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Background: Hepatitis E viruses (HEV) are an underestimated global cause of enterically transmitted viral hepatitis, which may persist in immunocompromised hosts, posing a risk for progressive liver fibrosis with limited treatment options. We previously established liver-humanized mice as a model for chronic HEV infections, which can be cleared by a 2-week pegylated (peg)-Interferon(IFN)α treatment course. However, severe side effects may hamper the use of IFNα in immunocompromised transplant recipient patients. IFNλ may be a valuable alternative, as its receptor is less ubiquitously expressed. Aims: In this study, we assess the in vitro and in vivo potency of pegIFNλ to induce innate immune signalling in liver cells and to clear a persistent HEV infection in liver-humanized mice. Methods & Results: We found that human liver cells expressed the IFNλ receptor (IFNLR1) and are responsive to pegIFNλ. Treatment with pegIFNλ of liver-humanized mice persistently infected with HEV genotype 3 showed that pegIFNλ was well tolerated. Dose escalation studies showed that although HEV was not cleared at pegIFNλ doses up to 0.12 mg/kg for a maximum of 8 weeks, a dose of 0.3 mg/kg pegIFNλ treatment resulted in complete clearance of HEV antigen and HEV RNA from the liver in 8 out of 9 liver-humanized mice. Conclusions: PegIFNλ is well tolerated in mice and leads to clearance of a persistent HEV infection in liver-humanized mice.

As pegylated interferon alpha (PEG-IFN-α) is increasingly used in combination regimens of novel drugs, we aimed to characterize ALT flares and their relationship with serum HBsAg and HBV RNA kinetics in a large combined cohort of chronic hepatitis B (CHB) patients on PEG-IFN-α-based therapy. In this post hoc analysis of four international randomized trials, 269/130/124/128 patients on PEG-IFN-α monotherapy, PEG-IFN-α plus nucleos(t)ide analogue (NA) de novo combination, PEG-IFN-α add-on to NA or NA monotherapy were included, respectively. A flare was defined as an episode of ALT ≥5 × ULN. The association between flares and HBsAg and HBV RNA changes were examined. On-treatment flares occurred in 83/651 (13%) patients (median timing/magnitude: week 8 [IQR 4–12], 7.6 × ULN [IQR 6.2–10.5]). Flare patients were more often Caucasians with genotype A/D and had higher baseline ALT, HBV DNA, HBV RNA and HBsAg levels than the no-flare group. More flares were observed on PEG-IFN-α monotherapy (18%) and PEG-IFN+NA de novo combination (24%) vs. PEG-IFN-α add-on (2%) or NA monotherapy (1%) (p 10 at the final visit declines started shortly before the flare, progressing towards 24 weeks thereafter. On-treatment flares were seen in 16/22 (73%) patients who achieved HBsAg loss. In conclusion, ALT flares during PEG-IFN-α treatment are associated with subsequent HBsAg and HBV RNA decline and predict subsequent HBsAg loss. Flares rarely occurred during PEG-IFN-α add-on therapy and associated with low HBsAg loss rates. Combination regimens targeting the window of heightened response could be promising.

Severe viral pneumonia caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by a hyperinflammatory state typified by elevated circulating pro-inflammatory cytokines, frequently leading to potentially lethal vascular complications including thromboembolism, disseminated intracellular coagulopathy and vasculitis. Though endothelial infection and subsequent endothelial damage have been described in patients with fatal COVID-19, the mechanism by which this occurs remains elusive, particularly given that, under naïve conditions, pulmonary endothelial cells demonstrate minimal cell surface expression of the SARS-CoV-2 binding receptor ACE2. Herein we describe SARS-CoV-2 infection of the pulmonary endothelium in postmortem lung samples from individuals who died of COVID-19, demonstrating both heterogeneous ACE2 expression and endothelial damage. In primary endothelial cell cultures, we show that SARS-CoV-2 infection is dependent on the induction of ACE2 protein expression and that this process is facilitated by type 1 interferon-alpha (IFNα) or -beta(β)—two of the main anti-viral cytokines induced in severe SARS-CoV-2 infection—but not significantly by other cytokines (including interleukin 6 and interferon γ/λ). Our findings suggest that the stereotypical anti-viral interferon response may paradoxically facilitate the propagation of COVID-19 from the respiratory epithelium to the vasculature, raising concerns regarding the use of exogenous IFNα/β in the treatment of patients with COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s10456-021-09823-4.

Background Interferons (IFNs) play a crucial role in antiviral immunity. Genetic defects in interferon receptors, IFNs, and auto-antibodies against IFNs can lead to the development of life-threatening forms of infectious diseases like a severe form of COVID-19. Case presentation A 13-year-old boy with a previously reported homozygous loss-of-function mutation in interferon alpha/beta receptor subunit 1 (IFNAR1) (c.674-2A > G) was diagnosed with severe COVID-19. He had cold symptoms and a high-grade fever at the time of admission. He was admitted to the pediatric intensive care unit after showing no response to favipiravir and being hypoxemic. High-resolution computed tomography (HRCT) scanning revealed lung involvement of 70% with extensive areas of consolidation in both lungs. Antibiotics, interferon gamma (IFN-γ), remdesivir, methylprednisolone pulse, and other medications were started in the patient. However, remdesivir and methylprednisolone pulse were discontinued because of their adverse side effects in the patient. His general condition improved, and a few days later was discharged from the hospital. Conclusion We reported a patient with severe COVID-19 who had a mutation in IFNAR1. Our finding suggests that patients with IFNAR1 deficiency are prone to severe forms of COVID-19. Besides, IFN-γ therapy may be a potential drug to treat patients with defects in IFN-α/β signaling pathways which needs further investigations.

По данным ВОЗ, каждый третий житель планеты ежегодно обращается за медицинской помощью по поводу острой респираторной инфекции. Результаты многих исследований показывают, что коррекция иммунных процессов в очаге воспаления дает больший эффект, чем влияние на иммунокомпетентные клетки кровеносного русла (при системном использовании препаратов). Поэтому логичным подходом к терапии респираторных вирусных инфекций, поражающих респираторный эпителий, является интраназальное применение препаратов интерферонов, которые обеспечивают противовирусное, иммуномодулирующее и противобактериальное действие в месте развития инфекционного процесса. В доступной литературе имеется достаточное количество клинических исследований, посвященных изучению эффективности назальных и аэрозольных форм интерферона альфа при острых респираторных вирусных инфекциях (ОРВИ). В них показано, что рекомбинантный интерферон альфа является эффективным препаратом для лечения и профилактики ОРВИ. Его применение сокращает сроки клинического выздоровления больных, уменьшает степень выраженности клинических симптомов заболевания, позволяет избежать манифестации заболевания. Также препараты интерферонов могут применяться как средство предотвращения ОРВИ и гриппа.

Introduction. Recommendations cover the current state of diagnosis and treatment of mastocytosis.Aim — а consolidation of the Russian experts’ opinion on treatment for adult mastocytosis.Main findings. The recommendations have been developed taking into account foreign literature, national experience and world clinical evidence on therapy for systemic and cutaneous mastocytoses, mast cell leukaemia and other mastocytosis forms. The significance of bone marrow and peripheral blood molecular genetic testing for the presence of KITD816V gene variants is demonstrated. The treatment regimens described are based on midostaurin, imatinib, cladribine, hydroxycarbamide, interferon alfa and haematopoietic stem cell transplantation. Prognosis in different forms of mastocytosis is provided.

