IFN-alpha Research Articles

Abstract 6880: Immune infiltration in inflammatory and myofibroblastic cancer-associated fibroblast high microenvironments of colorectal cancer

Abstract Background: Cancer-associated fibroblasts are major modulators of the tumor microenvironment (TME) and play a large role in the immune system’s response to tumors. The direct effect that myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs) have on immune infiltration is not well studied in colorectal cancer (CRC). Here we investigate the effects that myCAFs and iCAFs have on immune infiltration in human CRCs. Methods: The Cancer Genome Atlas (TCGA) Colorectal Adenocarcinoma PanCancer Atlas dataset was accessed via cBioPortal. Cancers were separated into myCAF prominent (MP) by high gene expression (Z-score > 1) of ACTA2 and TAGLN and iCAF prominent (IP) by expression of PDPN and ICAM1. Gene Set Enrichment Analysis (GSEA) was performed on differential expression results comparing these groups. Additionally, bulk RNA sequencing results were analyzed for immune cell subsets using Cibersortx. Statistical analysis was completed in R. Results: Of 592 cancer samples, 24 were MP and 9 IP. There was no significant difference in age (MP median age 63, IP median age 70, q = 0.6) nor sex (MP 17 female/7 male; IP 4 female/5 male, q=0.9). MP have 1/24 profiled patients with MSIsensor score >=3.5 and 2/24 patients with MSI MANTIS score > 0.4; IP have 3/9 profiled patients with MSIsensor score >=3.5 and 3/9 patients with MSI MANTIS score >0.4. IP cancers were enriched for gene sets associated with enhanced immune cell infiltration (Inflammatory Response, Interferon Gamma Response, Allograft rejection, TNFA signaling via NFKB, IL6 JAK STAT3 signaling, Interferon Alpha Response, Complement, IL2 STAT5 signaling and Apoptosis, all q< 0.001). MP cancers were enriched in the KRAS signaling Down gene set (q=.009). IP cancers had a higher proportion of infiltrating immune cells than MP cancers by CibersortX analysis (iCAF median = 2.829, myCAF median= 2.284, p < 0.01). IP cancers had higher CD4 memory cells (p <0.001, iCAF median = 0.455, myCAF mean = 0.318), NK resting cells (p<0.001, 0.228, 0.103), M1-like macrophages (p <0.01, 0.1977,0.107), and neutrophils (p<0.01, 0.0298, 0). MP cancers had a higher number of NK activated cells (p = 0.04, iCAF median = 0, myCAF median = 0). M1-like macrophage gene markers were higher expressed in IP cancers compared to MP cancers, though not significantly (NOS2 log2FC = 0.66, q = 0.652; IL1A 3.25, 0.0375; IL23A 1.34, 0.151; IL26 1.31, 0.32). Additionally, IP cancers tended to express markers for activated CD8+ T cells, though only IFNG was significant (GZMB, log2FC = 0.97, q = 0.337; IFNG, 2.16, q<0.001; PRF1, 1.12, q=0.198). Conclusion: These analyses indicate that iCAFs play the major role in modulating the immune infiltration of cancers. These data highlight the need for further research into the mechanisms by which different CAF subtypes alter the immune microenvironment. Citation Format: Yousef Gadalla, Katherine A. Johnson, Sharanya Nath, Cheri A. Pasch, Dustin A. Deming. Immune infiltration in inflammatory and myofibroblastic cancer-associated fibroblast high microenvironments of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6880.

Abstract 7568: Molecular effects of neo-adjuvant hormone therapy for locally advanced prostate cancer: An ancillary study of the ARNEO phase 2 trial

