DRD4 alleviates acute kidney injury by suppressing ISG15/NOX4 axis-associated oxidative stress.

Acute kidney injury (AKI) is a life-threatening health condition associated with increasing morbidity and mortality. Despite extensive research on the mechanisms underlying AKI, effective clinical tools for prediction and treatment remain scarce. Oxidative stress and mitochondrial damage play a critical role in AKI and dopamine D4 receptor (DRD4) has been confirmed to be associated with oxidative stress. In this study, we hypothesized that DRD4 could attenuate AKI through its antioxidative and antiapoptotic effects. In vivo, DRD4 was remarkably decreased in the kidneys of mice subjected to ischemia/reperfusion injury (IRI) or cisplatin treatment. Notably, DRD4 significantly attenuated nephrotoxicity by suppressing oxidative stress and enhancing mitochondrial bioenergetics through the downregulation of reactive oxygen species (ROS) generation and NADPH oxidase 4 (NOX4) expression. In vitro, DRD4 demonstrated the ability to ameliorate oxidative stress-induced apoptosis in HK-2 cells subjected to hypoxia/reoxygenation- or cisplatin treatment. Transcriptome sequencing revealed that, mechanistically, DRD4 reduced the expression of its downstream target, interferon-stimulated gene 15 (ISG15), suppressing NOX4 ISGylation, enhancing the ubiquitination of NOX4, leading to its degradation, and ultimately counteracting oxidative stress-induced AKI. Altogether, these findings underscore the significance of DRD4 in AKI and elucidate DRD4 as a potential protectant against IRI or cisplatin-induced nephrotoxicity.

Single-cell sequencing provides insights into the landscape of ovary in PCOS and alterations induced by CUMS.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder related to psychological distress. However, the mechanism underlying increased prevalence of depression in PCOS remained unclear. This study aimed to explore the unique transcriptional landscape of ovary and offered a platform to explore the mechanism of PCOS, as well as the influences caused by depression. The PCOS rat model was established by letrozole whereas PCOS rat model with depression was established by letrozole combined with chronic unpredicted mild stress (CUMS). Then single-cell RNA sequencing (scRNA-Seq) was applied to analyze the transcriptional features of rat ovaries. Granulosa cells (GCs) and fibroblasts (Fibros) accounted for the top two clusters of total 12 cell types. There were nine clusters in GCs, related to inflammatory response, endoplasmic reticulum (ER) stress, and steroidogenesis. The expression of differentially expressed genes (DEG) Hes1 was higher in PCOS and PCOS + CUMS groups, exhibiting enhanced expression by pseudotime and positively related to inflammation. Pseudotemporal analysis revealed that inflammation contributed to the different GCs distributions. Moreover, analysis of DEGs and gene ontology (GO) function enrichment revealed CUMS aggravated inflammation in PCOS GCs possibly via interferon signaling pathway. In theca cells (TCs), nine clusters were observed and some of them were relevant to inflammation, ER stress, and lipid metabolism. DEGs Ass1, Insl3, and Ifi27 were positively related to Cyp17a1, and Ces1d might contribute to the different trajectory of TCs. Subsequent scRNA-seq revealed a signature profile of endothelial cells (ECs) and Fibros, which suggest that inflammation-induced damage of ECs and Fibro, further exacerbated by CUMS. Finally, analysis of T cells and mononuclear phagocytes (MPs) revealed the existence of immune dysfunction, among which interferon signaling played a critical role. These findings provided more knowledge for a better understanding PCOS from the view of inflammation and identified new biomarkers and targets for the treatment of PCOS with psychological diseases.NEW & NOTEWORTHY In this study, we mapped the landscape of polycystic ovary syndrome (PCOS) ovary with rat model induced by letrozole and provided a novel insight into the molecular mechanism of PCOS accompanied by chronic unpredicted mild stress (CUMS) at single-cell transcriptomic level. These observations highlight the importance of inflammation in the pathogenesis of PCOS, which might also be the bridge between PCOS and psychological diseases.

GSDMD (Gasdermin D) Mediates Pathological Cardiac Hypertrophy and Generates a Feed-Forward Amplification Cascade via Mitochondria-STING (Stimulator of Interferon Genes) Axis.