Background Cytokine treatment with Interferon-alpha (IFN-α) represents a clinical model of immune associated depression, but it remains unclear if it is of the same entity as major depressive disorder (MDD). The study focuses on possible gender differences in IFN-α induced depression and effects of a pre-emptive antidepressant treatment. Methods Data from 181 patients with chronic hepatitis C infection (cHC) without history of mental illnesses undergoing treatment with IFN-α 2a and ribavirin were re-analyzed for gender effects. Patients with a pre-emptive antidepressant therapy with Escitalopram (n = 90, verum group) to prevent IFN-induced depression were compared to patients who received placebo (n = 91). Depressive symptoms before and during HCV-treatment were assessed using the Montgomery–Asberg Depression Rating Scale (MADRS), Beck's Depression Inventory (BDI) and the Hamilton Anxiety Rating Scale. Results We found significant differences regarding the incidence and severity of depressive symptoms between men and women for patients without antidepressant pre-treatment (placebo group). Significantly more women without pre-emptive antidepressant therapy suffered from clinically relevant depression (MADRS values ≥ 13, p = 0.041) and self-rated depressive symptoms (BDI ≥ 17, p = 0.024). Antidepressant pre-treatment showed comparable effects regarding the reduction of incidence and severity of depression in both women and men. Conclusions Compared to MDD, IFN-alpha-induced depression in patients with cHC is also characterized by gender differences with an increased risk for women but no gender difference regarding the effects of an antidepressant pre-treatment is found. Our data strengthens the hypothesis that Interferon-induced depression serves as a clinical model for immune related depressive disorders.

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.

The influence of antiviral therapy with ingaron on the dynamics of production of interferons α and γ and clinical effects in patients with chronic viral Epstein – Barr infection was studied. The study involved 51 patients (33 women and 17 men aged 35,27 ± 1,28 years) suffering from chronic infection caused by the Epstein – Barr virus. The duration of the disease from the appearance of the first complaints to laboratory confirmation of the Epstein – Barr virus infection and diagnosis was 2,23 ± 0,21 years. Determined the serum, spontaneous and induced production of cytokines interferons α and γ in serum and in the culture of lymphocytes. Three months after the end of antiviral therapy, in patients with an initially low level of induced interferon-γ, the production of interferon-γ increased. The absence of an increase in the production of induced interferon-γ in patients one and three months after the end of therapy with ingaron indicates the absence of the effect of the drug on the level of endogenous interferon-γ. It has been established that the initially low level of induced interferon-γ can be a marker of the positive effect of the therapy with ingaron. Correlation analysis revealed the effect of baseline interferon-γ induced on the clinical picture of the disease. Thus, initially a high level of induced interferon-γ (2706 ± 1058.94 pg/ml) inversely affects the development of sweating in patients ( r = –0.506, p = 0,023; τ = –0.419, р = 0.021), and initially low level of the induced IFN-γ (287.2 ± 64.65 pg/ml) — on development of weakness ( r = –0.405, р = 0.045; τ = –0.419, р = 0.037). In general, ingarone can be used in the therapy of patients with chronic Epstein virus — Bar infection at a dose of 500,000 IU every other day, at least 10 injections.

This study aims to explore the effect of the ITI (interferon alpha-1b, thalidomide, and interleukin-2) regimen on the AML1-ETO fusion gene in patients with t(8;21) acute myeloid leukemia (AML) who were in hematologic remission but positive for the AML1-ETO fusion gene. From September 2014 to November 2020; 20 patients with AML (15 from The Affiliated Cancer Hospital of Zhengzhou University, 4 from The First Affiliated Hospital; and College of Clinical Medicine of Henan University of Science and Technology, and 1 from Anyang District Hospital) with hematological remission but AML1-ETO fusion gene positivity were treated with different doses of the ITI regimen to monitor changes in AML1-ETO fusion gene levels. Twenty patients were treated with a routine dose of the ITI regimen, including 13 males and 7 females. The median patient age was 38 (14–70 years). The fusion gene was negative in 10 patients after 1 (0.5 ~ 8.6) month, significantly decreased in 4 patients after 2.8 (1 ~ 6) months, increased in 4 patients, and unchanged in 2 patients. The 4 patients with elevated levels of the fusion gene were treated with an increased dose of the ITI regimen, and all four patients became negative, for a total effective rate of 90%. The ITI regimen reduces AML1-ETO fusion gene levels in patients with AML who are in hematologic remission but are fusion gene–positive. Improvement was observed in patients’ response to a higher dose administration, and patients tolerated the treatment well.

Objectives The aim of this study was to evaluate the role of antiviral drugs in reducing the risk of developing severe illness in patients with moderate COVID-19 pneumonia. Methods This retrospective cohort study included 403 adult patients with moderate COVID-19 pneumonia who were admitted to Shenzhen Third People’s Hospital, China. The antiviral drugs arbidol, interferon alpha-1b, lopinavir–ritonavir and ribavirin were distributed to the patients for treatment. The primary endpoint of this study was the time to develop severe illness. Results Of the 462 patients admitted, 403 had moderate COVID-19 symptoms at hospital admission and were included in this study. 90 of the 403 (22.3%) patients progressed to severe illness. The use of arbidol was associated with a lower severity rate 3.5% compared to control group 30.5%, p-value p = 0.033). The use of interferon alpha-1b was associated with a lower severity rate 15.5% compared to control group 29.3%, with p-value p = 0.0005). The use of lopinavir–itonavir and ribavirin did not show significant differences in adjusted regression models. Early use of arbidol within 7 days of symptom onset was significantly associated with a reduced recovery time of − 5.2 days (IQR − 3.0 to − 7.5, p = 4e−06) compared with the control group. Conclusion Treatment with arbidol and interferon alpha-1b contributes to reducing the severity of illness in patients with moderate COVID-19 pneumonia. Early use of arbidol may reduce patients’ recovery time.

A descriptive cross-sectional study was conducted on 300 patients selected by random sampling who were reported with Hepatitis-C at GIMHS. Questions were asked from patients regarding symptoms and adverse drug reactions (ADR’S). Results were analyzed by using SPSS-22. Out of total patients (n=300) the frequency of male gender was (n=192) as compared to females (n=108). Among 300 patients some patients were on sofosbuvir (n=150), patients on interferon (n=150). Rate of ADR’S observed with interferon as fever (n=28), anemia (n=27), hair loss (n=21), headache (n=19), insomnia (n= 11), nausea (n=13), depression (n=14, 09), malaise (n=25), vomiting (n=06), ulcer (n=13), pain and redness at site of injection (n=17). While rate of ADR’S in patients who were on sofosbuvir, fever (n=33), chill (n=17), nausea (n=28), anemia (n=06), headache (n=14), insomnia (n=13), loss of appetite (n=5), diarrhea (n=1). This study concluded that as compared to Interferon, rate of ADR’S were less with Sofosbuvir.

Purpose: To study the combined effects of tenofovir and interferon α1b on viral load and peripheral blood regulatory T cell concentrations of chronic hepatitis B (CHB) subjects. Methods: Patients with chronic hepatitis B (86 cases) were randomly assigned to two groups: control group and study group. In control subjects, tenofovir was given orally (300 mg/kg bwt/day). In addition to tenofovir, the study group received interferon α1b injection intramuscularly at a dose of 50 μg/kg thrice a week. Liver function, serum hepatitis B viral (HBV) load, and serum levels of peripheral blood regulatory T-lymphocytes were determined. Clinical effectiveness and adverse reactions in both groups were also assessed. Results: After treatment, total effectiveness was higher in the study group (86.04 %) than in control patients (62.79 %) (p < 0.05). Serum aspartate transaminase (AST), alanine aminotransferase (ALT) and total bilirubin (TBIL) significantly decreased in the study group, relative to control, but HBV DNAnegative, HbeAg-negative and HbsAg-negative cells were markedly higher in patients in the study group (p < 0.05). Moreover, there were higher CD4+ T and CD8+ T counts, and CD4+ T/CD8+ T ratio in study subjects than in control subjects (p < 0.05). Conclusion: The combination of tenofovir with interferon α1b effectively improves liver functions in patients with CHB, reduces viral load, and exerts anti-HBV effect by regulating the levels of peripheral blood T-lymphocytes.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by a complex immune dysregulation leading to diverse clinical phenotypes. The preclinical lupus phase (preclinical SLE) is...

