was to analyze the clinical characteristics of chronic hepatitis B (CHB) cured by antiviral therapy. Methods: Forty-two patients with CHB were enrolled. All patients had been treated with peginterferon (Peg-IFN) in combination with nucleoside analogue (NA) therapy for variable amounts of time, and all had been successfully cured of the disease. Results: The combined treatment time for all participants was 124.7 ± 58.8 weeks, and the average Peg-IFN treatment time was 102.6 ± 56.1 weeks. At 24 weeks, Hepatitis B surface antigen (HBsAg) and Hepatitis B e antigen (HBeAg) had decreased more than 50% from baseline. Multivariate logistic regression analysis of the week 96 HBsAg-clearing group and the non-HBsAg-clearing group showed a statistically significant difference in baseline HBV DNA levels and week 48 HBsAg levels. Those which baseline HBV DNA was < 2.75 log10 IU/mL, and week 48 HBsAg levels were < 0.88 log10 IU/mL were more likely to achieve rapid HBsAg clearance at 96 weeks. This suggests that low levels of baseline HBV DNA and week 48 HBsAg are a predictor of rapid HBsAg clearance at 96 weeks. Conclusions: Individualized extension of combination therapy to more than 96 weeks depending on the patient’s response and adverse reaction conditions can help achieve a clinical cure. Patients with low baseline HBV DNA and low HBsAg levels at 48 weeks achieve HBsAg clearance more quickly than other populations.

Introduction Autoimmune thyroid diseases are reported in no treated hepatitis C virus (HCV) infection. The standard interferon alpha (IFNα) treatment is associated with an increase of thyroid damage and dysfunction. The present cohort prospective study compared thyroid function and autoimmunity in HCV patients’ monoinfected and coinfected HCV–HIV at baseline, during and after IFNα therapy. Methods We studied 790 HCV infected patients: G1 (monoinfected HCV: N = 580) and G2 (HCV–HIV coinfected: N = 210). They were evaluated for thyroid function and thyroid tiroperoxidase antibodies (TPOAb) at baseline and 235 patients (G1: 183; G2: 52) post IFNα therapy. If thyroid dysfunction (TD) was diagnosed, they were reevaluated at 12 month after discontinuation to determine whether the TD was transitory or definitive. Results No difference was found in the prevalence of TD at baseline in G1 (7.6%) and G2 (9%). However, monoinfected patients showed a higher prevalence of TPOAb positivity with a women preponderance in this group. There was no difference in TD between both groups during IFNα therapy (G1 23.5% vs G2 19.2%). In G1 the autoimmune TD was higher than in G2 (67.4% vs 30%, p = 0.02). Autoimmune TD during IFNα tended to evolve to definitive hypothyroidism and non-autoimmune TD recovered euthyroidism after IFNα discontinuation. The presence of positive TPOAb (RR 3.55) and female gender (RR 2.4) were associated with the development of TD with IFNα therapy. Conclusion Our hypothesis is the importance of HCV in G1 and G2, combined with IFNα in triggering TD and TPOAb positivity, not described in other diseases’ applications.

Summary Background The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment. Methods PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing). Findings Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3–201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4–169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response without the spleen criterion in the ropeginterferon alfa-2b group versus standard therapy group were: 53 (43%) of 123 patients versus 57 (46%) of 125 patients, p=0·63 at 12 months (PROUD-PV), and 67 (71%) of 95 patients versus 38 (51%) of 74 patients, p=0·012 at 36 months (CONTINUATION-PV). The most frequently reported grade 3 and grade 4 treatment-related adverse events were increased γ-glutamyltransferase (seven [6%] of 127 patients) and increased alanine aminotransferase (four [3%] of 127 patients) in the ropeginterferon alfa-2b group, and leucopenia (six [5%] of 127 patients) and thrombocytopenia (five [4%] of 127 patients) in the standard therapy group. Treatment-related serious adverse events occurred in three (2%) of 127 patients in the ropeginterferon alfa-2b group and five (4%) of 127 patients in the hydroxyurea group. One treatment-related death was reported in the standard therapy group (acute leukaemia). Interpretation In patients with early polycythaemia vera, who predominantly presented without splenomegaly, ropeginterferon alfa-2b was effective in inducing haematological responses; non-inferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months. Considering the high and durable haematological and molecular responses and its good tolerability, ropeginterferon alfa-2b offers a valuable and safe long-term treatment option with features distinct from hydroxyurea. Funding AOP Orphan Pharmaceuticals AG.