Abstract Intensified hormone therapy in combination with radiotherapy improves outcome for very high-risk locally advanced prostate cancer. The impact of hormone therapy with surgery, however, is uncertain. In order to understand this better, we ran an ancillary translational study on ARNEO (NCT03080116), a Phase 2 clinical trial, which randomized 89 locally-advanced prostate cancer patients to 12 weeks LHRHa +/- apalutamide (APA) followed by prostatectomy. We performed clinical-grade transcriptome-wide expression array analysis (Veracyte, Inc. San Diego, CA) of FFPE diagnostic core biopsies (N=89) and tumors removed at prostatectomy (N=32 LHRHa, N=23 LHRHa + APA). We also performed RNASeq on fresh frozen biopsies of prostatectomy tumors (N=42 LHRHa, N=45 LHRHa + apalutamide) and LHRHa-naive control cases (N=61) matched for clinical and pathological risk factors. Pre-surgery serum PSA decreased by a median of 98% (IQR:90.2-99.3) after hormone treatment. This decrease was better associated with tumor AR signaling (r2=0.11) versus pre-treatment serum PSA (r2=0.0005), or between pre-treatment serum PSA with diagnostic biopsies (r2=0.008). We confirmed APA more potently suppressed AR signaling than LHRHa alone, with no detectable difference in direction of effect for differentially regulated genes/pathways. LHRHa + APA had less residual tumor (median Residual Cancer Burden, RCB=0.48cm3) than in LHRHa (median RCB=1.7cm3) but in cases with sufficient tumor, we observed residual active AR signaling pathways at prostatectomy in both treatment arms. To orthogonally confirm this, we selected 28 ERG positive cases (by IHC pre-treatment) and found retained ERG expression in 12/13 on LHRHa and 10/15 on LHRHa + APA. Using pathway analysis in the RNAseq data, we identified LHRHa +/- APA induced down-regulation of AR, metabolic pathways, as well as DNA repair, and up-regulation of hallmark NOTCH, Hedgehog, TGF-beta, WNT and immune signaling (adjusted p-value cutoff=0.001). Comparing differentially expressed genes on RNASeq between treatment-naïve versus LHRHa +/- APA treated tumors, we observed STING1 as significantly higher in LHRHa +/- APA vs control (Wilcoxon rank sum test p-value <0.001). We found that expression of STING1 was positively correlated with hallmark interferon alpha response (r=0.7, rs=0.6) that was correlated with apoptosis (r=0.5, rs=0.5). Whilst we show that adding APA to LHRHa increases suppression of AR activity and ERG expression, we find that 12 weeks is insufficient to abrogate AR signaling in most tumors, despite ~98% decrease in serum PSA. We identify novel processes modulated in humans by potent suppression of androgen activity, including upregulation of STING1-type 1 interferon response as a potential key modulator of treatment effect. Citation Format: Mazlina Ismail, Wout Devlies, Marina Parry, Gaetan Devos, Stefanie Friedrich, Charles Parker, Larissa Mendes, Elai Davicioni, Mark Linch, Frank Claessens, Steven Joniau, Gerhardt Attard. Molecular effects of neo-adjuvant hormone therapy for locally advanced prostate cancer: An ancillary study of the ARNEO phase 2 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7568.

Abstract 6159: Single cell analysis of circulating peripheral blood mononuclear cells in African American men with prostate cancer and their association with lethal disease

Abstract Prostate cancer is a leading cause of cancer-related deaths among men in the United States and affects African American (AA) men more so than other men. We and others previously described a distinct tumor immunobiology in AA prostate cancer patients. Furthermore, we discovered a serum proteome-defined suppression of tumor immunity signature that is prevalent among these patients and associated with lethal prostate cancer. In the current study, we sought to investigate the composition of circulating peripheral blood mononuclear cells (PBMCs) in AA and European American (EA) prostate cancer patients and their association with patient group and lethal prostate cancer. We obtained high-quality RNA-sequencing data for 277336 single cells representing circulating PBMCs from 59 AA and EA men. In the analysis, being an AA patients associated with an increased abundance of exhausted T cells, higher numbers of plasma B cells and CD16+ monocytes. Gene signatures indicative of T cell exhaustion and Treg activity were generally elevated in AA PBMCs while T cell effector function features were decreased. Within the overall cell population, interferon gene signatures were robustly elevated in AA than EA patients. This gene signature pattern that we observed in AA patients also associated with lethal prostate cancer, namely the T cell exhaustion, Treg activity and elevated interferon signaling gene signatures, may contribute to immune dysfunction and immune injury; pointing to potential clinical implications. Lastly, the interferon-induced transmembrane protein (IFITM3), interferon alpha inducible protein (IFI6), cysteine rich protein-1 (CRIP1), and the RAC family small GTPase2 (RAC2) were notably upregulated in AA patient-derived immune cells. In summary, we show that circulating immune cell populations and the associated gene signatures differ between men of African and European descent. Those elevated in AA patients correlated with lethal prostate cancer. Citation Format: Md Shakir Uddin Ahmed, Tiffany Dorsey, Stefan Ambs. Single cell analysis of circulating peripheral blood mononuclear cells in African American men with prostate cancer and their association with lethal disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6159.