Aicardi-Goutieres Syndrome (AGS) is a monogenic leukodystrophy with pediatric onset, clinically characterized by a variable degree of neurologic impairment. It belongs to a group of condition called type I interferonopathies that are characterized by abnormal overproduction of interferon alpha, an inflammatory cytokine which action is mediated by the activation of two of the four human Janus Kinases. Thanks to an ever-increasing knowledge of the molecular basis and pathogenetic mechanisms of the disease, Janus Kinase inhibitors (JAKIs) have been proposed as a treatment option for selected interferonopathies. Here we reported the 24 months follow-up of the fifth AGS patient treated with ruxolitinib described so far in literature. The treatment was globally well tolerated; clinical examinations and radiological images demonstrated a progressively improving course. It is however to note that patients presenting with mild and spontaneously improving course have been reported. Large natural history studies on AGS spectrum are strongly required in order to get a better understanding of the results emerging from ongoing therapeutic trials on such rare disease.

Novel coronavirus infection (COVID-19) caused by SARS-CoV-2 has some specific clinical and immunopathogenic properties. SARS-CoV-2 is a single-stranded RNA virus that belongs to the Coronaviridae family, the Betacoronavirus genus. COVID-19 can be asymptomatic, the most common clinical manifestation of this disease is viral pneumonia. The development of acute respiratory distress syndrome is noted in less than 5% of cases. The entry gates of this virus are the epithelium of the upper respiratory tract and epithelial cells (epitheliocytes) of the gastrointestinal tract. When the virus enters the human respiratory tract, mucociliary clearance is inhibited and epithelial cells die, allowing the virus to enter the peripheral blood with subsequent damage to target organs (lungs, digestive tract, heart, kidneys). An important pathogenic characteristic of SARS-CoV-2 infection, especially with severe disease, is an excessive immune system response with massive release of cytokines, which causes acute respiratory distress syndrome. Clinical and experimental studies have shown that SARS-CoV-2 can be significantly more sensitive to type I interferons (IFN-I), than other coronaviruses. IFN-I deficiency is thought to play a key role in the pathogenesis of COVID-19, and several studies have shown that delayed IFN-I signaling is associated with sustained viral replication and serious complications. The use of interferon-based medicines (IFN-I) for the treatment and prevention of COVID-19 appears to be quite important to study attentively. This paper presents an original regimen of recombinant interferon alpha-2b-based medicine (Grippferon®, nasal drops and spray) for the medication-assisted post-exposure prevention of COVID-19 in healthcare specialists, working in the pediatric infectious disease hospital. The effectiveness and safety of this medication regimen for the COVID-19 prevention was shown. Key words: medication-assisted prevention, COVID-19, post-exposure protection of healthcare workers, recombinant interferon alpha-2b, Grippferon

Objective. To evaluate the efficacy and safety of human recombinant interferon alpha-2b (VIFERON®) as a part of comprehensive treatment for coronavirus infection COVID-19. Patients and methods. This prospective, comparative, controlled study included 140 patients with COVID-19 randomized in two groups. The experimental group (EG) included 70 patients who received standard therapy plus VIFERON® (one rectal suppository 3,000,000 IU three times a day and gel 36,000 IU/g 5 times a day applied to the nasal mucosa and palatine tonsils for 14 days); the control group (CG) comprised 70 patients who received standard therapy alone. Results. Patients in the EG demonstrated more rapid resolution of main symptoms, such as intoxication, bronchopulmonary and catarrhal manifestations. Normalization of the total score in the EG was observed 7 days earlier than in the CG. In the EG, the proportions of patients who had their D-dimer and CRP levels normalized were 42.7% and 18.7% higher than those in the CG, respectively (р < 0.05). Follow-up computed tomography demonstrated that the proportion of patients with positive dynamics in the EG was 8.1% higher than that among controls, whereas advanced disease with 51%–75% of lung tissue affected was 11.9% less common in participants from the EG than in controls (р = 0.019). We observed no adverse events associated with interferon alpha-2b (VIFERON®) or other medicines included in the treatment scheme. Conclusion. Our findings suggest high efficacy and safety of recombinant interferon alpha-2b (VIFERON®) used in combination with symptomatic agents, antibiotics, anticoagulants, which allows us to recommend this drug for inclusion into standard treatment schemes for COVID-19. Key words: COVID-19, coronavirus infection, human recombinant interferon alpha-2b

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.

Accurate biomarkers to predict the genesis and progression of pancreatic adenocarcinoma (PAAD) are needed in the fight against this deadly disease. Here, we combined multiple datasets (GEO, TCGA and GTEx) to conduct a comprehensive analysis of pancreatic cancer. Through an in-depth analysis, we discovered that the expression of the gene encoding interferon alpha-inducible protein 27 (IFI27) was significantly higher in pancreatic cancer tissues than that in normal tissues, and that higher expression of IFI27 was negatively correlated with the overall survival rate of pancreatic cancer patients. The functional annotation of IFI27 demonstrated relationships to cellular immunity and metabolism, especially glycolysis. Analysis of infiltrating immune cells displayed that higher expression of IFI27 expression correlates with decreased CD8 + T cells and increased M2 macrophages in the tumor immune microenvironment (TIME), then biochemical analyses of a mouse model and immunohistochemical (IHC) staining verified that glycolytic enzymes and M2 macrophages increased significantly in pancreatic cancer tissues. We speculate that IFI27 may affect the tumor microenvironment (TME) of PAAD by regulating cellular immunity and metabolism, thereby promoting the progression of pancreatic carcinoma and worsening the prognosis. These findings of our present study are solid evidence that IFI27 is a potential prognostic biomarker of pancreatic cancer and that it affects the tumor immune microenvironment.

DOI: 10.30906/2073-8099-2020-12-6-9-14 In experiments in mice, the effect of double-stranded yeast RNA (dsRNA) upon intranasal administration on the interferon synthesis by the upper respiratory tract tissues and on the activity of alveolar macrophages was studied. It has been shown that the dsRNA preparation at the dose of 15 mg/kg has interferon-inducing properties reflected in an increase in the level of interferon alpha in the tissues of the nasopharynx and lungs 5 hours after 1 – 2-fold administration, having the ability to modulate the phagocytic activity of alveolar macrophages. The data obtained indicate that dsRNA stimulates the factors of nonspecific resistance of upper respiratory tract playing an important role in the formation of antiviral defense response.

We present a case of complete deficiency of the interferon alpha/beta receptor alpha chain (IFNAR1) in a child with fatal systemic hyperinflammation, apparently provoked by live-attenuated viral vaccination. Such pathologic hyperinflammation, fulfilling criteria for hemophagocytic lymphohistiocytosis, is an emerging phenotype accompanying inborn errors of type I interferon immunity.

Type I interferon receptors are expressed by the majority of vagal C-fibre neurons innervating the respiratory tract Interferon alpha and beta acutely and directly activate vagal C-fibers in the airways. The interferon-induced activation of C-fibers occurs secondary to stimulation of type 1 interferon receptors Type 1 interferons may contribute to the symptoms as well as the spread of respiratory viral infections by causing coughing and other defensive reflexes associated with vagal C-fibre activation ABSTRACT: We evaluated the ability of type I interferons to acutely activate airway vagal afferent nerve terminals in mouse lungs. Using single cell RT-PCR of lung-specific vagal neurons we found that IFNAR1 and IFNAR2 were expressed in 70% of the TRPV1-positive neurons (a marker for vagal C-fibre neurons) and 44% of TRPV1-negative neurons. We employed an ex vivo vagal innervated mouse trachea-lung preparation to evaluate the effect of interferons in directly activating airway nerves. Utilizing 2-photon microscopy of the nodose ganglion neurons from Pirt-Cre;R26-GCaMP6s mice we found that applying IFNα or IFNβ to the lungs acutely activated the majority of vagal afferent nerve terminals. When the type 1 interferon receptor, IFNAR1, was blocked with a blocking antibody the response to IFNβ was largely inhibited. The type 2 interferon, IFNγ, also activated airway nerves and this was not inhibited by the IFNAR1 blocking antibody. The Janus kinase inhibitor GLPG0634 (1 μm) virtually abolished the nerve activation caused by IFNβ. Consistent with the activation of vagal afferent C-fibers, infusing IFNβ into the mouse trachea led to defensive breathing reflexes including apneas and gasping. These reflexes were prevented by pretreatment with an IFN type-1 receptor blocking antibody. Finally, using whole cell patch-clamp electrophysiology of lung-specific neurons we found that IFNβ (1000 U ml-1 ) directly depolarized the membrane potential of isolated nodose neurons, in some cases beyond to action potential threshold. This acute non-genomic activation of vagal sensory nerve terminals by interferons may contribute to the incessant coughing that is a hallmark of respiratory viral infections.

