IFN-alpha Research Articles

Efficacy of topical 5-Fluorouracil in the management of ocular surface squamous neoplasia: a study of 101 eyes.

To study the efficacy and side-effect profile of topical 5-Fluorouracil (5-FU) in the treatment of ocular surface squamous neoplasia (OSSN). Retrospective study of 101 eyes of 100 patients treated with 5-FU with one week on and 3weeks off regimen. Of the 100 patients (101 eyes), the mean age at diagnosis of OSSN was 49 (median, 52years; range, 11-87years). History of prior intervention was noted in 6 (6%) eyes. Tumor epicenter included bulbar conjunctiva (n = 54; 53%), limbus (n = 27; 27%), and cornea (n = 20;20%). Mean number of cycles of topical 5-FU administered was 3 (median, 3; range, 1-8). Complete tumor regression was achieved with topical 5-FU in 89 (88%) eyes with a mean number of 2 cycles (median, 2; range, 1-6) of 5-FU. The remaining 12 (12%) lesions underwent additional treatment including excisional biopsy (n = 7), extended enucleation (n = 3), and topical Interferon alpha 2b (n = 2) for complete tumor control. Over a mean follow-up period of 6months (median, 5months; range, 1-36months) following treatment, tumor recurrence was noted in 2 (2%) patients, and side-effects were noted in 7 (7%) eyes including conjunctival hyperemia (n = 1), punctal stenosis (n = 1), sterile keratitis (n = 4), and limbal stem cell deficiency (n = 1). Topical 5-FU is an effective non-invasive therapy for OSSN with a minimal side-effect profile.

Pharmacological correction of immunological disorders in perimenopausal women with recurrent epithelial cervical dysplasia associated with human papillomavirus infection

Despite the successes achieved in implementing screening programs and treating diseases caused by human papillomavirus (HPV) infection, the frequency of cervical intraepithelial neoplasia (CIN) of moderate and high grades associated with high-risk human papillomavirus (HR-HPV) remains between 9% to 21%. Vaginal dysbiosis and the development of immunodeficient states due to persistent HR-HPV infection require effective immunomodulatory and antiviral therapy before cervical surgery in perimenopausal women with recurrent CIN II.The objective: to evaluate the effectiveness of antiviral and immunomodulatory therapy by determining the state of vaginal biocenosis, immunological status and papillomavirus load of the cervical mucosa before surgical treatment in perimenopausal women with recurrent CIN II.Materials and methods. A prospective study was conducted on 98 women aged 40 to 55 years old, including 60 patients with morphologically verified recurrent CIN II associated with high-risk HPV, forming the main group. The control group comprised 38 women with negative HPV test results and without significant gynecological or somatic pathology. In the main group, a complex consisting of a blend of plant extracts of sod pike grass (Deschampsia caespitosa), ground cinquefoil grass (Calamagrostis epigeios), and echinacea purpurea grass (Echinaceae purpureae) was administered orally.Vaginal microbiota was assessed using Hey-Іson criteria, and immunological status was examined in patients using solid-phase enzyme-linked immunosorbent assay to determine IgG, IgM, IgA antibodies in serum and cervical mucus, levels of interleukin-1β (IL-1β), interferons alpha (IFN-α), gamma (IFN-γ), tumor necrosis factor alpha (TNF-α). Additionally, the DNA of high-risk HPV in cervical mucosa was quantitatively assessed using real-time PCR. The investigations were conducted before and after the applied therapy.Results. The investigation of vaginal content revealed the presence of bacterial vaginosis in 65.0% of patients in the main group, the frequency of which decreased by 2 times after treatment, with the number of women with an intermediate type of vaginal content increasing by 2.8 times (51.7%) and those with normal microbiota increasing by 2.5 times. Disruptions in cellular and humoral immunity systems were identified. After treatment, there was an increase in viral load in the significant «threshold» category (3–5 lg) by 1.25 times and in the «above threshold for progression» category (>5 lg) by 2.3 times, reflecting natural HPV clearance. No direct correlation was found between viral load activity and the degree of CIN or positive morphological changes regarding regression of cervical intraepithelial lesions.Conclusions. The use of a complex containing a blend of plant extracts of sod pike grass (Deschampsia caespitosa), ground cinquefoil grass (Calamagrostis epigeios), and echinacea purpurea grass (Echinacea purpureae) improves the state of vaginal biocenosis, indicators of cellular and humoral immunity, and promotes HPV elimination, it has adequate safety and tolerability, which determines the feasibility of its use in the complex treatment of cervical intraepithelial neoplasia at the preparatory stage before surgery and in the postoperative period to prevent complications and relapses.