Recurrent conjunctival papilloma: Case report

Papilloma is a histopathological term describing specific morphology of tumors. Conjunctival papilloma is a benign growth that arises from the stratified squamous epithelium of the conjunctiva. Two cases of recurrent conjunctival papilloma who were operated and adjunctive therapy given are presented here. Both the cases had history of recurrence of conjunctival papilloma following excision. The extent of papilloma was different in both the cases. One case has minimal symptoms and lesion the inferior quadrant while the other was symptomatic in form of diminution of vision, watering, forgien body sensation, photophobia and blepharospasm with alesion extending 270 degrees of limbal area and covering whole of the cornea. The management was same in both the cases : excisional biopsy in both the eyes under local anaesthesia, intraoperative crotherapy and use of mitomycin C and post operative use of chloramphenicol and mitomycin c eye drops. Various treatment modalities have been described for management of conjunctival papilloma. These comprise conservative management, topical use of interferon alpha 2b, excisional biopsy and use of adjunctive treatment such as carbon dioxide laser, cryoablation and application of mitomycin C to prevent recurrence. This patient was managed with excisional biopsy along with adjunctive treatment in form of cryoablation and mitomycin c application to prevent recurrence.

Interferon Lambda: An Anonymous Warrior of Host-Microbial Fray in The Pathogenesis of Periodontal Diseases

The current body of research focuses primarily on three fundamental groups of interferons: alpha, beta, and gamma interferons. However, little attention is paid to another important group of interferons called lambda interferons (IFN-λs), which have demonstrated activity against periodontal pathogens, particularly viruses. These recently discovered interferon-lambdas provide a striking contrast to the periodontal pathogens, exerting impact both at the capacity of the immune system and the cell, thereby affecting a variety of inflammatory and response pathways. Thus, this review sheds light on role of interferon lambda in the development of periodontal disease and associated activities. In order to collect the information necessary for this review, an exhaustive search of the relevant literature was conducted. The review focused on the structure, regulatory mechanisms, and role of interferon lambda in medical and periodontal infections and diseases. The findings of our review indicated that IFN-λs have an effect on the immunological regulatory mechanisms of the host in relation to viruses, bacteria, fungi, and parasites; nevertheless, their primary role is antiviral, and they have little to no effect on the immune system's ability to fight bacteria. Bangladesh Journal of Medical Science Vol.23 (Special Issue) 2024 p.S73-S78

Matrine and icariin can inhibit bovine viral diarrhoea virus replication by promoting type I interferon response in vitro

Abstract Introduction Bovine viral diarrhoea virus (BVDV) can cause diarrhoea (BVD) in an animal herd, leading to heavy economic losses. There are limited drugs available for treating and controlling BVD. This research aims to investigate the antiviral and immunoregulatory effects of two traditional Chinese herb extracts against BVDV infection. The extracts are matrine and icariin, which have been proved to have immunostimulant and antiviral effects. Material and Methods A cell counting kit-8 assay was used to analyse the toxicity of matrine and icariin to Madin–Darby bovine kidney (MDBK) cells. The model of MDBK cells infected with BVDV was utilised to uncover the antiviral mechanism of matrine and icariin, which along with their immunoregulatory ability was evaluated by quantitative reverse-transcription PCR and ELISA. Results The results showed that matrine and icariin can significantly inhibit the gene expression level of the BVDV 5′ untranslated region through various pathways. Both matrine and icariin can statistically upregulate the gene expression level of interferon alpha, interferon beta (IFN-β), toll-like receptor 3, retinoic acid–inducible gene I and interferon regulatory factor 3, and raise the concentration of IFN-β after BVDV infection. Conclusion This study proves that both matrine and icariin have inhibitory effects on BVDV replication by activating IFN production and the IFN signalling pathway. The finding is promising and should open up the possibility of larger-scale in vitro research followed by in vivo experiments evaluating matrine and icariin as therapeutic agents in BVD cases.