Purpose In many cases, the diagnosis of a periprosthetic joint infection (PJI) consisting of the clinical appearance, laboratory tests, and other diagnostic tools remains a difficult task. Single serum biomarkers are easy to collect, are suitable for periodical assessment, and are a crucial tool in PJI diagnosis, but limited sensitivity or specificity is reported in literature. The aim of this study was to combine the best-performing single serum biomarkers into a multi-biomarker model aiming to improve the diagnostic properties. Methods Within a 27-month period, 124 surgical procedures (aseptic or septic revision total knee arthroplasty (TKA) or total hip arthroplasty (THA)) were prospectively included. The serum leukocyte count, C-reactive protein (CRP), interleukin-6, procalcitonin, interferon alpha, and fibrinogen were assessed 1 day prior to surgery. Logistic regression with lasso-regularization was used for the biomarkers and all their ratios. After randomly splitting the data into a training (75%) and a test set (25%), the multi-biomarker model was calculated and validated in a cross-validation approach. Results CRP (AUC 0.91, specificity 0.67, sensitivity 0.90, p value 0.03) and fibrinogen (AUC 0.93, specificity 0.73, sensitivity 0.94, p value 0.02) had the best single-biomarker performances. The multi-biomarker model including fibrinogen, CRP, the ratio of fibrinogen to CRP, and the ratio of serum thrombocytes to CRP showed a similar performance (AUC 0.95, specificity 0.91, sensitivity 0.72, p value 0.01). Conclusion In this study, multiple biomarkers were tested for their diagnostic performance, with CRP and fibrinogen showing the best results regarding the AUC, accuracy, sensitivity, and specificity. It was not possible to further increase the diagnostic accuracy by combining multiple biomarkers using sophisticated statistical methods.

Objectives To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients. Methods A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed. Results An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048). Conclusions Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT 04251871 at www.clinicaltrials.gov) Electronic Supplementary Material Supplementary material is available in the online version of this article at 10.1007/s11655-020-3426-7.

Hairy cell leukemia. Clinical recommendations

Japanese encephalitis (JE) is now a public health concern due to limitation of the available vaccine and nonexistence of specific antiviral therapy and thus demands new potential therapeutical strategies. The present study was conducted to evaluate the effect of atropine in controlling JE virus infection in chick embryo, which is already established as an ideal model for study of various host–pathogen interactions and screening of newer antiviral agents. In this experiment we pre-treated 12 day old embryos with atropine sulphate to see whether it can give protection from JE virus challenge. There were significant decrease in the viral loads in the brain, chorioallantoic membrane and amniotic fluid of the embryo in atropine sulphate pre-treated groups compared to the infection groups. Atropine sulphate pre-treated group showed significant up-regulation of interferon alpha and toll like receptor-3 mRNA, than other analogous groups. The histological changes showed significant reduction of necrosis, inflammation and other co-morbid pathology in the atropine sulphate pre-treated groups. Hence this study demonstrated the protective role of atropine in controlling the JE virus replication and its organ-tropic dissemination to brain which may pave way for a prospective therapy in the future treatment of JE.

Drug development in oncology has witnessed a revolutionary growth from its humble beginning with nitrogen mustard in 1940 to immunotherapy in 1986 (Interferon alpha). The arsenal of cytotoxics is ever increasing, contributing to better survival outcomes and improved quality of life. Over the years, many cytotoxics have fallen out of favor too, due to its side effects and availability of drugs with better efficacy and toxicity profile. Taxane, a microtubule stabilizing agent extracted from the poisonous Yew tree, was discovered in 1964 and came into clinical use in 1992 with its approval for ovarian cancer. This group has grown into a cornerstone of many treatment protocols, spanning multiple tumor types. This review discusses in brief the salient features of cytotoxic agents in this drug group, its history, physico-chemical properties, mechanism of action, pharmacodynamics, and pharmacokinetics. Though the benefits of taxanes are well understood, there are unique problems associated with the use of taxanes and there is an expanding literature on taxane resistance. We briefly look at the resistance mechanisms. There have been significant efforts to circumvent the problems related to conventional taxanes, with an attempt at creating newer carrier molecules and adjunct drugs with taxanes, which is slowly gaining traction in clinical practice.

Specific antiviral activity is one of the key indicators characterising pharmaceutical quality and pharmacological efficacy of interferon alpha products (IFN-α). Specific activity is determined using a bioassay measuring antiviral activity in cell culture. The aim of the study was to select the most appropriate conditions for in vitro determination of IFN-α product specific activity. Materials and methods: Vero, MDBK, Hep-2, and A-549 homologous and heterologous cell cultures, as well as vesicular stomatitis Indiana virus (VSV) and murine encephalomyocarditis (EMC) virus at a dose of 100 TCD50 /0.1 mL were used for determination of specific antiviral activity. The international reference standard of recombinant interferon alpha-2b activity (Interferon alpha 2b, human, rDNA, E. coli-derived, 2nd WHO International Standard, 1999, NIBSC Code No. 95/566) and human recombinant interferon alpha 2b in the form of solution (batch No. 040214, Pharmapark LLC, Russia) were used as IFN-α samples. Results: the analysis of the obtained data helped to determine: the combinations of cell lines and the indicator virus most sensitive to IFN-α; the optimal concentration of fetal serum in the medium, and the optimal time parameters; the preferred method of reporting test results. Conclusions: the following test conditions were found to be optimal: the MDBK/VSV and Hep-2/EMC combinations proved to be the most sensitive to IFN-α; the optimal period of interferon and cell culture incubation—24 hours; the optimal concentration of fetal bovine serum in the culture medium used for diluting interferon products—2–5%. The instrumental procedure is preferred for reporting the results of interferon antiviral activity determination, because it is up-to-date, reliable, accurate and time-efficient.

Despite interferon alpha having a broad spectrum of antiviral activity and strong antiproliferative activity, its applications are severely limited due to the intrinsic properties of proteins, such as poor stability and short serum half-life. In our study, canine interferon alpha (CaIFNα) gene was fused with the ricin toxin B chain (RTB) to form rCaIFNα/RTB, which encodes a 463-amino acid protein containing a 15-amino acid encoded (G4S)3 flexible linker. After expression in prokaryote, purification and renaturation, the cytotoxicity and antiviral activity of rCaIFNα/RTB were investigated in Madin–Darby canine kidney (MDCK) cells. rCaIFNα/RTB exerted a superior anti-vesicular stomatitis virus (VSV) activity on MDCK cells. Furthermore, we have developed a nanoparticle formulation of rCaIFNα/RTB by using polyethylenimine (PEI) through electrostatic interaction. rCaIFNα/RTB@PEI10000 is more stable than rCaIFNα/RTB at various pH and temperature levels, and it possesses enhanced antiviral activity. Our findings facilitate further research on the role of type I IFN in antiviral defense responses in Canis lupus familiaris.

Objectives.—To assess mortality and survival analysis for patients with hairy cell leukemia, taking into consideration the effect of new therapies. Background.—Hairy cell leukemia (HCL) is a chronic B-cell disorder and an uncommon malignancy. Initially, therapeutic options were limited, and outcomes were poor. However, with the introduction of alpha interferon in 1984, followed by two purine nucleoside analogues pentostatin (1986) and cladribine (1990) and more recently, rituximab, a monoclonal antibody, HCL outcomes have improved, translating HCL from a disease with limited treatment options to a highly treatable disease with a near-normal survival. Methods.—A SEER-17 database survival analysis was conducted on patients diagnosed with HCL in the US. Using the International Classification of Diseases code for HCL (9940), the SEER database was interrogated for patients diagnosed from 1973-2013. Analysis was based on comparing the survival of patients in the last 4 decades to the expected survival population generated by the SEER data. Analysis using mortality and survival methodology was used to calculate the excess death rate (EDR), mortality ratios, and survival ratios. Results.—In patients with HCL diagnosed from 1973-1983 compared to those diagnosed from 1984-1993, the survival improved by 6% in the first year and reached 26% by year 5, 30% by year 10, 33% by the year 15, and 40% by year 20. Calculations of relative mortality showed a decrease in mortality from decade 1973-1983 to decade 1984-1993 of 66% in the first year, 96% by year 5, 66% by year 10, 46% by year 15, and 40% by year 20. Conclusions.—The survival of patients diagnosed with HCL has improved over the last 3 decades, with a significant benefit being seen since 1984. Thanks to the introduction of newer drugs, the outcome of patients with HCL has been transformed into a highly treatable form of leukemia, and patients now have a near-normal life expectancy.