Plasma interferon-alpha protein levels during pregnancy are associated with lower birth weight in systemic lupus erythematosus.

Adverse pregnancy outcomes are more common in women with systemic lupus erythematosus (SLE) compared with healthy women, but we lack prognostic biomarkers. Plasma interferon alpha (IFNα) protein levels are elevated in a subgroup of pregnant women with SLE, but whether this is associated with pregnancy outcomes is unknown. We investigated the relationship between IFNα, adverse pregnancy outcomes and the presence of autoantibodies in SLE pregnancy. We followed 76 women with SLE prospectively. Protein levels of IFNα were quantified in plasma collected in the 2nd and 3rd trimester with single-molecule array. Positivity for antinuclear and antiphospholipid antibodies was assessed during late pregnancy with multiplexed bead assay. Clinical outcomes included the adverse pregnancy outcomes small for gestational age (SGA), preterm birth, and preeclampsia. During SLE pregnancy, women with SGA infants compared with those without had higher levels of plasma IFNα protein, and IFNα positivity was associated with lower birth weight of the infant. Preterm birth was associated with autoantibodies against chromatin. IFNα protein levels associated positively with autoantibodies against chromatin, Smith/ribonucleoprotein (SmRNP) and RNP, but negatively with phospholipid antibodies. Elevated IFNα protein in plasma of women with SLE is a potential risk factor for lower birth weight of their infants. The association between IFNα and lower birth weight warrants further investigation regarding the pathophysiological role of IFNα during SLE pregnancy.

Exploring the protective association between COVID-19 infection and laryngeal cancer: insights from a Mendelian randomization study.

Viral infections have been implicated as a risk factor for laryngeal cancer. Given the possible effects of Corona virus disease 2019 (COVID-19) on the laryngeal tissue, we investigated the causal link between COVID-19 and laryngeal cancer using a two-sample Mendelian randomization (MR) approach. We utilized genetic data from the 5th Genome-wide association studies (GWAS) edition of the COVID-19 Host Genetics Initiative (published on January 18, 2021) and a large-scale laryngeal cancer GWAS comprising 180 cases and 218,612 controls of European ancestry. We applied inverse variance weighting, MR Egger, and weighted median methods to infer causality. We performed sensitivity analysis using the "leave-one-out" method to verify robustness. We found no evidence of a causal association between gene-predicted COVID-19 and laryngeal cancer [Odds ratio (OR)=0.24 (95% Confidence intervals (CI), 0.05-1.26), P=0.09]. However, we observed significant inverse associations between gene-predicted COVID-19 hospitalization [OR=0.51 (95% CI, 0.28-0.95), P=0.03] and severe patients [OR=0.62 (95% CI, 0.43-0.90), P=0.01] and laryngeal cancer. Notably, the study detected important genetic variants, such as rs13050728, that modulate the expression of interferon alpha receptor 2 (IFNAR2), indicating possible roles for immune response pathways in both COVID-19 and cancer. This study reveals a potential interaction between COVID-19 severity, genetic factors, and laryngeal cancer, underscoring the importance of investigating the immune response mechanisms in both conditions. These findings contribute to the understanding of the complex interactions between COVID-19 and laryngeal cancer and may guide future research on the role of immune response, particularly involving IFNAR2.

Synergic Chemoimmunotherapy of Cervical Cancer by Combining Cisplatin with Thermosensitive Polypeptide Fused Interferon Alpha

AbstractCervical cancer is the fourth most common female malignancy. Surgery and concurrent chemoradiotherapy are the main treatment methods. Although immunotherapy and targeted therapy have made tremendous progress in cancer therapy, they show limited therapeutic effects in treating advanced or recurrent cervical cancer. In this study, a first‐line drug for cervical cancer chemotherapy, cisplatin, is combined with a modified immunomodulatory agent, interferon‐alpha genetically fused to a thermosensitive polypeptide, for synergistic immunochemotherapy of cervical cancer. The unique thermosensitivity of the fusion protein makes it possible to greatly improve the pharmacokinetics of interferon‐alpha, leading to increased tumor accumulation and thus enhanced antitumor efficiency in mice bearing cervical cancers. Moreover, the combination of the fusion protein and cisplatin can inhibit the development of cervical cancer much more effectively than the fusion protein alone, cisplatin alone, or interferon‐alpha plus cisplatin, demonstrating the enhanced synergistic effect of the fusion protein plus cisplatin in cervical cancer immunochemotherapy over interferon‐alpha plus cisplatin. These results show that the synergistic combination of thermosensitive polypeptide fused interferon‐alpha and cisplatin can provide an effective and promising strategy for cervical cancer.