BACKGROUND: Cardiac hypertrophy is initially an adaptive response of cardiomyocytes to neurohumoral or hemodynamic stimuli. Evidence indicates that Ang II (angiotensin II) or pressure overload causes GSDMD (gasdermin D) activation in cardiomyocytes and myocardial tissues. However, the direct impact of GSDMD on cardiac hypertrophy and its underlying mechanisms are not fully understood. METHODS AND RESULTS: In this study, we examined the aberrant activation of GSDMD in mouse and human hypertrophic myocardia, and the results showed that GSDMD deficiency reduced Ang II or pressure overload-induced cardiac hypertrophy, dysfunction, and associated cardiomyocyte pyroptosis in mice. Mechanistically, Ang II-mediated GSDMD cleavage caused mitochondrial dysfunction upstream of STING (stimulator of interferon genes) activation in vivo and in vitro. Activation of STING, in turn, potentiated GSDMD-mediated cardiac hypertrophy. Moreover, deficiency of both GSDMD and STING suppressed cardiac hypertrophy in cardiac-specific GSDMD-overexpressing mice. CONCLUSIONS: Based on these findings, we propose a mechanism by which GSDMD generates a self-amplifying, positive feed-forward loop with the mitochondria-STING axis. This finding points to the prospects of GSDMD as a key therapeutic target for hypertrophy-associated heart diseases.

Interferons as the First Choice of Cytoreduction in Essential Thrombocythemia and Polycythemia Vera.

Interferons are cytokines with immunomodulatory properties that have been used in the treatment of myeloproliferative neoplasms (MPNs) for decades. However, their widespread use has been hampered by their adverse effect profile and difficulty with administration. Recently there has been a resurgence of interest in the use of interferons in MPNs given the development of pegylated formulations with improved tolerability. Currently, treatments for polycythemia vera (PV) and essential thrombocythemia (ET) are targeted toward decreasing the risk of thrombotic complications, because there are no approved therapies that are known to modify disease. However, recent data on interferons in MPNs have suggested the potential for disease-modifying activity, including the achievement of molecular remission and sustained clinical response. This development has led to the question of whether interferons should move forward as the preferred frontline cytoreductive agent for ET and PV, and challenges the criteria currently used to initiate therapy. We review randomized controlled trial data evaluating interferon's efficacy and tolerability in patients with ET and PV. We then consider the data in the context of interferon's known advantages and disadvantages to address whether interferons should be the first choice for cytoreductive treatment in patients with ET and PV.

Antiviral Therapy for Patients Chronically Infected with Hepatis C Virus at Tokai University Hospital.

OBJECTIVE: Hepatitis C virus (HCV) was identified in 1989. In 2020, three decades after HCV identification, three researchers won the Nobel Prize in Physiology or Medicine for the discovery of this virus. In 1992, three years after the discovery, interferon (IFN) was launched as the first anti-HCV therapy in Japan; however, the efficacy of IFN therapy was far from acceptable due to severe adverse effects. The advent of IFN-free direct-acting antivirals (DAAs) in 2014 dramatically improved the outcomes of antiviral treatment without serious adverse effects. In this study, we aimed to summarize anti-HCV therapy at the Tokai University Hospital. METHODS: We identified patients who underwent anti-HCV therapy by searching medical records from January 1992 to December 2020, analyzed their background, and compared safety and efficacy among treatments. RESULTS: A total of 1777 treatments were given to 1299 patients. The sustained virologic response rate has dramatically increased over the past 30 years, with only 7% for IFN monotherapy and 95% or higher for recent IFN-free DAA therapies. CONCLUSIONS: We documented the results of anti-HCV therapy at the Tokai University Hospital. In the 30 years since the discovery of HCV, surprisingly successful progress has been accomplished in the anti-HCV treatment.

Engineering interferons and interleukins for cancer immunotherapy.

Cytokines are a class of potent immunoregulatory proteins that are secreted in response to various stimuli and act locally to regulate many aspects of human physiology and disease. Cytokines play important roles in cancer initiation, progression, and elimination, and thus, there is a long clinical history associated with the use of recombinant cytokines to treat cancer. However, the use of cytokines as therapeutics has been limited by cytokine pleiotropy, complex biology, poor drug-like properties, and severe dose-limiting toxicities. Nevertheless, cytokines are crucial mediators of innate and adaptive antitumor immunity and have the potential to enhance immunotherapeutic approaches to treat cancer. Development of immune checkpoint inhibitors and combination immunotherapies has reinvigorated interest in cytokines as therapeutics, and a variety of engineering approaches are emerging to improve the safety and effectiveness of cytokine immunotherapy. In this review we highlight recent advances in cytokine biology and engineering for cancer immunotherapy.