Metastatic clear cell renal cell carcinomas (mRCC) over-express the vascular endothelial growth factor (VEGF). Hence, the anti-VEGF antibody bevacizumab/Avastin (BVZ) combined with interferon alpha (IFN) was approved for the treatment of mRCC. However, approval was lost in July 2016 due to the absence of sustained efficacy. We previously showed that BVZ accelerates tumor growth in experimental models of mRCC in mice, results in part explained by down-regulation of the phospho tyrosine phosphatase receptor kappa (PTPRκ) in tumor cells. The epidermal growth factor receptor (EGFR) is a direct target of PTPRκ. Its down-regulation leads to constitutive activation of EGFR, an observation which prompted us to test the effect of the EGFR inhibitor erlotinib/Tarceva (ERLO) in addition to BVZ/IFN. The influence of the long non-coding RNA, EGFR-AS1, on ERLO efficacy was also addressed. Methods: The effect of BVZ/IFN/ERLO was tested on the growth of experimental tumors in nude mice. The presence of germline mutation in the EGFR was evaluated on cell lines and primary RCC cells. In vitro translation and transfections of expression vectors coding the wild-type or the EGFR mutated gene in HEK-293 cells were used to test the role of EGFR mutation of the ERLO efficacy. Correlation between EGFR/EGFR-AS1 expression and survival was analyzed with an online available data base (TCGA). Results: Tumor growth was strongly reduced by the triple combination BVZ/IFN/ERLO and linked to reduced levels of pro-angiogenic/pro-inflammatory cytokines of the ELR+CXCL family and to subsequent inhibition of vascularization, a decreased number of lymphatic vessels and polarization of macrophages towards the M1 phenotype. Cells isolated from surgical resection of human tumors presented a range of sensitivity to ERLO depending on the presence of a newly detected mutation in the EGFR and to the presence of EGFR-AS1. Conclusions: Our results point-out that the BVZ/IFN/ERLO combination deserves testing for the treatment of mRCC that have a specific mutation in the EGFR.

Introduction The safety and efficacy of combination therapy comprising immune checkpoint inhibitors and cancer-specific peptide vaccines have not yet been established. Case presentation A 71-year-old female metastatic renal cell carcinoma patient with multiple lung and pleural metastases. She had been treated with interferon alpha, sunitinib, axitinib, and pazopanib sequentially, but no clinical efficacy was observed. She participated in a clinical trial using cancer-specific peptide vaccine therapy. Initially no antitumor effect was observed, and vaccine therapy was ceased after two courses. But 3 months after the start of nivolumab, remarkable tumor shrinkage was observed at all metastatic sites, which resulted in almost complete response at 6 months. At 10 months, nivolumab was stopped due to cellulitis at the peptide vaccine inoculation site. Intriguingly, even after nivolumab discontinuation, complete response was maintained for more than 1 year. Conclusion We experienced a remarkable antitumor effect by nivolumab in a patient who was previously treated with vaccine therapy.

Background: Chronic Hepatitis C is common problem worldwide treated by combination of interferon alpha and ribavirin. Retinopathy is one of the side effects of interferon therapy. Aim: determine the frequency and risk factors of retinopathy in patients with chronic hepatitis C treated by interferon and ribavirin combination therapy in Egypt. Methods and Results: Total 100 patients were enrolled among which, 16 (16%) developed retinopathy in the form of cotton wool spots and 14(14%) developed atypical complications. Conclusion: Retinopathy may occur in patients with chronic hepatitis C receiving interferon alpha and ribavirin.

BACKGROUND: Although tyrosine kinase inhibitors (TKIs) are the gold standard in clinical management of chronic myeloid leukemia, it is not feasible to use these drugs in at least some cases when patients are resistance to all available TKIs due to compound BCR-ABL mutations, due to patient safety profile or due to the nonavailability of drugs in developing countries on account of cost or logistic issues. We reported earlier that interferon alpha can eradicate compound BCR-ABL mutations and induce stable responses. Here, we report a follow-up of this study. PATIENTS AND METHODS: Some chronic myeloid leukemia (CML) patients did not get TKIs directly because of very high cost of imatinib and were given interferon alpha (experimental group) until the provision of imatinib free of cost through GLIVEC® International Patient Assistance Program while the other groups of patients (control group) were directly given imatinib. A very sensitive allele-specific polymerase chain reaction was employed to detect BCR-ABL compound mutations before treatment and confirmation of mutations was carried out using reliable molecular assays. Mutations were reinvestigated at all important time points during the long-term follow-up studies. RESULTS: The use of interferon-alpha for 6 months prior to TKIs eradicated compound BCR-ABL mutations (Phe311Val/Met351Thr and Thr315Ile/Phe311Val/Met351Thr) and provided deep molecular responses without any progression or mortality in CML patients (experimental group) as compared with patients who did not use interferon and was directly given TKIs (control group). CONCLUSIONS: Interferon alpha can eradicate highly resistant BCR-ABL mutations and lead to durable deep molecular responses to TKIs in CML. Therefore, interferon-alpha is recommended for CML patients with compound mutations resistant to TKIs, specifically in those scenarios where some TKIs are not available or not safe to use for CML patients. Our long-term follow-up study is well supported by recently published literature.

Інтерферон альфа-2b – це інтерферон лейкоцитарного типу, який використовують при лікуванні вірусних та онкологічних захворювань. Сучасні методи генетичної інженерії дозволяють отримувати для потреб медицини рекомбінантний інтерферон, що синтезується бактеріальними штамами E.coli. Але також рекомбінантний інтерферон можна синтезувати і в рослинах. Використання рослин для синтезу рекомбінантних білків є безпечнішим та дешевшим, у порівнянні з бактеріями, крім того, рослини здатні забезпечити правильну посттрансляційну модифікацію білка. Метою нашої роботи було отримання трансгенних рослин капусти броколі, в яких проходить синтез лейкоцитарного інтерферону людини альфа-2b. Ми вибрали капусту броколі об´єктом дослідження, тому що у молодих пагонах цієї рослини міститься речовина сульфорафан, що відомий своєю протипухлинною активністю. Поєднання сульфорафану та інтерферону може покращити протипухлинний ефект таких трансгенних рослин. Для отримання трансгенних рослин проводили Agrobacterium-опосередковану трансформацію рослин капусти броколі генетичним вектором, що містить гени людського інтерферону альфа-2b та фосфінотрицинацетилтрансферази. Як експланти ми використовували гіпокотилі 10-денних асептичних проростків капусти броколі сорту Романеско, оскільки вони продемонстрували найвищу здатність до регенерації. Регенерацію експлантів проводили на середовищі Мурасіге-Скуга, що містило бензиламинопурин 3 мг/л, нафтилоцтову кислоту - 0,05 мг/л, а також 5 мг/л фосфінотрицину для селекції трансгенних рослин. Активна регенерація рослин брокколі спостерігалася на трансформованих експлантатах через чотири тижні після трансформації. У цьому дослідженні були отримані стійкі до фосфінотрицину рослини броколі сорту Романеско, які потенційно містять людський ген інтерферону альфа-2b.