DNA methylation-environment interactions in the human genome

Previously, we showed that a massively parallel reporter assay, mSTARR-seq, could be used to simultaneously test for both enhancer-like activity and DNA methylation-dependent enhancer activity for millions of loci in a single experiment (Lea et al., 2018). Here, we apply mSTARR-seq to query nearly the entire human genome, including almost all CpG sites profiled either on the commonly used Illumina Infinium MethylationEPIC array or via reduced representation bisulfite sequencing. We show that fragments containing these sites are enriched for regulatory capacity, and that methylation-dependent regulatory activity is in turn sensitive to the cellular environment. In particular, regulatory responses to interferon alpha (IFNA) stimulation are strongly attenuated by methyl marks, indicating widespread DNA methylation-environment interactions. In agreement, methylation-dependent responses to IFNA identified via mSTARR-seq predict methylation-dependent transcriptional responses to challenge with influenza virus in human macrophages. Our observations support the idea that pre-existing DNA methylation patterns can influence the response to subsequent environmental exposures—one of the tenets of biological embedding. However, we also find that, on average, sites previously associated with early life adversity are not more likely to functionally influence gene regulation than expected by chance.

DNA methylation-environment interactions in the human genome.

Previously, we showed that a massively parallel reporter assay, mSTARR-seq, could be used to simultaneously test for both enhancer-like activity and DNA methylation-dependent enhancer activity for millions of loci in a single experiment (Lea et al., 2018). Here, we apply mSTARR-seq to query nearly the entire human genome, including almost all CpG sites profiled either on the commonly used Illumina Infinium MethylationEPIC array or via reduced representation bisulfite sequencing. We show that fragments containing these sites are enriched for regulatory capacity, and that methylation-dependent regulatory activity is in turn sensitive to the cellular environment. In particular, regulatory responses to interferon alpha (IFNA) stimulation are strongly attenuated by methyl marks, indicating widespread DNA methylation-environment interactions. In agreement, methylation-dependent responses to IFNA identified via mSTARR-seq predict methylation-dependent transcriptional responses to challenge with influenza virus in human macrophages. Our observations support the idea that pre-existing DNA methylation patterns can influence the response to subsequent environmental exposures-one of the tenets of biological embedding. However, we also find that, on average, sites previously associated with early life adversity are not more likely to functionally influence gene regulation than expected by chance.

Construction of viral-based expression vectors for high-level production of human interferon alpha 2b in plants

Human interferon (hINF) alpha 2b is clinically important pharmaceutical product included in combinatory therapy against chronic hepatitis C and B and complex therapy against several cancer diseases. Here, we created the genetic constructions, based on genome elements of potato virus X (PVX), carrying the infα2b gene for transient expression in plant cells. The created plasmid vector constructions were tested through Agrobacterium-mediated transient gene expression method in two plant species—Nicotiana benthamiana and Ocimum basilicum (sweet basil). Production of recombinant hINF alpha 2b was more efficient in N. benthamiana than that in O. basilicum plants. The average yield of hINF alpha 2b produced in N. benthamiana plants was 0.56 mg/g of fresh leaf weight (FW) or 6% of the total soluble cell proteins (TSP). The maximal level reached up to 1.2 mg/g FW or 9% TSP. We estimated that about 0.67 mg of hINF can be obtained from one N. benthamiana plant. The yield of hINF alpha 2b obtained with the PVX-based expression cassette was about 80 times higher than the yield of hINF alpha 2b obtained with a simple expression cassette in which the infα2b gene was controlled by the 35S promoter of cauliflower mosaic virus.Key points• PVX-based expression vectors provide efficient transient expression of infα2b gene• N. benthamiana plants can produce human interferon alpha 2b at high levels• The yield of the hINF α2b reached up to 1.2 mg/g of fresh leaf weight

Correlation between double-stranded DNA and acute urticaria.

Acute urticaria is a prevalent inflammatory dermatosis characterized by fulminant wheals, often accompanied by severe pruritis. It may also cause nausea, vomiting, and abdominal pain. Numerous studies have substantiated the pivotal involvement of double-stranded DNA (dsDNA) in autoimmunity. However, the role of dsDNA in the pathogenesis of acute urticaria is unclear. We measured serum dsDNA levels in patients and controls. The relationship between dsDNA levels and environmental exposures (temperature, ultraviolet [UV] index, and season) was investigated by correlating disease onset dates with archived meteorological data. Finally, we used quantitative PCR to determine the expressions of genes encoding dsDNA receptors, single-stranded RNA (ssRNA) receptors, exosome formation, and type I interferon in the peripheral blood of patients and controls. Serum dsDNA levels were significantly higher in patients with acute urticaria compared with controls (mean values 1.38 and 0.94 ng/ml, respectively, P < 0.001). dsDNA levels were higher in patients exposed to higher environmental temperatures and UV indices and were higher during the summer months. We also found that the expressions of genes encoding dsDNA receptors, ssRNA receptors, absent in melanoma factor 2 (AIM2)-related inflammatory factors, and interferon alpha were up-regulated in patients. We demonstrated that serum dsDNA levels are elevated in acute urticaria and are influenced by climatic factors such as temperature, ultraviolet index, and season. We also found that elevated dsDNA promotes the expression of AIM2-related factors and type I interferons. This study generates new hypotheses regarding the pathogenesis of acute urticaria and suggests novel therapeutic targets.