Therapeutic agents affecting the immune system and drug-induced inflammatory bowel disease (IBD): A review on etiological and pathogenetic aspects.

In recent years, therapeutic agents affecting the immune system have been largely implemented in the treatment of various hematological, rheumatological and dermatological disorders. Their clinical use has offered important benefits for affected patients and has also ameliorated clinical outcome and prognosis in many cases. Nonetheless, as any treatment, the use of these drugs may be associated with side effects. One of the target organs in such cases is the gastrointestinal tract. In particular, the exacerbation or the onset of inflammatory bowel disease (IBD) in treated patients is not infrequent, although the mechanism of action of these agents may be different. In this review we will focus on the use of therapeutic agents affecting the immune system and the development or exacerbation of IBD, with a mention on the possible underlying pathogenetic mechanisms.

In Vitro Effects of Sulforaphane on Interferon-Driven Inflammation and Exploratory Evaluation in Two Healthy Volunteers.

Interferonopathies are rare genetic conditions defined by systemic inflammatory episodes caused by innate immune system activation in the absence of pathogens. Currently, no targeted drugs are authorized for clinical use in these diseases. In this work, we studied the contribution of sulforaphane (SFN), a cruciferous-derived bioactive molecule, in the modulation of interferon-driven inflammation in an immortalized human hepatocytes (IHH) line and in two healthy volunteers, focusing on STING, a key-component player in interferon pathway, interferon signature modulation, and GSTM1 expression and genotype, which contributes to SFN metabolism and excretion. In vitro, SFN exposure reduced STING expression as well as interferon signature in the presence of the pro-inflammatory stimulus cGAMP (cGAMP 3 h vs. SFN+cGAMP 3 h p value < 0.0001; cGAMP 6 h vs. SFN+cGAMP 6 h p < 0.001, one way ANOVA), restoring STING expression to the level of unstimulated cells. In preliminary experiments on healthy volunteers, no appreciable variations in interferon signature were identified after SFN assumption, while only in one of them, presenting the GSTM1 wild type genotype related to reduced SFN excretion, could a downregulation of STING be recorded. This study confirmed that SFN inhibits STING-mediated inflammation and interferon-stimulated genes expression in vitro. However, only a trend towards the downregulation of STING could be reproduced in vivo. Results obtained have to be confirmed in a larger group of healthy individuals and in patients with type I interferonopathies to define if the assumption of SFN could be useful as supportive therapy.

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France.

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39-3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18-0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon.

Corrected QT interval in hospitalized patients with coronavirus disease 2019: Focus on drugs therapy.

ABSTRACT: Corrected QT (QTc) interval prolongation has been associated with poor patient prognosis. In this study, we assessed the effects of different drugs and cardiac injury on QTc interval prolongation in patients with coronavirus disease 2019 (COVID-19).The study cohort consisted of 395 confirmed COVID-19 cases from the Wuhan Union Hospital West Campus. All hospitalized patients were treated with chloroquine/hydroxychloroquine (CQ/HCQ), lopinavir/ritonavir (LPV/r), quinolones, interferon, Arbidol, or Qingfei Paidu decoction (QPD) and received at least 1 electrocardiogram after drug administration.Fifty one (12.9%) patients exhibited QTc prolongation (QTc ≥ 470 ms). QTc interval prolongation was associated with COVID-19 severity and mortality (both P < .001). Administration of CQ/HCQ (odds ratio [OR], 2.759; 95% confidence interval [CI], 1.318-5.775; P = .007), LPV/r (OR, 2.342; 95% CI, 1.152-4.760; P = .019), and quinolones (OR, 2.268; 95% CI, 1.171-4.392; P = .015) increased the risk of QTc prolongation. In contrast, the administration of Arbidol, interferon, or QPD did not increase the risk of QTc prolongation. Notably, patients treated with QPD had a shorter QTc duration than those without QPD treatment (412.10 [384.39-433.77] vs 420.86 [388.19-459.58]; P = .042). The QTc interval was positively correlated with the levels of cardiac biomarkers (creatine kinase-MB fraction [rho = 0.14, P = .016], high-sensitivity troponin I [rho = .22, P < .001], and B-type natriuretic peptide [rho = 0.27, P < .001]).In conclusion, QTc prolongation was associated with COVID-19 severity and mortality. The risk of QTc prolongation was higher in patients receiving CQ/HCQ, LPV/r, and quinolones. QPD had less significant effects on QTc prolongation than other antiviral agents.