Objectives Treatment-free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML-CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon-α in addition to TKI has shown promising efficacy but with dose-dependent toxicity and discontinuations. NordCML007 was initiated to study the efficacy and safety of low dose pegylated IFN-α (PegIFN-α) in combination with dasatinib (DAS) in CML-CP. Methods Forty patients with newly diagnosed CML-CP were given DAS upfront. After month 3 (M3) 15 μg/wk of PegIFN-α was added and increased to 25 μg/wk from M7 until M15. DAS treatment was continued and adverse events and BCR-ABL1 qRT-PCR values were reported yearly after M24. Results from M1 to M18 have previously been published, and here we present long-term data. Results After 5 years of follow-up, there were no suspected unexpected serious adverse reactions, no increase in serosal effusions, no disease progressions and no CML-related deaths. Rates of MR3.0 (MMR), MR4.0 and MR4.5 were 84.6%, 64.1% and 51.3% respectively at M60, and 95% of patients reached MMR at some point during the study. Conclusion Initial addition of PegIFN-α to DAS shows good long-term efficacy without increased toxicity. Title in Web of Science: Long-term tolerability and efficacy after initial PegIFN-alpha addition to dasatinib in CML-CP: Five-year follow-up of the NordCML007 study

Purpose To describe the clinical course of a patient presenting with unilateral retinopathy after perilesional interferon alpha injections for treatment of ocular surface squamous cell carcinoma. Observations A patient, who was being treated with interferon alpha for ocular squamous cell carcinoma, presented with new onset decreased vision in her left eye. Upon examination, she was found to have cotton wool spots and retinal hemorrhages in the affected eye. Conclusions and Importance Retinopathy is a well-documented side effect of systemic usage of interferon alpha. However, retinopathy has not been well discussed in the scenario of perilesional injections of interferon. It is important for clinicians to monitor for such pathology when using interferon alpha not only systemically, but also locally.

Introduction Maxillofacial (MF) giant cell lesions (GCLs) are benign, often locally aggressive lesions with potential for recurrence. Systemic treatments have included interferon alpha, calcitonin, bisphosphonates, and denosumab. Sclerostin (SOST) is typically thought to be a negative regulator of bone metabolism and anti-SOST agents have been used to treat osteoporosis; however, its role in central giant cell granuloma is unknown. The purpose of this study was to evaluate the expression of SOST in MF GCLs. Materials and methods This was a retrospective study of patients with MF GCLs treated at a single institution between 1993 and 2008 with a minimum follow-up of 6 months. Representative tissue was used to create a tissue microarray and SOST immunohistochemical (IHC) staining and grading was performed. The primary outcomes were IHC staining of the stromal cells and giant cells. The secondary outcomes included correlation of IHC staining and patient predictor variables including clinically benign and aggressive lesions. All analyses were completed using univariate statistical tests. Results A total of 37 subjects were included (29 clinically aggressive and 8 clinically benign). Sclerostin staining was present in 30 of 37 subjects (81%). Of these, 22 (60%) had stromal cell staining and 28 (76%) had giant cell staining. The presence or absence of staining, of either cell type, was not associated with aggressiveness, presence of clinical symptoms, tumor size, previous interferon therapy, previous surgery, or the race or age of the patient. Discussion Maxillofacial GCLs have an overall high level of SOST staining; however, the role of SOST in treatment and prognosis is unknown and warrants further study.

IntroductionFunctional cure has been proposed as an alternative to lifelong antiretroviral therapy and therapeutic vaccines represent one of the most promising approaches.Materials and MethodsWe conducted a double-blind randomized placebo-controlled clinical trial to evaluate the safety, immunogenicity, and effect on viral dynamics of a therapeutic vaccine produced with monocyte-derived dendritic cells (MD-DC) loaded with a high dose of heat-inactivated autologous (HIA) HIV-1 in combination with pegylated interferon alpha 2a (IFNα-2a) in people with chronic HIV-1.ResultsTwenty-nine male individuals on successful ART and with CD4+ ≥450 cells/mm3 were randomized 1:1:1:1 to receive three ultrasound-guided inguinal intranodal immunizations, one every 2 weeks: (1) vaccine ~107 MD-DC pulsed with HIA-HIV-1 (1010 HIV RNA copies) (n = 8); (2) vaccine plus three doses of 180 mcg IFNα-2a at weeks 4–6 (n = 6); (3) placebo = saline (n = 7); and (4) placebo plus three doses of 180 mcg IFNα-2a (n = 8). Thereafter, treatment was interrupted (ATI). Vaccines, IFNα-2a, and the administration procedures were safe and well tolerated. All patients’ viral load rebounded during the 12-week ATI period. According to groups, changes in viral set-point between pre-ART and during ATI were not significant. When comparing all groups, there was a tendency in changes in viral set-point between the vaccine group vs. vaccine + IFNα-2a group (>0.5log10p = 0.05). HIV-1-specific T-cell responses (IFN-ƴ Elispot) were higher at baseline in placebo than in the vaccine group (2,259 ± 535 vs. 900 ± 200 SFC/106 PBMC, p = 0.028). A significant difference in the change of specific T-cell responses was only observed at week 4 between vaccine and placebo groups (694 ± 327 vs. 1,718 ± 282 SFC/106 PBMC, p = 0.04). No effect on T-cell responses or changes in viral reservoir were observed after INFα-2a administration.DiscussionResults from this study show that intranodally administered DC therapeutic vaccine in combination with IFNα-2a was safe and well-tolerated but had a minimal impact on viral dynamics in HIV-1 chronic infected participants.Clinical Trial Registration(www.ClinicalTrials.gov), identifier NCT02767193

BACKGROUND & AIMS Proof-of-concept studies demonstrated lonafarnib (LNF), a first-in-class, oral prenylation inhibitor, efficacy in HDV-infected patients. The LOnafarnib With Ritonavir for HDV-2 (LOWR-2) study's aim was to identify optimal combination regimens of lonafarnib + ritonavir (RTV) ± pegylated interferon alfa (PEG-IFNα) with efficacy and tolerability for longer term dosing. Here we report the safety and efficacy at end of treatment (EOT) for up to 24 weeks. APPROACH & RESULTS 55 patients with chronic HDV were consecutively enrolled in an open-label single-center phase 2 dose-finding study. There were 3 main treatment groups: high dose lonafarnib (lonafarnib ≥ 75 mg po bid + ritonavir) (N=19, 12 wks); all-oral low dose lonafarnib (lonafarnib 25 or 50 mg po bid + ritonavir) (N=24, 24 wks) and combination low dose lonafarnib with PEG-IFNα (lonafarnib 25 or 50 mg po bid + ritonavir + PEG-IFNα) (N=12, 24 wks). The primary endpoint, ≥ 2 log10 decline or < LLOQ of HDV-RNA from baseline at EOT, was reached in 46% (6/13) and 89% (8/9) of patients receiving the all-oral regimen of lonafarnib 50 mg bid + ritonavir, and combination regimens of lonafarnib (25 or 50 mg bid) + ritonavir + PEG-IFNα, respectively. In addition, multiple patients experienced well-tolerated transient post-treatment ALT increases resulting in HDV RNA negativity and ALT normalization. The proportions of grade 2 and 3 GI adverse events in the high vs low dose groups were 49% (37/76) and only 22% (18/81), respectively. CONCLUSIONS Lonafarnib, boosted with low dose ritonavir, is a promising all-oral therapy, and maximal efficacy achieved with PEG-IFNα addition. The identified optimal regimens support the first Phase 3 (D-LIVR) study of lonafarnib for the treatment of HDV.