An alternative strategy to increasing influenza virus replication for vaccine production in chicken embryo fibroblast (DF-1) cells by inhibiting interferon alpha and beta using peptide-conjugated phosphorodiamidate morpholino oligomers.

Introduction. Influenza is a global health issue causing substantial health and economic burdens on affected populations. Routine, annual vaccination for influenza virus is recommended for all persons older than 6 months of age. The propagation of the influenza virus for vaccine production is predominantly through embryonated chicken eggs.Hypothesis/Gap Statement. Many challenges face the propagation of the virus, including but not limited to low yields and lengthy production times. The development of a method to increase vaccine production in eggs or cell lines by suppressing cellular gene expression would be helpful to overcome some of the challenges facing influenza vaccine production.Aims. This study aimed to increase influenza virus titres by using a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO), an antisense molecule, to suppress protein expression of the host genes interferon alpha (IFN-α) and interferon beta (IFN-β) in chicken embryo fibroblast (DF-1) cells.Methods. The toxicity of PPMOs was evaluated by cytotoxicity assays, and their specificity to inhibit IFN-α and IFN-β proteins was measured by ELISA. We evaluated the potential of anti-IFN-α and anti-IFN-β PPMOs to reduce the antiviral proteins in influenza virus-infected DF-1 cells and compared the virus titres to untreated controls, nonsense-PPMO and JAK/STAT inhibitors. The effects of complementation and reconstitution of IFN-α and IFN-β proteins in PPMO-treated-infected cells were evaluated, and the virus titres were compared between treatment groups.Results. Suppression of IFN-α by PPMO resulted in significantly reduced levels of IFN-α protein in treated wells, as measured by ELISA and was shown to not have any cytotoxicity to DF-1 cells at the effective concentrations tested. Treatment of the self-directing PPMOs increased the ability of the influenza virus to replicate in DF-1 cells. Over a 2-log10 increase in viral production was observed in anti-IFN-α and IFN-β PPMO-treated wells compared to those of untreated controls at the initial viral input of 0.1 multiplicity of infection. The data from complementation and reconstitution of IFN-α and IFN-β proteins in PPMO-treated-infected cells was about 82 and 97% compared to the combined PPMO-treated but uncomplemented group and untreated group, respectively. There was a 0.5-log10 increase in virus titre when treated with anti-IFN-α and IFN-β PPMO compared to virus titre when treated with JAK/STAT inhibitors.Conclusions. This study emphasizes the utility of PPMO in allowing cell cultures to produce increased levels of influenza for vaccine production or alternatively, as a screening tool to cheaply test targets prior to the development of permanent knockouts of host gene expression.

Clinical and Real-World Effectiveness of Mogamulizumab: A Narrative Review.

Mogamulizumab (MOG) is an antibody targeting the CCR4 receptor, authorized for relapsed or refractory peripheral T-cell (PTCL) and cutaneous T-cell lymphomas (CTCL). Its adoption in guidelines and endorsement by FDA and EMA established it as a systemic treatment, especially for advanced disease stages due to its comparatively lower toxicity. Clinical trials and real-world evidence have underscored its efficacy in advanced CTCLs, including mycosis fungoides and Sézary syndrome; PTCLs; and adult T-cell leukemia/lymphoma (ATLL), showcasing positive outcomes. Notably, the drug has demonstrated significant response rates, disease stability, and extended periods of progression-free survival, suggesting its applicability in cases with multiple treatment lines. Its safety profile is generally manageable, with adverse events (AEs) primarily related to the skin, infusion-related reactions, drug eruptions, autoimmune diseases, and skin disorders. The latter seem to appear as CCR4 can promote the skin-specific homing of lymphocytes, and MOG is directed against this receptor. While combination with immunostimulatory agents like interferon alpha and interleukin 12 has shown promising results, caution is urged when combining with PD1 inhibitors due to the heightened risk of immune-mediated AEs. The introduction of MOG as a systemic treatment implies a significant advancement in managing these diseases, supported by its favorable safety profile and complementary mechanisms.