Interferon therapy in patients with SARS, MERS, and COVID-19: A systematic review and meta-analysis of clinical studies.

Concern regarding coronavirus (CoV) outbreaks has stayed relevant to global health in the last decades. Emerging COVID-19 infection, caused by the novel SARS-CoV2, is now a pandemic, bringing a substantial burden to human health. Interferon (IFN), combined with other antivirals and various treatments, has been used to treat and prevent MERS-CoV, SARS-CoV, and SARS-CoV2 infections. We aimed to assess the clinical efficacy of IFN-based treatments and combinational therapy with antivirals, corticosteroids, traditional medicine, and other treatments. Major healthcare databases and grey literature were investigated. A three-stage screening was utilized, and included studies were checked against the protocol eligibility criteria. Risk of bias assessment and data extraction were performed, followed by narrative data synthesis. Fifty-five distinct studies of SARS-CoV2, MERS-CoV, and SARS-CoV were spotted. Our narrative synthesis showed a possible benefit in the use of IFN. A good quality cohort showed lower CRP levels in Arbidol (ARB) + IFN group vs. IFN only group. Another study reported a significantly shorter chest X-ray (CXR) resolution in IFN-Alfacon-1 + corticosteroid group compared with the corticosteroid only group in SARS-CoV patients. In a COVID-19 trial, total adverse drug events (ADEs) were much lower in the Favipiravir (FPV) + IFN-α group compared with the LPV/RTV arm (P = 0.001). Also, nausea in patients receiving FPV + IFN-α regimen was significantly lower (P = 0.03). Quantitative analysis of mortality did not show a conclusive effect for IFN/RBV treatment in six moderately heterogeneous MERS-CoV studies (log OR = -0.05, 95% CI: (-0.71,0.62), I2 = 44.71%). A meta-analysis of three COVID-19 studies did not show a conclusive nor meaningful relation between receiving IFN and COVID-19 severity (log OR = -0.44, 95% CI: (-1.13,0.25), I2 = 31.42%). A lack of high-quality cohorts and controlled trials was observed. Evidence suggests the potential efficacy of several combination IFN therapies such as lower ADEs, quicker resolution of CXR, or a decrease in inflammatory cytokines; Still, these options must possibly be further explored before being recommended in public guidelines. For all major CoVs, our results may indicate a lack of a definitive effect of IFN treatment on mortality. We recommend such therapeutics be administered with extreme caution until further investigation uncovers high-quality evidence in favor of IFN or combination therapy with IFN.

How do we treat psoriasis patients with hepatitis C infections in real-world situations? A retrospective analysis of 34 patients.

BACKGROUND: There is still relatively limited data on psoriasis and hepatitis C virus (HCV) infections. OBJECTIVE: This study investigated the clinical characteristics and treatment of psoriasis patients with HCV infections in real-world practice. METHODS: Medical records of all psoriasis patients with HCV infections who attended the outpatient clinic at Siriraj Hospital over a 10-year period were retrospectively reviewed. RESULTS: Of 34 patients, 26 and 8 patients were men and women, respectively with a mean age of 57.0 ± 8.7 (range, 42.2-77.2) years. The median age of psoriasis onset was 42.7 ± 12.7 (range, 8-67.25) years. With a median follow-up period of 13.6 years, cirrhosis and hepatocellular carcinoma were found in 67.6% and 29.4% of the patients, respectively. The interferon used for HCV treatment exacerbated the psoriasis in 20% of those patients. Conventional treatments and anti-tumor necrosis factors (anti-TNFs) were used in strict collaboration with hepatologists. No patients experienced a worsening of their HCV infection. CONCLUSION: Despite a limited number of patients, a male predominance and late-onset psoriasis were frequently observed. Although, interferon therapy for HCV can exacerbate psoriasis, it is not contraindicated. All conventional treatments and anti-TNFs can be used, provided that there is strict collaboration with hepatologists.

Assessment of the Potential Adverse Events Related to Ribavirin-Interferon Combination for Novel Coronavirus Therapy.