Tofaticinib as a potential therapeutic agent: a review

Tofacitinib is a Food and Drug Administration (FDA) approved second generation immunosuppressive disease-modifying anti-rheumatic drug (DMARD) that is used in the treatment of conditions like rheumatoid arthritis, ulcerative colitis polyarticular course juvenile idiopathic arthritis and psoriatic arthritis. Tofacitinib can be used to treat adult RA patients who are intolerant to methotrexate. At cellular level tofacitinib selectively inhibits Janus kinase (JAKs) in human genome and thereby stops the cytokine receptor-based signalling of interleukins viz., IL2, IL4, IL6, IL7, IL15, IL21, interferon alpha (IFNa) and IFNc in synovial fibroblasts and CD14 monocytes, thereby leading to disruption of immune and inflammatory responses. Tofacitinib is marketed as orally administered conventional tablets (5 mg and 10 mg doses) extended-release tablets (11 mg dose) and oral solutions (1 mg/ml dose). Tofacitinib is quickly absorbed after oral administration with systemic bioavailability of 74%. Tofacitinib is metabolized majorly by CYP3A4 and clearance is 70% via hepatic metabolism and 30% via renal excretion. Half-life of orally administered tofacitinib was observed to be 3 hours. Patients receiving tofacitinib therapy should be monitored for TB, renal impairment, hepatic impairment or any kind of bacterial, viral or fungal infections before initiating or during therapy. Most common reported adverse events of tofacitinib are headache, diarrhoea, nasopharyngitis, sore throat, hypertension and respiratory tract infections. Tofacitinib therapy should be cautiously used in females of reproductive age and in patients receiving renal transplant. Tofacitinib is not recommended with other immunosuppressants and vaccines. Thus, tofacitinib being a potential therapeutic agent the current review elaborates the history, detailed pharmacology, dosing, adverse events, interactions and contraindications of tofacitinib.

Phase 3 study of the lysine-specific demethylase 1 (LSD1) inhibitor bomedemstat in patients with essential thrombocythemia (ET).

TPS6596 Background: ET is a myeloproliferative neoplasm (MPN) driven by mutations in JAK2, CALR, and MPL that is characterized by thrombocytosis and megakaryocyte hyperplasia. Currently available treatments can prevent thrombotic complications but do not substantially alter the natural history of ET. LSD1 is an enzyme that regulates hematopoietic stem and progenitor cell proliferation and is overexpressed in MPNs. In a phase 2 study, the LSD1 inhibitor bomedemstat was generally well tolerated and improved symptoms, durably reduced platelet and white blood cell counts, and reduced mutation burden in patients with ET. Here, we describe the methods for a randomized, open-label, phase 3 study (NCT06079879) that has been designed to evaluate bomedemstat versus best available therapy in patients with ET who had an inadequate response to or were intolerant of hydroxyurea. Methods: Key eligibility criteria include age ≥18 years, a diagnosis of ET per World Health Organization 2016 diagnostic criteria, a bone marrow fibrosis score of grade 0 or 1, a platelet count of >450 x 109/L, and an absolute neutrophil count of ≥0.75 x 109/L. All patients must have a history of inadequate response to or intolerance of hydroxyurea per modified European LeukemiaNet (ELN) criteria. Patients will be randomly assigned 1:1 to bomedemstat 50 mg/day by mouth (starting dose) or investigator’s choice of best available therapy (anagrelide, busulfan, interferon alfa/pegylated interferon alpha, or ruxolitinib). Bomedemstat dose will be titrated to a target platelet count of ≥150 to ≤350 x 109/L. After 52 weeks, patients receiving best available therapy can cross over to bomedemstat at the investigator’s discretion and patients in the bomedemstat arm can continue on treatment (maximum of 156 weeks on study). Randomization will be stratified by hydroxyurea history (inadequate response vs intolerance) and MFSAF v4.0 baseline score (≥4 vs <4). Clinic visits will occur every 2 weeks until week 12 and monthly thereafter. Adverse events will be graded per NCI CTCAE v5.0 criteria and monitored for up to 30 days after last dose of study drug. The primary end point is durable clinicohematologic response rate per modified ELN criteria. Secondary end points are duration of clinicohematologic response, duration of hematologic remission, change from baseline in total symptom and fatigue score per MFSAF v4.0 criteria, change from baseline in total fatigue score per the PROMIS Fatigue SF-7a scale, incidence of thrombotic or major hemorrhagic events, transformation to post-ET myelofibrosis or myelodysplastic syndrome/acute myeloid leukemia, event-free survival, and safety. Exploratory end points include pharmacokinetics, the proportion of patients reporting stability or improvement versus decline on the MSAF v4.0 and PROMIS Fatigue SF-7a domains, and molecular biomarkers. Approximately 300 patients will be enrolled. Clinical trial information: NCT06079879 .