Summary Background Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due to mutations in the Janus kinase 2 (JAK2) gene. Ruxolitinib, a JAK 1 and JAK 2 inhibitor, showed superiority over best available therapy in a phase 2 study in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. We aimed to compare the long-term safety and efficacy of ruxolitinib with best available therapy in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. Methods We report the 5-year results for a randomised, open-label, phase 3 study (RESPONSE) that enrolled patients at 109 sites across North America, South America, Europe, and the Asia-Pacific region. Patients (18 years or older) with polycythaemia vera who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to receive either ruxolitinib or best available therapy. Patients randomly assigned to the ruxolitinib group received the drug orally at a starting dose of 10 mg twice a day. Single-agent best available therapy comprised hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or observation without pharmacological treatment. The primary endpoint, composite response (patients who achieved both haematocrit control without phlebotomy and 35% or more reduction from baseline in spleen volume) at 32 weeeks was previously reported. Patients receiving best available therapy could cross over to ruxolitinib after week 32. We assessed the durability of primary composite response, complete haematological remission, overall clinicohaematological response, overall survival, patient-reported outcomes, and safety after 5-years of follow-up. This study is registered with ClinicalTrials.gov , NCT01243944 . Findings We enrolled patients between Oct 27, 2010, and Feb 13, 2013, and the study concluded on Feb 9, 2018. Of 342 individuals screened for eligibility, 222 patients were randomly assigned to receive ruxolitinib (n=110, 50%) or best available therapy (n=112, 50%). The median time since polycythaemia vera diagnosis was 8·2 years (IQR 3·9–12·3) in the ruxolitinib group and 9·3 years (4·9–13·8) in the best available therapy group. 98 (88%) of 112 patients initially randomly assigned to best available therapy crossed over to receive ruxolitinib and no patient remained on best available therapy after 80 weeks of study. Among 25 primary responders in the ruxolitinib group, six had progressed at the time of final analysis. At 5 years, the probability of maintaining primary composite response was 74% (95% CI 51–88). The probability of maintaining complete haematological remission was 55% (95% CI 32–73) and the probability of maintaining overall clinicohaematological responses was 67% (54–77). In the intention-to-treat analysis not accounting for crossover, the probability of survival at 5 years was 91·9% (84·4–95·9) with ruxolitinib therapy and 91·0% (82·8–95·4) with best available therapy. Anaemia was the most common adverse event in patients receiving ruxolitinib (rates per 100 patient-years of exposure were 8·9 for ruxolitinib and 8·8 for the crossover population), though most anaemia events were mild to moderate in severity (grade 1 or 2 anaemia rates per 100 patient-years of exposure were 8·0 for ruxolitinib and 8·2 for the crossover population). Non-haematological adverse events were generally lower with long-term ruxolitinib treatment than with best available therapy. Thromboembolic events were lower in the ruxolitinib group than the best available therapy group. There were two on-treatment deaths in the ruxolitinib group. One of these deaths was due to gastric adenocarcinoma, which was assessed by the investigator as related to ruxolitinib treatment. Interpretation We showed that ruxolitinib is a safe and effective long-term treatment option for patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Taken together, ruxolitinib treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population. Funding Novartis Pharmaceuticals Corporation.

Background and aim Recently, the role of albumin-bilirubin (ALBI) score in chronic hepatitis B (CHB) has not been well-understood. We aimed to investigate the association of ALBI score with natural history of chronic HBV infection and treatment response of CHB patients. Methods The ALBI score in a cohort of 849 individuals including 721 chronic HBV-infected patients naive to anti-HBV treatment in different phases and 128 healthy controls were estimated. Additionally, the dynamic changes of ALBI score of 243 hepatitis B e antigen (HBeAg)-positive CHB patients treated with pegylated interferon-alpha (PEG-IFN-α) or nucleos(t)ide analogues (NAs) were tested for 72 weeks. Results ALBI score differed among phases, with the highest score in HBeAg-positive CHB patients, followed by HBeAg-negative CHB patients, HBeAg-positive chronic HBV infection, and HBeAg-negative chronic HBV infection. Besides, CHB patients harbouring high baseline ALBI score exhibited a relatively stronger therapeutic response to PEG-IFN-α or NAs. Moreover, the rate of HBeAg and HBsAg loss in patients with ALBI grade 2 was persistently higher than that in patients with ALBI grade 1 throughout the course of treatment. Furthermore, ALBI score was an independent predictor of sustained response achievement. The combined use of ALBI score, HBeAg and ALT could enhance the predictive value of treatment response. Conclusions ALBI score differed significantly across the natural course of chronic HBV infection and was correlated with PEG-IFN-α and NAs treatment response in HBeAg-positive CHB patients, which suggested that ALBI score could be useful as an auxiliary clinical factor to determine the initiation of therapy and predict stronger antiviral treatment response.