Case report - Introduction Bechet’s is a rare chronic inflammatory multisystem disease of unknown cause. It is characterised by recurrent oral ulcerations, genital ulcerations, ocular inflammation and skin involvement. Bechet’s disease is rarely observed during childhood and the clinical picture can be incomplete, thus making the diagnosis challenging. Ocular involvement represents 10—20% of the initial presenting feature. Ocular involvement typically involves anterior and/or posterior uveitis and retinal vasculitis. Severe vision loss can be seen in patients. Prognosis is improving due to enhanced therapeutic options. The use of biologics, particularly anti-TNF drugs, are a positive advance, though more evidence in paediatrics is required. Case report - Case description This young man presented in 2014 at 12 years old to paediatric ophthalmology with a right panuveitis. He was treated with a weaning dose of oral steroids. His right eye became quiet. He reported some oral ulceration, not recurrent, and no genital ulcers. He did not fulfil Bechet’s criteria. Pathergy test and HLA B51 were negative. In 2017 he presented with right macular retinal infiltrate. Vision was reduced to counting fingers. Mycophenolate mofetil (MMF) was started with weaning prednisolone. Despite this, activity was ongoing with inflammation in the anterior chamber and vitreous. Humira was started in August 2017. There was resolution of the inflammation in the right eye but central vision remained poor due to irreversible macular damage. Left eye was normal. Oral steroids were weaned. In 2018, he developed acne and folliculitis type lesions. He reported sore joints and fatigue. He was felt to have probable Behcet’s. Quaternary review by the Bechet’s centre, Liverpool, agreed. A switch from MMF to azathoprine (AZA) was advised. Interferon alpha would have been suitable, but was no longer available. Skin lesions returned when switched to AZA; patient requested switch back to MMF. Over the next 2 years steroids were weaned. MMF and 2-weekly Humira continued. In November 2020 he presented with peripheral retinitis in his left, better-seeing eye, haemorrhaging, with patchy vision. MMF was increased and oral steroids recommenced. In December 2020 visual acuity was hand movements in his right eye and 6/7.5 in his left eye with ongoing inflammation. Adalimumab was increased to weekly. In January 21 there were 3 + of cells in his anterior chamber, extensive haemorrhages and retinal infiltrates in keeping with Behcet’s. He was admitted for pulsed IV methylprednisolone and switched from Humira to infliximab. Eyes are currently quiescent and prednisolone is weaning. Case report - Discussion Bechet’s disease is a multiorgan disease typified by an immune-mediated occlusive vasculitis. The aetiology of Bechet’s remains unclear. HLA-B51 is a major predisposing genetic factor. There is involvement of the innate immune system, propagated by the adaptive immune system. Ophthalmic involvement can be the presenting feature of Bechet’s. Eye disease in Bechet’s is most commonly a non-granulomatous uveitis with necrotising obliterative retinal vasculitis. This can be found in either the anterior or posterior segment or both. Recurrent inflammation in the posterior segment can lead to severe sight loss. Young males typically have the worst ocular prognosis. The treatment of ocular Bechet’s can be challenging as our case emphasises. Treatment follows a step-wise approach. Therapy consists of topical steroid, followed by intravenous or oral steroid. Maintenance therapy of either AZA 2mg/kg/day, MMF (max3 g daily) or ciclosporin max 5mg/kg/day should be commenced. The next step will typically be a TNF inhibitor; in our patient we used adalimumab initially. Infliximab is becoming a popular first choice anti-TNF. Certainly since January 2021 our patient’s eyes have remained quiescent on Infliximab. The alternative to infliximab is interferon alpha but unfortunately this is no longer commercially available. A further treatment that could be offered is rituximab – initially to be given as a one-off cycle. Optimum treatment of ocular Bechet’s involves good multidisciplinary team working between ophthalmology and rheumatology. By early initiation of systemic treatment and regular reviews secondary complications may be avoided/lessened. Case report - Key learning points

The development of tyrosine kinase inhibitors (TKIs) in the early 2000s revolutionized the therapeutic landscape for chronic phase (CP) chronic myeloid leukemia (CML). Interferon alpha was previously the standard treatment for patients with CP CML prior to the development of TKIs; however, survival was dismal, with a median of 5-6 years (1). With the advent of TKI therapy, the estimated 10-year overall survival increased from less than 20% to more than 80% (2). When optimal therapy is instituted with appropriate monitoring, patients with CP CML now live close to normal life spans (3, 4). Imatinib, the first of these revolutionary medications, was approved by the FDA for the treatment of CML after failure of interferon-alpha therapy in 2001 and for newly diagnosed CP CML patients in 2003. Shortly thereafter, following preclinical and clinical data demonstrating increased potency against the BCR-ABL target, frontline approvals for the second-generation TKIs (dasatinib, nilotinib, and bosutinib) soon followed based on the results of their respective clinical trials (DASISION, ENEST and BFORE) (5–7). Each of these trials compared the efficacy of imatinib 400 mg daily with the corresponding second-generation TKI. Notably, no significant survival difference has been demonstrated between imatinib and any of the second-generation inhibitors. Accordingly, the European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) practice guidelines recommend choosing a therapeutic agent based on risk scoring, age, and comorbidities (8, 9). Thus, the optimal frontline treatment of CP CML has become the subject of debate. A recently published meta-analysis sought to answer this question by comparing the safety and efficacy of imatinib versus dasatinib, nilotinib, bosutinib and ponatinib for initial treatment of CP CML (10). Second- and third-generation TKIs demonstrated superior clinical outcomes but also increased toxicity. The authors concluded that the choice of frontline therapy should depend on patients’ age and comorbidities. They suggested that patients without comorbidities should receive second-generation TKIs as initial therapy and that imatinib should be the preferred initial therapy for older patients or those with comorbidities. Notably, third-generation TKI (ponatinib) has not been approved nor is recommended as the frontline treatment of CP AML. Herein, we will review this recently published work and present the arguments for and against the use of second-generation TKIs as initial therapy for CP CML.

N6 -methyladenosine (m6 A) is a chemical modification present in multiple RNA species and is most abundant in mRNAs. Studies on m6 A reveal its comprehensive roles in almost every aspect of mRNA metabolism, as well as in a variety of physiological processes. Although some recent discoveries indicate that m6 A can affect the life cycles of numerous viruses as well as the cellular antiviral immune response, the roles of m6 A modification in type I interferon (IFN-I) signaling are still largely unknown. Here, we reveal that WT1-associated protein (WTAP), one of the m6 A "writers", is degraded via the ubiquitination-proteasome pathway upon activation of IFN-I signaling. With the degradation of WTAP, the m6 A levels of IFN-regulatory factor 3 (IRF3) and interferon alpha/beta receptor subunit 1 (IFNAR1) mRNAs are reduced, leading to translational suppression of IRF3 and instability of IFNAR1 mRNA. Thus, the WTAP-IRF3/IFNAR1 axis may serve as negative feedback pathway to fine-tune the activation of IFN-I signaling, which highlights the roles of m6 A in the antiviral response by dictating the fate of mRNAs associated with IFN-I signaling.

Siglec-H is a DAP12-associated receptor on plasmacytoid dendritic cells (pDCs) and microglia. Siglec-H inhibits TLR9-induced IFN-α production by pDCs. Previously, it was found that Siglec-H-deficient mice develop a lupus-like severe autoimmune disease after persistent murine cytomegalovirus (mCMV) infection. This was due to enhanced type I interferon responses, including IFN-α. Here we examined, whether other virus infections can also induce autoimmunity in Siglec-H-deficient mice. To this end we infected Siglec-H-deficient mice with influenza virus or with Lymphocytic Choriomeningitis virus (LCMV) clone 13. With both types of viruses we did not observe induction of autoimmune disease in Siglec-H-deficient mice. This can be explained by the fact that both types of viruses are ssRNA viruses that engage TLR7, rather than TLR9. Also, Influenza causes an acute infection that is rapidly cleared and the chronicity of LCMV clone 13 may not be sufficient and may rather suppress pDC functions. Siglec-H inhibited exclusively TLR-9 driven type I interferon responses, but did not affect type II or type III interferon production by pDCs. Siglec-H-deficient pDCs showed impaired Hck expression, which is a Src-family kinase expressed in myeloid cells, and downmodulation of the chemokine receptor CCR9, that has important functions for pDCs. Accordingly, Siglec-H-deficient pDCs showed impaired migration towards the CCR9 ligand CCL25. Furthermore, autoimmune-related genes such as Klk1 and DNase1l3 are downregulated in Siglec-H-deficient pDCs as well. From these findings we conclude that Siglec-H controls TLR-9-dependent, but not TLR-7 dependent inflammatory responses after virus infections and regulates chemokine responsiveness of pDCs.