The immunomodulatory impacts of endocrine therapy on host immunity in early-stage hormone receptor positive, HER2 negative breast cancer.

572 Background: Endocrine therapy (ET) reduces mortality in hormonally driven breast cancer (BC). The impacts of ET on the estrogen receptor are well known; however, there is limited data on the impact of ET on the host's immune system. This project aims to elucidate the potential immunomodulatory effects of ET-induced estrogen deprivation in HR+/HER2 negative early-stage breast cancer patients (pts) as well as baseline differences between BC pts and healthy controls (HC). Methods: Pts with Stage I-III HR+/HER2- BC initiating ET after completion of local regional therapy and/or chemotherapy were enrolled (NCT03719495). Whole blood, E1 (estrone) and E2 (estradiol) levels were collected at baseline (T1), 4 weeks (T2), 12 weeks (T3) and 24 weeks (T4) after ET initiation. 5 cohorts were enrolled: premenopausal and postmenopausal HCs, premenopausal pts on tamoxifen (TAM) or aromatase inhibitors (AIs) plus ovarian suppression, postmenopausal pts on AIs. Bulk RNA sequencing of whole blood was performed using NuGEN mRNA-seq on the Illumina Nova-seq platform. Differential expression analysis was performed using DESeq2 between HC and ET groups at T1, and between T1 and T4 within BC pts. The Benjamini-Hochberg method was used to adjust the P values for multiple comparisons. A curated set of 192 immune related gene signatures was used in the gene signature analysis. For each signature/module, a score was computed by taking the median of the expression values from all genes in each gene signature. CIBERSORT analysis was performed using the LM22 signature gene file and 100 permutations. Paired t-test was performed to compare T1 and T4. Results: Between 2019 and 2023, 64 pts were enrolled. Pts with missing samples or prior chemotherapy were excluded in this analysis. T1 samples of 25 pts with BC versus 14 HCs revealed marked changes in circulating immune cell (IC) composition with 537 DEGs (p value < 0.05). Circulating ICs in BC pts had marked upregulation of genes associated with oxidative phosphorylation, adipogenesis, interferon alpha, reactive oxygen species compared to HCs. Immune cell composition was inferred by CIBERSORT analysis which suggests that BC pts had fewer circulating naïve B cells (p=0.048) whereas regulatory T cells (p=0.025) and activated NK cells (p=0.0039) were higher in BC pts than HCs at T1. BC pts with reductions in E1/E2 levels 6 months after ET had 77 DEGs in PBMCs between T1 and T4. Gene signature analysis shows that B cells and NK cells (p=0.0077) signatures are elevated post ET whereas a reduction of neutrophil signature (p=0.0034) was noted. Conclusions: There are significant differences in the baseline IC repertoire/activity in BC pts compared to HCs. The reduction in B cell activity/number and an increase in regulatory T cell number suggests a possible compromised immune system in BC pts. After surgery and 6 months of ET, these suppressed immune phenotypes reversed. Clinical trial information: NCT03719495 .

A phase 1/1b first-in-human (FIH) study of JZP898 as monotherapy and in combination with pembrolizumab in adult patients with advanced or metastatic solid tumors.