PURPOSE: We aimed to analyze and evaluate the safety signals of ribavirin-interferon combination through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS), so as to provide reference for the rationale use of these agents in the management of relevant toxicities emerging in patients with novel coronavirus pneumonia (COVID-19). METHODS: Reports to the FAERS from 1 January 2004 to 8 March 2020 were analyzed. The proportion of report ratio (PRR), reporting odds ratio (ROR), and Bayesian confidence interval progressive neural network (BCPNN) method were used to detect the safety signals. RESULTS: A total of 55 safety signals were detected from the top 250 adverse event reactions in 2200 reports, but 19 signals were not included in the drug labels. All the detected adverse event reactions were associated with 13 System Organ Classes (SOC), such as gastrointestinal, blood and lymph, hepatobiliary, endocrine, and various nervous systems. The most frequent adverse events were analyzed, and the results showed that females were more likely to suffer from anemia, vomiting, neutropenia, diarrhea, and insomnia. CONCLUSION: The ADE (adverse drug event) signal detection based on FAERS is helpful to clarify the potential adverse events related to ribavirin-interferon combination for novel coronavirus therapy; clinicians should pay attention to the adverse reactions of gastrointestinal and blood systems, closely monitor the fluctuations of the platelet count, and carry out necessary mental health interventions to avoid serious adverse events.

Evaluation of the efficacy and safety of favipiravir and interferon compared to lopinavir/ritonavir and interferon in moderately ill patients with COVID-19: a structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: We will evaluate the efficacy and safety of favipiravir and interferon beta-1a compared to lopinavir/ritonavir and interferon beta-1a in patients with confirmed COVID-19, who are moderately ill. TRIAL DESIGN: This is a phase 3, single-center, randomized, open-label, controlled trial with a parallel-group design carried out at Shahid Mohammadi Hospital, Bandar Abbas, Iran. PARTICIPANTS: All patients with age ≥ 20 years admitted at the Severe Acute Respiratory Syndrome Departments of the Shahid Mohammadi Hospital, Bandar Abbas, Iran, will be screened for the following criteria. INCLUSION CRITERIA: 1. Confirmed diagnosis of infection with SARS-CoV-2 using polymerase chain reaction and/or antibody tests. 2. Moderate COVID-19 pneumonia (via computed tomography and/or X-ray imaging), requiring hospitalization. 3. Hospitalized ≤ 48 h. 4. Signing informed consent and willingness of the participant to accept randomization to any assigned treatment arm. EXCLUSION CRITERIA: 1. Underlying conditions, including chronic hepatitis, cirrhosis, cholestatic liver diseases, cholecystitis, peptic ulcers, acute and chronic renal failure, and peptic ulcers. 2. Severe and critical COVID-19 pneumonia. 3. History of allergy to favipiravir, lopinavir/ritonavir, and interferon beta-1a. 4. Pregnancy and breastfeeding. INTERVENTION AND COMPARATOR: Intervention group: favipiravir (Zhejiang Hisun, China) with interferon beta-1a (CinnaGen, Iran). This group will receive 1600 mg favipiravir twice a day for the first day and 600 mg twice a day for the following 4 days with five doses of 44 mcg interferon beta-1a every other day. CONTROL GROUP: lopinavir/ritonavir (Heterd Company, India) with interferon beta-1a (CinnaGen, Iran). This group will receive 200/50 mg lopinavir/ritonavir twice a day for 7 days with five doses of 44 mcg interferon beta-1a every other day. Other supportive and routine care will be the same in both groups. MAIN OUTCOMES: The primary outcome of the trial is the viral load of SARS-CoV-2 in the nasopharyngeal samples assessed by RT-PCR after 7 days of randomization as well as clinical improvement of fever and O2 saturation within 7 days of randomization. The secondary outcomes are the length of hospital stay and the incidence of serious adverse drug reactions within 7 days of randomization. RANDOMIZATION: Eligible patients will be allocated to one of the study arms using block randomization in a 1:1 ratio (each block consists of 10 patients). A web-based system will be used to generate random numbers for the allocation sequence. Each number relates to one of the study arms. BLINDING (MASKING): This is an open-label trial without blinding and placebo control. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): A total of 60 patients will be randomized into two groups (30 patients in the intervention group and 30 patients in the control group). TRIAL STATUS: The trial protocol is version 1.0, 22 July 2020. Recruitment began on 25 July 2020 and is anticipated to be completed by 25 September 2020. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT) IRCT20200506047323N3 . Registered on 22 July 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting the dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Antiviral Activity of Type I, II, and III Interferons Counterbalances ACE2 Inducibility and Restricts SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is a recently emerged respiratory coronavirus that has infected >23 million people worldwide with >800,000 deaths. Few COVID-19 therapeutics are available, and the basis for severe infections is poorly understood. Here, we investigated properties of type I (ß), II (γ), and III (λ1) interferons (IFNs), potent immune cytokines that are normally produced during infection and that upregulate IFN-stimulated gene (ISG) effectors to limit virus replication. IFNs are already in clinical trials to treat COVID-19. However, recent studies highlight the potential for IFNs to enhance expression of host angiotensin-converting enzyme 2 (ACE2), suggesting that IFN therapy or natural coinfections could exacerbate COVID-19 by upregulating this critical virus entry receptor. Using a cell line model, we found that beta interferon (IFN-ß) strongly upregulated expression of canonical antiviral ISGs, as well as ACE2 at the mRNA and cell surface protein levels. Strikingly, IFN-λ1 upregulated antiviral ISGs, but ACE2 mRNA was only marginally elevated and did not lead to detectably increased ACE2 protein at the cell surface. IFN-γ induced the weakest ISG response but clearly enhanced surface expression of ACE2. Importantly, all IFN types inhibited SARS-CoV-2 replication in a dose-dependent manner, and IFN-ß and IFN-λ1 exhibited potent antiviral activity in primary human bronchial epithelial cells. Our data imply that type-specific mechanisms or kinetics shape IFN-enhanced ACE2 transcript and cell surface levels but that the antiviral action of IFNs against SARS-CoV-2 counterbalances any proviral effects of ACE2 induction. These insights should aid in evaluating the benefits of specific IFNs, particularly IFN-λ, as repurposed therapeutics.IMPORTANCE Repurposing existing, clinically approved, antiviral drugs as COVID-19 therapeutics is a rapid way to help combat the SARS-CoV-2 pandemic. Interferons (IFNs) usually form part of the body's natural innate immune defenses against viruses, and they have been used with partial success to treat previous new viral threats, such as HIV, hepatitis C virus, and Ebola virus. Nevertheless, IFNs can have undesirable side effects, and recent reports indicate that IFNs upregulate the expression of host ACE2 (a critical entry receptor for SARS-CoV-2), raising the possibility that IFN treatments could exacerbate COVID-19. Here, we studied the antiviral- and ACE2-inducing properties of different IFN types in both a human lung cell line model and primary human bronchial epithelial cells. We observed differences between IFNs with respect to their induction of antiviral genes and abilities to enhance the cell surface expression of ACE2. Nevertheless, all the IFNs limited SARS-CoV-2 replication, suggesting that their antiviral actions can counterbalance increased ACE2.