Interferon alpha 2b or Mitomycin-C as Adjuvant Therapy of Pigmented Conjunctival Malignancy : A Literature Review

Abstract&#x0D; Introduction &amp; Objectives : To compare the efficacy and safety between Mitomycin C (MMC) and Interferon alpha-2b (IFN-α2b) eye drops as adjuvant therapy for conjunctival melanoma.&#x0D; Methods : Literature searching was conducted using PubMed, ScienceDirect, and Google Scholar. All studies that met the inclusion and exclusion criteria were categorized based on the level of evidence. The data of patients demographics, staging of disease, type of treatments, and outcomes of this review including local control rate, side effect, and recurrence and/or metastases were also reported.&#x0D; Results : From twelve articles, topical adjuvant chemotherapy with MMC and IFN α-2b showed favourable complete remission rate. Local control (complete remission) of IFN α-2b group is 46%, while in MMC group is 57%. The most side effect of MMC group were severe corneal-conjunctival irritation and corneal defect, while the IFN α-2b group showed mild side effect. Recurrency rate of IFN α-2b group and MMC group both is 35%. Metastases case of IFN α-2b group is 3.8%, while none of cases from MMC group metastases.&#x0D; Conclusion : Topical adjuvant chemotherapy with MMC and IFN α-2b showed favourable local control rate even though the recurrency rate also relatively high. Both medications showed promising results to reduce residual tumor size after wide excision surgery, preserving eye so reduce the chance of exenteration in various stages. It is important to consider adjuvant therapy following wide excision surgery as the first line treatment.

IRF3 function and immunological gaps in sepsis.

Lipopolysaccharide (LPS) induces potent cell activation via Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD-2), often leading to septic death and cytokine storm. TLR4 signaling is diverted to the classical acute innate immune, inflammation-driving pathway in conjunction with the classical NF-κB pivot of MyD88, leading to epigenetic linkage shifts in nuclear pro-inflammatory transcription and chromatin structure-function; in addition, TLR4 signaling to the TIR domain-containing adapter-induced IFN-β (TRIF) apparatus and to nuclear pivots that signal the association of interferons alpha and beta (IFN-α and IFN-β) with acute inflammation, often coupled with oxidants favor inhibition or resistance to tissue injury. Although the immune response to LPS, which causes sepsis, has been clarified in this manner, there are still many current gaps in sepsis immunology to reduce mortality. Recently, selective agonists and inhibitors of LPS signals have been reported, and there are scattered reports on LPS tolerance and control of sepsis development. In particular, IRF3 signaling has been reported to be involved not only in sepsis but also in increased pathogen clearance associated with changes in the gut microbiota. Here, we summarize the LPS recognition system, main findings related to the IRF3, and finally immunological gaps in sepsis.

A cross-sectional survey on the types of antiviral treatment plans for patients with chronic hepatitis B

Objective: To understand the current antiviral treatment status and various clinical types of treatment plans in Xiamen City so as to explore ways to improve and optimize the diagnosis and treatment standards for chronic hepatitis B. Methods: A cross-sectional survey method was used to study the antiviral treatment status and treatment plans for chronic hepatitis B patients who visited and were diagnosed in the Department of Infectious Diseases and Hepatology of all tertiary hospitals in Xiamen City at 0:00~23:59 on May 25, 2022. Results: A total of 665 cases were surveyed in this study, with an antiviral treatment rate of 81.2%(540/665). The antiviral treatment rate of patients who accorded with the current guidelines for antiviral treatment indications was 85.8%(507/591). The antiviral treatment rate for 362 outpatients was 72.9%(264/362). Among them, the antiviral treatment rates were 80.1%, 89.3%, and 25.0%(226/282, 25/28, 13/52), respectively, for patients diagnosed with chronic hepatitis B, hepatitis B cirrhosis, and hepatitis B surface antigen-carrying status. The treatment plan for all outpatient patients was mainly oral nucleos(t)ide analogues, accounting for 59.1%(214/362). The antiviral treatment rate for 303 inpatients was 91.1%(276/303). The various clinical types of antiviral therapy rates among all patients were 70%~95%. The antiviral treatment plan for inpatients was mainly based on pegylated interferon alpha treatment, accounting for 72.6%(220/303). Conclusion: Antiviral treatment for chronic hepatitis B in Xiamen City can still be strengthened to meet the current demand for expanding antiviral treatment indications. Antiviral treatment rates and various types of treatment plans differ between outpatients and inpatients; thus, further awareness and acceptance of the goal of improving antiviral therapy, especially in outpatients, and the possibility for a clinical cure based on pegylated interferon alpha treatment are needed to maximize the benefit to more patients.