Hepatitis C virus (HCV) regulates many cellular genes in modulating the host immune system for benefit of viral replication and long-term persistence in a host for chronic infection. Long noncoding RNAs (lncRNAs) play an important role in the regulation of many important cellular processes, including immune responses. We recently reported that HCV infection downregulates lncRNA Linc-Pint (long intergenic non-protein-coding RNA p53-induced transcript) expression, although the mechanism of repression and functional consequences are not well understood. In this study, we demonstrate that HCV infection of hepatocytes transcriptionally reduces Linc-Pint expression through CCAAT/enhancer binding protein β (C/EBP-β). Subsequently, we observed that the overexpression of Linc-Pint significantly upregulates interferon alpha (IFN-α) and IFN-β expression in HCV-replicating hepatocytes. Using unbiased proteomics, we identified that Linc-Pint associates with DDX24, which enables RIP1 to interact with IFN-regulatory factor 7 (IRF7) of the IFN signaling pathway. We furthermore observed that IFN-α14 promoter activity was enhanced in the presence of Linc-Pint. Together, these results demonstrated that Linc-Pint acts as a positive regulator of host innate immune responses, especially IFN signaling. HCV-mediated downregulation of Linc-Pint expression appears to be one of the mechanisms by which HCV may evade innate immunity for long-term persistence and chronicity. IMPORTANCE The mechanism by which lncRNA regulates the host immune response during HCV infection is poorly understood. We observed that Linc-Pint was transcriptionally downregulated by HCV. Using a chromatin immunoprecipitation (ChIP) assay, we showed inhibition of transcription factor C/EBP-β binding to the Linc-Pint promoter in the presence of HCV infection. We further identified that Linc-Pint associates with DDX24 for immunomodulatory function. The overexpression of Linc-Pint reduces DDX24 expression, which in turn results in the disruption of DDX24-RIP1 complex formation and the activation of IRF7. The induction of IFN-α14 promoter activity in the presence of Linc-Pint further confirms our observation. Together, our results suggest that Linc-Pint acts as a positive regulator of host innate immune responses. Downregulation of Linc-Pint expression by HCV helps in escaping the innate immune system for the development of chronicity.

During chronic infection with Helicobacter pylori, Schlafen 4-expressing myeloid-derived suppressor cells (SLFN4(+) MDSCs) create a microenvironment favoring intestinal metaplasia and neoplastic transformation. SLFN4 can be induced by alpha interferon (IFN-α), which is mainly secreted from plasmacytoid dendritic cells (pDCs). This study tested the hypothesis that Helicobacter pylori infection promotes SLFN4(+) MDSC differentiation by inducing pDCs to secrete IFN-α. C57BL/6 mice were gavaged with H. pylori, and infection lasted 2, 4, or 6 months. Mouse pDCs were isolated from bone marrow of wild-type C57BL/6J mice. The results showed that H. pylori infection increased the number of SLFN4(+) MDSCs by inducing IFN-α expression in mice. Further mechanistic experiments unraveled that IFN-α induced SLFN4 transcription by binding to the Slfn4 promoter. Furthermore, H. pylori infection stimulated pDCs to secrete IFN-α by activating the TLR9-MyD88-IRF7 pathway. Collectively, Helicobacter pylori infection promotes SLFN4(+) MDSC differentiation by inducing secretion of IFN-α from pDCs.

To report the results of interferon (IFN) α-2a treatment in patients with cystoid macular edema (CME) secondary to acute retinal necrosis (ARN).We reviewed the records of seven patients (eight eyes) who received IFNα-2a for post-ARN CME. The initial dose of IFNα-2a was 3 MIU/day and it could be tapered down to 3 MIU twice a week. Efficacy was assessed by central macular thickness (CMT) on spectral-domain optical coherence tomography and visual acuity.Age range of seven patients (four men, three women) was 36-74 years. Mean CMT decreased from 477.9 ± 167.5 μm to 367.3 ± 120.5 μm at first week, and vision improved up to five lines in five eyes. CME relapsed after cessation of IFNα-2a in all and improved following reinstitution of treatment. Treatment was discontinued in one patient because of depression. Three patients electively discontinued treatment due to poor tolerability or lack of functional improvement.IFNα-2a is an effective therapeutic option for post-ARN CME, though side effects such as fatigue, elevated liver enzymes, neutropenia, and depression may limit tolerability. Lower initial doses may be a better tolerated.

Autoantibodies against IFN-α and IFN-ω (type I IFNs) were recently reported as causative for severe COVID-19 in the general population. Autoantibodies against IFN-α and IFN-ω are present in almost all patients with autoimmune polyendocrine syndrome type 1 (APS-1) caused by biallelic deleterious or heterozygous dominant mutations in AIRE. We therefore hypothesized that autoantibodies against type I IFNs also predispose patients with APS-1 to severe COVID-19. We prospectively studied 6 patients with APS-1 between April 1, 2020 and April 1, 2021. Biobanked pre–COVID-19 sera of APS-1 subjects were tested for neutralizing autoantibodies against IFN-α and IFN-ω. The ability of the patients’ sera to block recombinant human IFN-α and IFN-ω was assessed by assays quantifying phosphorylation of signal transducer and activator of transcription 1 (STAT1) as well as infection-based IFN-neutralization assays. We describe 4 patients with APS-1 and preexisting high titers of neutralizing autoantibodies against IFN-α and IFN-ω who contracted SARS-CoV-2, yet developed only mild symptoms of COVID-19. None of the patients developed dyspnea, oxygen requirement, or high temperature. All infected patients with APS-1 were females and younger than 26 years of age. Clinical penetrance of neutralizing autoantibodies against type I IFNs for severe COVID-19 is not complete.

Introduction: There are no robust molecular predictors for response of TNBC to chemotherapy. Microscaled proteogenomics (PMC6985126) was therefore applied to biopsies from TNBC patients undergoing neoadjuvant carboplatin/docetaxel. Approach: Sufficient tumor-rich tumor core biopsies were accrued from 59 patients. A second biopsy was collected from 16 patients on day 3. Study endpoints were pathological complete response (pCR) and residual cancer burden (RCB). Analyses included exome-based mutational signatures, RNA-based TNBC subtyping, immune cell infiltrate scores, and multi-gene proliferation scores, protein and phosphoprotein-based stimulatory and inhibitory immunomodulators. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used for gene set and pathway scoring. Non-parametric tests and outlier analyses were applied to identify differential genes, proteins and pathways. Results: Most cases were PAM50 basal-like and all Lehmann TNBC subtypes were represented. BRCA1/2 and PALB2 homologous recombination (HRD) mutations were observed in 7 cases. Neither subtype, HRD mutation nor HRD mutation signature associated with pCR, but higher mismatch repair defect signature associated with higher RCB. Comparison of baseline pCR vs non-pCR cases showed higher ssGSEA scores for metabolic pathways including oxidative phosphorylation, fatty-acid metabolism, and glycolysis in the non-pCR cases at the protein but not at mRNA level. Non-pCR cases were associated with chromosomal deletions in chemokine receptors, JAK2, and PD-L1, lower PD-L1 protein levels, and lower immune activation. Consistently, ssGSEA scores for interferon alpha and gamma response pathways were higher in pCR cases. Phospho-PD-L1 levels were anti-correlated with developmental pathways. Matched comparisons of baseline and on-treatment samples revealed increase in proteins involved in cell cycle, DNA replication, and mismatch repair following treatment. Metabolic proteins were also upregulated following treatment, while complement activation, immune, and cell adhesion-related proteins were downregulated. Conclusion: Microscaled proteogenomic analysis revealed a wealth of biological features associated with chemotherapy resistance beyond immune response markers, including metabolic features that are only present at the protein level. These data suggests that the development of a microscaled proteogenomic chemotherapy response predictor is a feasible objective for future studies. Citation Format: Meenakshi Anurag, Eric Jaehnig, Shankha Satpathy, Karsten krug, Jonathan T. Lei, Yongchao Dou, Beom-Jun Kim, Cathy M. Sullivan, D. R. Mani, Erik J. Bergstrom, Gloria V. Echeverria, Ian S. Hagemann, Kristen Otte, Henry Rodriguez, Ana I. Robles, Michael T. Lewis, Michael Gillette, Bing Zhang, Mothaffar F. Rimawi, Steven Carr, Foluso O. Ademuyiwa, Matthew J. Ellis. Molecular dissection of chemotherapy response in triple negative breast cancer (TNBC) using microscaled proteogenomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 18.