The innate immune system senses viral and bacterial RNA or DNA via different cytoplasmic or endosomal localized pattern recognition receptors. In general, the preference of these receptors for single-stranded (ss), double-stranded (ds) RNA or DNA has been thoroughly characterized. Recently, RNA-DNA hybrids have also been identified as ligands for pattern recognition receptors such as Toll-like receptor 9 (TLR9). However, a comparison of RNA-DNA hybrids and ssDNA in terms of TLR9 stimulation potential and intracellular stability has not been addressed. RNA-DNA hybrids are formed transiently during normal cellular processes (e.g. replication), consist as part of some viral genomes (e.g. cytomegalovirus (CMV) or hepatitis B virus (HBV)) and exist during retroviral infection. Here we report that virus-derived synthetic RNA-DNA hybrids stimulate human peripheral blood mononuclear cells (PBMCs) as well as murine FMS-like tyrosine kinase 3 ligand (FLT3L) induced dendritic cells to secrete interferon alpha (IFN-α) in a TLR9-dependent manner. Furthermore, we could show that RNA-DNA hybrids exhibit increased intracellular stability, which correlates with enhanced activation of TLR9 in comparison to corresponding ssDNA. Overall, these data suggest a prominent role for TLR9 in the immune recognition of RNA-DNA hybrids in retroviral and CMV infection.

Introduction: Type I Interferons (INFαs and INF β) are known to be proinflammatory cytokines that promote atherosclerosis. IFNA21 is a member of alpha Interferon gene cluster on short arm of chromosome 9. We analyzed the potential link between 9p21 coronary artery disease (CAD) risk locus and IFNA21. Objectives: a) study of association between serum IFNA21 levels and 14 demographic/clinical variables, including age, gender, diabetes, hypertension, and duration of CAD, b) study of association between high serum IFNA21 levels and 30 9p21 SNP genotypes. Methods: To estimate serum circulating levels of IFNA21, we performed sandwich ELISA in 184 controls and 167 CAD cases. The IFNA21 levels could be classified into two broad classes: a) Low-level group: ≤15.6 pg/ml b) High-level group: >15.6 pg/ml. We also performed SNP genotyping for 30 SNPs at 9p21 locus in all study subjects using Sequenom MassARRAY technology. Statistical software SPSS (Version 21) was used to analyze the data obtained. Results: Our analysis indicates that there could be an association of high IFNA21 levels with variables – gender, age, and duration of CAD in the study population. SNPs rs10757272 (TT), rs10757274 (GG), rs10757283 (TT), rs1333045 (CC), rs1333048 (CC), rs1333049 (CC), and rs4977574 (GG) showed significant risk association with high-level IFNA21 group. Conclusions: IFNA21 may be involved in inflammatory processes in an age-dependent manner and in progression of CAD. This IFNA21-mediated mechanism may be more active in females. Several 9p21 SNPs may modulate inflammatory processes mediated by IFNA21 and may, therefore, contribute to pathophysiology of CAD. Keywords: Coronary artery disease, 9p21.3 CAD risk locus, Interferon alpha 21, Inflammation, Single-nucleotide polymorphism

The incidence of metastatic melanoma continues to increase each decade. Although surgical treatment is often curative for localized stage I and stage II disease, the median survival for patients with distant metastases is less than 1 year. The last 2 decades have witnessed a breakthrough in therapeutic options with the development of immune checkpoint inhibitors, small molecule targeted therapy, and oncolytic viral therapy. This article provides an overview of the treatment options available for advanced melanoma, including chemotherapy, targeted therapy, immunotherapy, interleukin-2, and oncolytic viral agents.

The Type I Interferon cytokine family member, Interferon-α2b (hIFN-α2b), modulates a number of important biological mechanisms including anti-proliferation, immunoregulation and antiviral responses. Due to its role in the immune system, hIFN-α2b has been used as a therapeutic modulator in hepatitis C as well as some forms of leukaemia. Clinical grade hIFN-α2b is typically produced in bacterial expression systems that involves complex refolding protocols and subsequent loss of yields. In this study, we describe an expression and purification system for hIFN-α2b from mammalian cells. Application of the Trypsin-1 signal peptide-propeptide domain significantly improved the expression and secretion of hIFN-α2b from HEK293 cells. We established a simple purification strategy that yields homogenous, pure hIFN-α2b that is stable and biologically active.