Health-related quality of life and fatigue in patients with chronic hepatitis C with therapy with direct-acting antivirals agents interferon-free.

INTRODUCTION: Interferon (IFN)-free regimens for the treatment of chronic hepatitis C have shown high rates of sustained virological response (SVR) and improved patient-reported outcomes (PROs). The aim of this study was to evaluate the health-related quality of life (HRQoL) and fatigue of patients with chronic hepatitis C (HCV) treated with IFN-free direct-acting antiviral (DAA) agents that achieved SVR following treatment and identify the predictive factors related to HRQoL. METHODS: Prospective cohort study that included patients with HCV treated with DAA who obtained an SVR. The patients answered three self-reported questionnaires (PROs): Short Form 36 (SF-36), the Chronic Liver Diseases Questionnaire (CLDQ), and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire at baseline, weeks 6 and 12 of treatment, and at 12 weeks after therapy. Patients were treated with DAA with or without ribavirin (RBV). The PRO scores were compared using analysis of variance (ANOVA). A comparison of PROs and serum hemoglobin levels was performed between the group that used ribavirin and the one that did not use ribavirin using the t student test. Predictive factors were calculated using a multiple linear regression model. RESULTS: Among the 113 patients selected, 105 presented an SVR and were included in the study, in which, 54% men, 80% genotype 1, 44% cirrhosis and 46% with RBV. At 12 weeks after the end of treatment, there was a significant improvement in the scores of the patient self-reports (PROs) when compared with baseline for the CLDQ (+10.52%, p<0.001), SF-36-Physical Summary (+19%, p<0.001), and FACIT (+17.34%, p<0.001). Patients who used RBV had worse PROs and serum hemoglobin levels compared to the group that did not use RBV (p<0,05). As predictors of worsening of the PROs we had the presence of diabetes mellitus, liver cirrhosis and HIV co-infected. CONCLUSION: Patients treated with IFN free regimens presents significant improvement in PROs. The presence of diabetes mellitus, cirrhosis, and HIV co-infected has a negative effect on HRQoL before, during and after treatment of hepatitis C. The addition of ribavirin to the antiviral regimens used compromises the HRQoL indexes during antiviral therapy.