Flu in children: Clinical, laboratory indicators and cytokine profile parameters

Introduction. Respiratory diseases occupy a leading place in the structure of pathology of childhood. The proportion of influenza and acute respiratory viral infections among all infectious diseases is 90 %. The literature describes gender differences in the immune response to respiratory infections in children, but there is a gap in the description of the cytokine profile in children with influenza depending on gender and age.The aim. To analyze clinical and laboratory parameters as well as cytokine profile parameters in children with influenza.Materials and methods. A single-stage descriptive study was conducted with the participation of 50 children from 1 to 11 years of age with a diagnosis of influenza who were on inpatient treatment at the Irkutsk Regional Infectious Diseases Clinical Hospital from December 2018 to January 2019. The clinical and laboratory features of the course of influenza in children, the duration of treatment were determined. The concentration of cytokines interleukin (IL) 1β, IL-4, IL-6, IL-8, tumor necrosis factor alpha (TNF-α), interferon alpha and gamma (INF-α, INF-γ) in blood plasma was determined by enzyme-linked immunosorbent assay (ELISA) using diagnostic test systems manufactured by Vector-Best (Novosibirsk, Russian Federation) on the analyzer Multiscan EX (Thermo Electron, Germany).The control group consisted of practically healthy children without signs of acute respiratory viral infection (n = 50; mean age 5.3 ± 2.6 years).Results. When comparing clinical and laboratory data and cytokine profile parameters in children with influenza, no gender differences were found. There was a statistically significant increase in the level of pro-inflammatory cytokines IL-1β, IL-6, IL-8, TNF-α, INF-α, as well as CRP, anti-inflammatory cytokine IL-4 in influenza in all age categories, in contrast to the control group (p &lt; 0.05).Conclusion. Influenza in children of different sexes proceeds classically without a statistical difference in clinical and laboratory parameters and in the level of cytokines.

Influence of alpha-glutamil-tryptophan on the background and induced activity of factors of adaptive immunity for prevention

Background. During the ongoing COVID-19 pandemic and in the season of rising incidence of other respiratory infections, it is relevant to use preventive measures of non-specific prophylaxis. Synthetic peptides are widely considered as a tool. The representative of this group is the synthetic analogue of thymus regulatory peptides Thymogen, which has been used in Russia for more than 20 years in the treatment of acute and chronic infection diseases.The aim of the study. To evaluate the effect of Thymogen, a dosed nasal spray, on induced parameters of the immune system during prophylactic use in healthy volunteers.Materials and methods. Twenty healthy volunteers received Thymogen nasal dosed spray (JSC “Cytomed”, Russia) at a dose of 25 μg twice a day for 10 days. A comparative assessment of immunological parameters was carried out in dynamics: before the start of therapy, on days 6 and 11 of taking the drug and 14 days after the end of the course. Clinical observation was carried out from day 1 to day 11, registration of adverse events – the entire period of the study for 24 days. The first day was considered the day the drug was started.Results. In the course of the work, according to the data of immunological examination, a statistically significant increase in the virus-induced production of interferon alpha (INF-α) by a culture of peripheral blood cells was revealed. The growth rate was recorded on day 11 of taking Thymogen and persisted for 14 days after the end of the course. Significant differences in the dynamics of bactericidal and phagocytic activity of neutrophils, serum α- and γ-interferon were not obtained.Conclusion. The use of Thymogen spray at a dose of 25 μg for 10 days was safe and contributed to a significant induction of interferon-alpha in response to exposure to a viral pathogen, which allows us to recommend the drug for prophylactic use during the period of rising incidence of acute respiratory diseases.

Hepatitis C: The Story of a Long Journey through First, Second, and Third Generation NS3/4A Peptidomimetic Inhibitors. What Did We Learn?