Bleomycin is a well-recognized antineoplastic drug. However, pulmonary fibrosis (PF) is considered to be the principal drawback that greatly limits its use. Here, we sought to investigate ability of the neurokinin receptor 1 blocker, aprepitant, to prevent PF caused by bleomycin. Male adult Wistar rat groups were given a single intratracheal injection of bleomycin, either alone or in combination with aprepitant therapy for 3 or 14 days. Collagen deposition and a rise in transforming growth factor beta (TGF-β) immunoreactivity in lung tissue serve as evidence of bleomycin-induced PF. The serum levels of lactate dehydrogenase, alkaline phosphatase, and total antioxidant improved after aprepitant therapy.Additionally, it reduced the protein expressions of interferon alpha, tumor necrosis factor alpha, and lung lipid peroxidation. Moreover, aprepitant treatment led to an increase in the antioxidant indices glutathione, glutathione peroxidase, and catalase. Aprepitant is postulated to protect against bleomycin-induced PF by decreasing TGF-β, phosphorylating Smad3, and increasing interleukin 37, an anti-fibrotic cytokine, and G Protein-coupled Receptor Kinase 2. Aprepitant for 14 days considerably exceeded aprepitant for 3 days in terms of improving lung damage and having an anti-fibrotic impact. In conclusion, aprepitant treatment for 14 days may be used as an adjuvant to bleomycin therapy to prevent PF, mostly through inhibiting the TGF-/p-Smad3 fibrotic pathway.

Natural Killer cells (NK) are crucial in host defense against viruses. There are many unanswered questions about the immune system in COVID-19, especially the mechanisms that contribute to the development of mild or severe forms of the disease. Although NK cells may have an essential role in the pathogenesis of COVID-19, the mechanisms involved in this process are not yet fully elucidated. Here, we demonstrate that CD3

ATR kinase is a central regulator of the DNA damage response (DDR) and cell cycle checkpoints. ATR kinase inhibitors (ATRi's) combine with radiation to generate CD8

The therapeutic repertoire available for advanced renal cell carcinoma (RCC), including tyrosine kinase inhibitors (TKIs) and immunotherapy, required for molecular biomarkers for response.This was a phase I to II trial on the combination of pazopanib with interferon-alpha (INF-2A) as first-line treatment for advanced RCC. The primary endpoint was recommended phase II dose (RP2D) and efficacy in terms of objective response rate (ORR, RECIST 1.1 criteria). Secondary endpoints included safety and a translational study of molecular biomarkers in serum and exosomes from peripheral blood samples at three-time points: baseline, 8 weeks of treatment, and progression of the disease.Between July 2011 and July 2017, 53 eligible patients were treated and followed up (I, n = 20; II, n = 33). Pazopanib 800 mg + INF-2A 3 MIUs showed a manageable safety profile; therefore, it was selected for dose expansion. Overall, grade 3/4 toxicities were reported in 24 (72.7%) patients. The ORR was 27.2%. The 12-month OS rate was 83.6% (median not reached), and after 30.9 months of follow-up, 24 (72.7%) patients were still alive. CCL2, IL8, TNF-α, and PD-L1 were significantly overexpressed after treatment initiation, while TGF-β1 and CCL5 were significantly decreased. TNF-α, endoglin, and PD-L1 expression are correlated with the response after treatment initiation.The trial did not reach its pre-specified target ORR. However, OS was longer than expected with pazopanib monotherapy. Changes in the molecular profile suggest a crucial role of vascular remodeling and inflammatory-mediated immune cell infiltration in optimal response to pazopanib plus INF-2A.

Psoriasis is a common, inflammatory autoimmune skin disease. Early detection of an IFN-1 signature occurs in many psoriasis lesions, but the source of IFN production remains debated. IFN-κ is an important source of IFN-1 production in the epidermis. We identified a correlation between IFN-regulated and psoriasis-associated genes in human lesional skin. We thus wanted to explore the effects of IFN-κ in psoriasis using the well-characterized imiquimod psoriasis model. Three mouse strains aged 10 weeks were used: wild-type C57Bl/6, C57Bl/6 that overexpress Ifnk in the epidermis (i.e., transgenic), and total body Ifnk(‒/‒) (i.e., knockout) strain. Psoriasis was induced by topical application of imiquimod on both ears for 8 consecutive days. Notably, the severity of skin lesions and inflammatory cell infiltration was more significantly increased in transgenic than in wild-type than in knockout mice. Gene expression analysis identified greater upregulation of Mxa, Il1b, Tnfa, Il6, Il12, Il23, Il17, and Ifng in transgenic compared to wild-type compared to knockout mice after imiquimod treatment. Furthermore, imiquimod increased CD8(+) and CD4(+) T-cell infiltration more in transgenic than in wild-type than in knockout mice. In summary, we identified IFN-κ as a rheostat for initiation of psoriasiform inflammation. This suggests that targeting IFN-1s early in the disease may be an effective way of controlling psoriatic inflammation.