The current status of biological treatment for uveitis.

INTRODUCTION: Noninfectious uveitis represents one of the leading causes of blindness in developed Countries, compromising patients' quality of life and social functioning. The main treatment goals are the control of ocular inflammation, to avert and treat sight-threatening complications, thus preserving and/or restoring visual function. AREAS COVERED: This manuscript deals with systemic therapy with biologic drugs for noninfectious uveitis. An extensive literature search in the MEDLINE database (via PubMed) has been performed up to June 2020. The major classes of biologic molecules employed in ocular inflammatory diseases have been reviewed, focusing on TNF inhibitors, IL-1, IL-6, IL-17, IL-23 inhibitors, interferons, rituximab, and abatacept efficacy and safety. An overview of most recent developments in the field has been provided as well, with reference to the experience with JAK inhibitors and with biosimilar drugs. EXPERT OPINION: The development of the concept of targeted therapy and the subsequent introduction of biologic molecules in clinical practice have revolutionized the prognosis of uveitis. The target of a rapid and sustained steroid-free remission of ocular inflammation should be pursued for all patients early in the disease course, in order to have a better chance to improve the final visual outcome.

Autoimmune Hemolytic Anemia in Chronic Myeloid Leukemia.

BACKGROUND: Autoimmune hemolytic anemia (AIHA) might be associated with underlying hematological malignancies such as chronic lymphocytic leukemia. However, the association between AIHA and chronic myelogenous leukemia is extremely unusual. SUMMARY: We reviewed case reports and series of 54 patients with chronic myeloid leukemia (CML) who developed autoimmune hemolysis between 1952 and 2018. Almost all the patients were in the chronic phase and were classified into transplant and non-transplant groups. The onset of autoimmune hemolysis was earlier in the transplant group and required second- and third-line therapy to control it. The etiology of hemolysis is poorly understood but attributed in the transplant group to immune reconstitution, viral infections, or CML relapse. On the other hand, it is thought to be related in the non-transplant group to CML medications, especially interferon. Key Messages: Although AIHA is uncommon in chronic myelogenous leukemia patients, it should be in the differential diagnosis list for those who develop a sudden drop in hemoglobin without a bleeding source.

Drug-Related Cutaneous Adverse Events in Philadelphia Chromosome-Negative Myeloproliferative Neoplasms: A Literature Review.

Since myeloproliferative neoplasms (MPN) pose a significant risk for vascular and thrombotic complications, cytoreductive therapies, such as hydroxyurea (HU), interferon (IFN) inhibitors, and Janus kinase (JAK) inhibitors are recommended for patients at high risk. However, these agents also place patients at increased risk for drug-related cutaneous adverse events. Herein, we review the literature on skin toxicity related to the use of drugs for the treatment of MPN. Overall, the cytoreductive agents used for MPN are generally well tolerated and considered to be safe, except IFN, for which dropout rates as high as 25% have been reported. While IFN is known to give rise to flu syndrome, it rarely leads to hematological alterations. The most common hematological side effects of HU are mild and include granulocytopenia, anemia, and thrombocytopenia. The JAK inhibitor ruxolitinib has been associated with cytopenia and a higher incidence of viral infections, as well as increased risk for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Based on the present analysis, it can be concluded that cutaneous toxicity is not a negligible complication of commonly used treatments for MPN. While further research is needed, patients on these agents, and especially those with a history of cutaneous malignancies, should undergo thorough skin examination before and during therapy. In addition, detailed history is critical since many patients who develop non-melanoma skin cancer have multiple preexisting risk factors for cutaneous carcinogenesis.