Hepatitis C viral (HCV) infection is the leading cause of liver failure and still represents a global health burden. Over the past decade, great advancements made HCV curable, and sustained viral remission significantly improved to more than 98%. Historical treatment with pegylated interferon alpha and ribavirin has been displaced by combinations of direct-acting antivirals. These regimens include drugs targeting different stages of the HCV life cycle. However, the emergence of viral resistance remains a big concern. The design of peptidomimetic inhibitors (PIs) able to fit and fill the conserved substrate envelope region within the active site helped avoid contact with the vulnerable sites of the most common resistance-associated substitutions Arg155, Ala156, and Asp168. Herein, we give an overview of HCV NS3 PIs discovered during the past decade, and we deeply discuss the rationale behind the structural optimization efforts essential to achieve pangenotypic activity.

Impaired activation of plasmacytoid dendritic cells via toll-like receptor 7/9 and STING is mediated by melanoma-derived immunosuppressive cytokines and metabolic drift.

Plasmacytoid dendritic cells (pDCs) infiltrate a large set of human cancers. Interferon alpha (IFN-α) produced by pDCs induces growth arrest and apoptosis in tumor cells and modulates innate and adaptive immune cells involved in anti-cancer immunity. Moreover, effector molecules exert tumor cell killing. However, the activation state and clinical relevance of pDCs infiltration in cancer is still largely controversial. In Primary Cutaneous Melanoma (PCM), pDCs density decreases over disease progression and collapses in metastatic melanoma (MM). Moreover, the residual circulating pDC compartment is defective in IFN-α production. The activation of tumor-associated pDCs was evaluated by in silico and microscopic analysis. The expression of human myxovirus resistant protein 1 (MxA), as surrogate of IFN-α production, and proximity ligation assay (PLA) to test dsDNA-cGAS activation were performed on human melanoma biopsies. Moreover, IFN-α and CXCL10 production by in vitro stimulated (i.e. with R848, CpG-A, ADU-S100) pDCs exposed to melanoma cell lines supernatants (SN-mel) was tested by intracellular flow cytometry and ELISA. We also performed a bulk RNA-sequencing on SN-mel-exposed pDCs, resting or stimulated with R848. Glycolytic rate assay was performed on SN-mel-exposed pDCs using the Seahorse XFe24 Extracellular Flux Analyzer. Based on a set of microscopic, functional and in silico analyses, we demonstrated that the melanoma milieu directly impairs IFN-α and CXCL10 production by pDCs via TLR-7/9 and cGAS-STING signaling pathways. Melanoma-derived immunosuppressive cytokines and a metabolic drift represent relevant mechanisms enforcing pDC-mediated melanoma escape. These findings propose a new window of intervention for novel immunotherapy approaches to amplify the antitumor innate immune response in cutaneous melanoma (CM).

Exploring cytokine dynamics in tuberculosis: A comparative analysis of patients and controls with insights from three-week antituberculosis intervention.

Despite developing new diagnostics, drugs, and vaccines, treating tuberculosis (TB) remains challenging. Monitoring inflammatory markers can contribute to more precise diagnostics of TB, identifying its active and latent forms, or monitoring its treatment success. We assessed alterations in plasma levels of 48 cytokines in 20 patients (17 males) with active pulmonary TB compared to age-matched healthy controls (n = 18). Blood samples were collected from individuals hospitalised with TB prior to commencing antibiotic therapy, after the first week, and following the third week. The majority of patients received treatment with a combination of four first-line antituberculosis drugs: rifampicin, isoniazid, ethambutol, and pyrazinamide. Plasmatic cytokine levels from patients three times and controls were analyzed using a Bio-Plex Pro Human Cytokine Screening Panel. The results showed significantly higher levels of 31 cytokines (p<0.05) than healthy controls. Three-week therapy duration showed significantly decreased levels of nine cytokines: interferon alpha-2 (IFN-α2), interleukin (IL) 1 alpha (IL-1α), IL-1 receptor antagonist (IL-1ra), IL-6, IL-10, IL-12 p40, IL-17, leukemia inhibitory factor (LIF), and tumor necrosis factor alpha (TNF-α). Out of these, only levels of IL-1α and IL-6 remained significantly elevated compared to controls. Moreover, we have found a negative correlation of 18 cytokine levels with BMI of the patients but no correlation with age. Our results showed a clinical potential for monitoring the levels of specific inflammatory markers after a short treatment duration. The reduction in cytokine levels throughout the course of therapy could indicate treatment success but should be confirmed in studies with more individuals involved and a longer observation period.