Immune checkpoint inhibitors (ICIs) have revolutionised cancer immunotherapy but their success is wholly dependent on amplifying an existing immune response directed against the tumour. A recent study by Tsuchiya et al. suggests how the properties of induced pluripotent stem cells (iPSCs) may be exploited for the targeted delivery of interferon-α (IFNα) to elicit an appropriate response.

to analyse the association between interferon-1α (INF1α), interleukin-10 (IL-10) and BLyS concentrations and clinical activity in systemic lupus erythematosus (SLE).A cross-sectional, observational study of 142 SLE patients and 34 healthy controls was performed, through a complete blood and urine test and review of their medical history. Serum concentration of INF1α, IL-10 and BLyS was determined by colorimetric methods. A biostatistical analysis was performed with R (3.3.2.).69% of our SLE patients showed at least one cytokine increased. INF1α, IL-10 and BLyS are higher in SLE patients than in healthy controls (P.001, P=.005 and P=.043, respectively), being INF1α the most frequent. Patients were categorised according to low or high concentrations of the three cytokines. We found a significant association between increased IL-10/INF1α concentrations and a higher clinical activity measured by SELENA-SLEDAI (P.0001) and, to a lesser extent, an association with increased INF1α/IL-10/BLyS concentrations. Elevated levels of IL-10/INF1α and INF1α/IL-10/BLyS related to increased C3-C4 consumption (P.001 and P=.001 respectively) and anti-dsDNA titres (P=.001 and P=.002 respectively). Elevated INF1α/BLyS related to higher anti-dsDNA titres (P=.004) and ENA positivity (P.001). Increased levels of INF1α/IL-10/BLyS related to positivity of ANAs (P.001) and APL (P=.004).INF1α, IL-10 and BLyS are higher in SLE patients than in healthy controls. Increased IL-10 levels, regardless of whether or not there were also increased levels of BLyS and/or INF1α, was the cytokine that best fit with clinical activity in SLE measured with classic methods.

Interferon (IFN)-alpha, until recently the standard treatment of hepatitis C virus (HCV) infection, is associated with a significant risk of major depressive episode (MDE, or IFN-alpha-induced depression). However, it is little studied the comparisons of clinical manifestations between IFN-alpha-induced depression and major depressive disorder (MDD). In addition, IFN-alpha induces different neuroinflammation and neuroendocrine status throughput the HCV treatment course; however, the clinical presentations have never been compared between early-onset and later-onset IFN-alpha-induced depression. We assessed 200 HCV patients starting IFN-alpha therapy bi-weekly for 24 weeks, with the structured interview for confirmation of diagnosis of IFN-alpha-induced depression and with clinical rating scales for depressive symptoms and neuropsychiatric symptoms. Subjects developed IFN-alpha-induced depression (n = 59, 30%) during the first 6 weeks of IFN-alpha therapy were defined as the early-onset group (n = 32), while those developed depression after the 6th week were defined as the late-onset group (n = 27). A matched group of MDD patients (n = 60) was used to compare specific clusters of depressive symptoms with early- and late-onset IFN-alpha-induced depression. Compared to the matched group of MDD patients, IFN-alpha-induced depression was significantly associated with more somatic symptoms and fewer symptoms of mood, anxiety and negative cognition. More somatic symptoms were also found in those who became clinically depressed at early stage of IFN-alpha therapy. We suggest that the specific somatic features of interferon-alpha-induced depression, and especially of early-onset depression, characterise individuals who are more sensitive to cytokines-induced changes in mood.

Background: Secondary prevention of hepatocellular carcinoma (HCC) among patients with chronic hepatitis C (CHC) who achieve sustained virologic response (SVR) with interferon-based therapy has been proved effective. However, tertiary prevention with PegIFN/RBV therapy of HCC recurrence seems limited effect in CHC-HCC patients post curative therapies. This study aims to investigate the timing and impact of PegIFN/RBV treatment on prevention of HCC recurrence in patients after RFA treatment. Methods: From 2013 to 2016, a total of 137 CHC-HCC patients from a 508 patient based cohort receiving complete RFA treatment in Chang Gung Memorial Hospital, Linkou Medical Center were retrospectively recruited. Pre-RFA patient demographics were analyzed by cox regression analysis for prediction on tumor recurrence. Statistics analysis was performed with SPSS V.20 (IBM, USA). Results: The mean age of the 137 patients were 69.6 year-old and 71.5% of patients were cirrhotic. After propensity score matching, one hundred and two patients were enrolled into the analysis. Fifty-one patients (50%) received PegIFN/RBV therapy and twenty-seven patients (52.9%) achieved SVR. Patients who could achieve SVR had lower tumor recurrence rate than non-SVR and untreated groups (29.6% vs. 66.7% vs. 49.0%, P = 0.030). The effect is more prominent in those achieve SVR prior to compared with after RFA despite not reach statistically significant (26.1% vs. 50.0%, P = 0.334). Conclusion: Timely treatment with SVR achievement has the lowest tumor recurrence rate in CHC-HCC patients. Secondary prevention might be even more important than tertiary prevention in CHC patients, especially regarding prevention of post RFA HCC recurrence. Keywords: Radiofrequency ablation, Haptocellular carcinoma, Peginterferon and ribavirin, Prognosis

Background: The improvement in liver histology is an important aim in the management of hepatitis C virus (HCV) infection. Previous studies suggest that antiviral treatment could reduce the progression of hepatic fibrosis, especially in patients with sustained virological response (SVR). However, most studies were limited by short-term evaluations and the liver stiffness was assessed by non-invasive methods. In our study, we performed a paired liver biopsy study aimed at analyzing the long-term histological changes in patients with SVR. Methods: We included 31 patients who had been previously treated with peginterferon plus ribavirin. All patients achieved SVR and had received pre- and post-treatment liver biopsies. The histological appearance of fibrosis and inflammation were assessed with METAVIR scoring system and Histological Activity Index (HAI) criteria. We analyzed several factors associated with the histological response. Results: The median interval between two biopsies was 93.0 months. The percentage of patients with fibrosis regression, stable, and progression were 19%, 45%, and 36%. A total of 71% of patients achieved inflammation improvement, whereas 6% and 23% of patients had stable disease and disease-progression, respectively. We showed that the patients without baseline advanced fibrosis and those having a lower baseline HAI score had higher risk of fibrosis worsening. Baseline fibrosis and necroinflammation status did not influence HAI change significantly. Conclusion: The progression of hepatic fibrosis and inflammation can be reversed in some patients who had long-term virological suppression. Patients with advanced baseline fibrosis and higher inflammatory stages seemed to receive more histologic benefit from successful antiviral treatments. Keywords: Biopsy, Hepatitis C, Histology, Fibrosis, Therapeutics

Background TLR9 agonists are being developed as immunotherapy against malignancies and infections. TLR9 is primarily expressed in B cells and plasmacytoid dendritic cells (pDCs). TLR9 signalling may be critically important for B cell activity in lymph nodes but little is known about the in vivo impact of TLR9 agonism on human lymph node B cells. As a pre-defined sub-study within our clinical trial investigating TLR9 agonist MGN1703 (lefitolimod) treatment in the context of developing HIV cure strategies ( NCT02443935 ), we assessed TLR9 agonist-mediated effects in lymph nodes. Methods Participants received MGN1703 for 24 weeks concurrent with antiretroviral therapy. Seven participants completed the sub-study including lymph node resection at baseline and after 24 weeks of treatment. A variety of tissue-based immunologic and virologic parameters were assessed. Findings MGN1703 dosing increased B cell differentiation; activated pDCs, NK cells, and T cells; and induced a robust interferon response in lymph nodes. Expression of Activation-Induced cytidine Deaminase, an essential regulator of B cell diversification and somatic hypermutation, was highly elevated. During MGN1703 treatment IgG production increased and antibody glycosylation patterns were changed. Interpretation Our data present novel evidence that the TLR9 agonist MGN1703 modulates human lymph node B cells in vivo. These findings warrant further considerations in the development of TLR9 agonists as immunotherapy against cancers and infectious diseases. Fund This work was supported by Aarhus University Research Foundation , the Danish Council for Independent Research and the NovoNordisk Foundation . Mologen AG provided study drug free of charge.

Highlights • Maternally-derived neutralizing antibodies impair PRRS vaccination immune responses in piglets. • Maternally-derived neutralizing antibodies reduce PRRS vaccine efficacy in piglets. • IFNa may also interfere with PRRS vaccination., Modified live virus (MLV) vaccines are commonly used to reduce the impact of porcine reproductive and respiratory syndrome (PRRS) but limited efficacy is achieved in field conditions. Here, we evaluated the impact of maternally-derived neutralizing antibodies (MDNAs) on vaccine efficacy after PRRS virus (PRRSV) challenge. Piglets with low (A−) or high (A+) MDNA levels derived from a commercial pig herd were moved to experimental facilities to be vaccinated (V+) or not (V−) with a PRRSV-1 MLV vaccine at 3 weeks of age (woa). Because of unexpectedly low vaccine detection in A−V+ piglets post-vaccination (pv), all V+ piglets received a second vaccination at 4 woa. Five weeks (W5) pv, piglets were inoculated with a PRRSV-1 field strain to evaluate vaccine protection, and were mingled 24 h later with non-inoculated piglets of similar immune status to assess viral transmission. Vaccine strain was detected at W2 pv in 69% and 6% of A−V+ and A+V+ piglets, and at W5 pv in 50% and 25% of A−V+ and A+V+ piglets, respectively. At W5 pv, 94% of A−V+ and 44% of A+V+ piglets seroconverted, with a significant IFNg response induction in the A−V+ group only. After challenge, compared to the V− inoculated group, viremia was 100-fold lower at 10 days post-infection in A−V+ whereas viremia was not significantly reduced in A+V+ piglets. A lower transmission rate was estimated for the A−V+ group: 0.15 [0.07–0.29] versus 0.44 [0.18–1.76] and 0.32 [0.14–0.68] for the A+V+ and V− groups, respectively. Investigations about the low vaccine strain detection after the first vaccination suggested a relationship between IFNa levels and vaccine strain detection in A−V+ piglets. We showed that MDNAs impair vaccine efficacy against PRRSV both in inoculated and contact piglets, probably by reducing vaccine replication. IFNa may also interfere with PRRSV vaccination. These new data could help improving vaccination protocols.

Despite multiple antitumor activities, interferon-alpha (IFNα) therapy alone is less effective in solid tumors. Autophagy has been reported to play a key role in tumor chemoresistance. Therefore, it is meaningful to explore whether autophagy can be activated by IFNα in head and neck squamous cell carcinoma (HNSCC) and serve as a potential target to improve efficacy of IFNα therapy. In this study, we report that IFNα not only exhibits anti-proliferation activity and induces apoptosis, but also activates autophagy in HNSCC cells. Moreover, silencing autophagy-related protein 5 (ATG5) and signal transducer and activator of transcription 1 (STAT1) suppresses autophagy flux. Furthermore, IFNα and autophagy inhibitors (hydroxychloroquine and wortmannin) show clear synergistic effects on inhibiting growth and promoting apoptosis in HNSCC cells and xenograft models. Our findings indicate that IFNα-induced autophagy plays a cytoprotective role and blocking autophagy flux promotes IFNα-mediated apoptosis in HNSCC. These results suggest that the combination of IFNα and autophagy inhibitors represents a novel strategy for HNSCC treatment.

Background/Purpose: While direct-acting antiviral regimens have been approved for chronic hepatitis C (CHC) patients in Taiwan, reimbursement is limited to certain populations. Thus, pegylated interferon plus ribavirin (PEG-IFN/RBV) remains the standard of care for many patients. The aim of this study was to investigate the percentage of CHC patients who were recommended and willing to receive PEG-IFN/RBV, and to identify reasons why patients were not recommended or unwilling to receive treatment. Methods: 822 Taiwanese CHC patients were enrolled from May–August 2016 in this cross-sectional study. PEG-IFN/RBV recommendation and patient willingness to receive treatment were evaluated through surveys. Patient characteristics associated with treatment recommendation and willingness were assessed. Results: 311 (37.8%) patients were recommended PEG-IFN/RBV while 102 (12.4%) were willing to follow treatment recommendation. Rates of recommendation and willingness were lower in treatment-experienced, hepatitis C virus genotype 1 (GT1) and cirrhotic patients, and those treated in Northern Taiwan. Multivariate analyses found factors such as prior treatment experience, GT1, cirrhosis and low hemoglobin levels to be associated with lower recommendation rates while advanced age, GT1 and low baseline viral loads were associated with lower willingness rates. Physicians' top reasons for not recommending PEG-IFN/RBV included the wish to wait for better treatment options (60.3%), prior treatment failure (21.3%) and patients’ advanced age (20.9%). Patients were unwilling to receive treatment mainly due to concerns about side effects (91.4%), the wish to wait for better treatment options (71.3%) and inconvenience (25.4%). Conclusion: A minority of Taiwanese CHC patients were recommended PEG-IFN/RBV, of which few were willing to receive treatment. Keywords: Hepatitis C, Pegylated interferon, Ribavirin, Direct acting antiviral, Taiwan

Introduction and aims Interferon-α (IFN) has shown potential benefits in patients with hepatocellular carcinoma (HCC), and these effects may be mediated by inhibiting cancer cell proliferation. However, the detailed mechanisms underlying the anti-proliferative effects of IFN remain obscure. In this study, we evaluate the role of the novel oncogenic microRNA (miRNA) miR-155 in the anti-proliferative effects of pegylated interferon-α (PEG-IFN) on HCC cells. Methods The effects of PEG-IFN on HepG2 cell proliferation, migration and invasion were determined using the MTT assay, flow cytometry analysis and the Transwell assay, respectively. Reverse transcription quantitative polymerase chain reaction was used to analyze miR-155 expression. The levels of proteins involved in Wnt/β-catenin signal transduction were determined by western blot analysis and immunofluorescence staining. Mimics of miR-155 were transfected into HepG2 cells to assess the role of miR-155 in the PEG-IFN-induced anti-proliferative effect. Results PEG-IFN significantly inhibited the proliferation, migration and invasion of HepG2 cells in a dose-dependent manner by inhibiting cell cycle progression. In parallel with reduced cell proliferation, migration and invasion, miR-155 was efficiently downregulated by PEG-IFN in a dose-dependent manner. Moreover, the transfection of miR-155 decreased the inhibitory effect of PEG-IFN on HepG2cell proliferation, migration and invasion, as well as the downregulation of proteins in the Wnt/β-catenin pathway. Conclusions The anti-proliferative effects of PEG-IFN on HCC are at least partially attributable to the downregulation of miR-155.

Porcine interferon-α (pIFN-α) could be used as the vaccine adjuvant to enhance the antiviral ability of porcine in swine industry. In here, a combinational strategy integrating codon optimization, multiple gene insertion, strong AOX1 promoter, and efficient secretion signal sequence was developed to obtain high-level secreted pIFN-α in Pichia pastoris GS115. The codon optimized pIFN-α shared 76% sequence identity with the original pIFN-α, which was inserted into the P. pastoris genome under AOX1d1-2x201 promoter and MF4I secretion sequence. Our results showed positive correlation between the mRNA and secreted protein levels with the copy numbers of genome-integrated pIFN-α gene in the recombinant P. pastoris strains. The recombinant opt-pIFN-α-6C strain bearing six copies of pIFN-α expression cassette produced the highest extracellular secretion of pIFN-α of 3.2 ± 0.1 mg/mL in shake flask experiment, and 17.0 ± 0.8 mg/mL in a 5 L high-cell-density cultivation after methanol induction of 84 h. The antiviral activity of secreted pIFN-α from the high-cell-density cultivation was determined to be approximately 2.8 ± 0.9 × 109 IU/mL against the vesicular stomatitis virus (VSV) infected Madin-Darby bovine kidney (MDBK) cells. This strategy provided an efficient way to generate recombinant P. pastoris strains in a non-antibiotics-selection manner, which might also give general guidance for the heterologous expression of other proteins in P. pastoris.

Correction: Volume: 119 Pages: 200-201 DOI: 10.1016/j.ejca.2019.04.012 Published: SEP 2019 Background: Nivolumab-ipilimumab demonstrated a survival benefit over sunitinib in first-line setting for metastatic renal cell carcinomas (mRCCs) and is becoming a new standard of care for naive patients with intermediate or poor risk prognosis (International mRCC Database Consortium). The efficacy of subsequent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) after nivolumab-ipilimumab failure remains unclear. Methods: Medical records of mRCC patients treated with nivolumab-ipilimumab, who received subsequent TKI, as part of Checkmate 214 study were reviewed in 13 institutions. Baseline characteristics, outcome data including progression-free survival (PFS), response, overall survival (OS) and toxicities were retrospectively collected. Results: Overall 33 patients received subsequent TKI after nivolumab-ipilimumab failure. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (>= 6 months) with 8 versus 5 months for short responder (= 3. Conclusion: This is the first report of outcomes with TKI, after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence. (C) 2018 Published by Elsevier Ltd.