TPS3190 Background: JZP898 is a conditionally activated prodrug of interferon alpha (IFNα) that can preferentially deliver IFNα to the tumor microenvironment while potentially minimizing systemic IFNα therapy-associated toxicity. Antitumor activity of IFNα is well-established, but concerns regarding systemic toxicity restrict its use in clinical practice. JZP898, in combination with a checkpoint inhibitor such as pembrolizumab, may provide lasting and potent antitumor activity with minimal additive toxicity attributed to conventional or pegylated IFNα. This phase 1 FIH study will determine a maximum tolerated dose (MTD)/recommended dose (RD) and investigate safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary antitumor activity of JZP898 monotherapy and JZP898 combined with pembrolizumab in adult patients with advanced or metastatic solid tumors. Methods: This phase 1, FIH, open-label, multicenter study (NCT06108050) is investigating JZP898 intravenous infusion in adult patients (≥18 years old) with histological or cytological diagnosis of advanced or metastatic solid tumors, European Cooperative Oncology Group performance status ≤1, and measurable disease per RECIST v1.1 criteria. The study consists of a dose finding phase (JZP898 as monotherapy and in combination with pembrolizumab; Part A) and a combination dose expansion phase (JZP898 in combination with pembrolizumab; Part B). In Part A (dose finding), the JZP898 MTD and/or monotherapy RD will be determined using Bayesian optimal interval (BOIN) design based on the incidence of dose-limiting toxicities (DLTs) and all available safety and PK data; the combination recommended phase 2 dose (RP2D) will be determined using BOIN criteria and all available safety, PK/PD, immunogenicity, and preliminary signal of antitumor activity data. Patients will be treated until disease progression, death, unacceptable toxicity, or withdrawal from the study. All patients will be followed for survival until 18 months after the last patient starts study intervention. Primary endpoints include: the incidence and nature of DLTs (Part A); investigator-assessed objective response rate (ORR) per RECIST v1.1 (Part B); the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events; changes in laboratory values or vital signs; and the incidence of dose modifications or discontinuations due to TEAEs. Secondary endpoints include: PK parameters; incidence of antidrug antibodies; investigator-assessed duration of response; progression-free survival; disease control rate; investigator-assessed ORR (Part A); and overall survival (Part B). The study is actively enrolling patients with a planned enrollment of up to 177 patients. Clinical trial information: NCT06108050 .

Pan-cancer analysis of CDKN2A alterations identifies a subset of gastric cancer with a cold tumor immune microenvironment

BackgroundAlthough CDKN2A alteration has been explored as a favorable factor for tumorigenesis in pan-cancers, the association between CDKN2A point mutation (MUT) and intragenic deletion (DEL) and response to immune checkpoint inhibitors (ICIs) is still disputed. This study aims to determine the associations of CDKN2A MUT and DEL with overall survival (OS) and response to immune checkpoint inhibitors treatment (ICIs) among pan-cancers and the clinical features of CDKN2A-altered gastric cancer.MethodsThis study included 45,000 tumor patients that underwent tumor sequencing across 33 cancer types from four cohorts, the MSK-MetTropism, MSK-IMPACT, OrigiMed2020 and TCGA cohorts. Clinical outcomes and genomic factors associated with response to ICIs, including tumor mutational burden, copy number alteration, neoantigen load, microsatellite instability, tumor immune microenvironment and immune-related gene signatures, were collected in pan-cancer. Clinicopathologic features and outcomes were assessed in gastric cancer. Patients were grouped based on the presence of CDKN2A wild type (WT), CDKN2A MUT, CDKN2A DEL and CDKN2A other alteration (ALT).ResultsOur research showed that CDKN2A-MUT patients had shorter survival times than CDKN2A-WT patients in the MSK MetTropism and TCGA cohorts, but longer OS in the MSK-IMPACT cohort with ICIs treatment, particularly in patients having metastatic disease. Similar results were observed among pan-cancer patients with CDKN2A DEL and other ALT. Notably, CDKN2A ALT frequency was positively related to tumor-specific objective response rates to ICIs in MSK MetTropism and OrigiMed 2020. Additionally, individuals with esophageal carcinoma or stomach adenocarcinoma who had CDKN2A MUT had poorer OS than patients from the MSK-IMPACT group, but not those with adenocarcinoma. We also found reduced levels of activated NK cells, T cells CD8 and M2 macrophages in tumor tissue from CDKN2A-MUT or DEL pan-cancer patients compared to CDKN2A-WT patients in TCGA cohort. Gastric cancer scRNA-seq data also showed that CDKN2A-ALT cancer contained less CD8 T cells but more exhausted T cells than CDKN2A-WT cancer. A crucial finding of the pathway analysis was the inhibition of three immune-related pathways in the CDKN2A ALT gastric cancer patients, including the interferon alpha response, inflammatory response, and interferon gamma response.ConclusionsThis study illustrates the CDKN2A MUT and DEL were associated with a poor outcome across cancers. CDKN2A ALT, on the other hand, have the potential to be used as a biomarker for choosing patients for ICI treatment, notably in esophageal carcinoma and stomach adenocarcinoma.

Sézary Syndrome in West Sweden: Exploring Epidemiology, Clinical Features, and Treatment Patterns in a Registry-Based Retrospective Analysis.

Sézary syndrome (SS) is a rare primary cutaneous T-cell lymphoma variant. Despite various treatment options, it remains incurable, with a poor prognosis. There is an urgent need for additional descriptive research to enhance our understanding and treatment of SS. The aim of this retrospective register-based study was to outline patients' demographic characteristics; investigate the clinical, histopathological, and molecular findings; and assess treatment effectiveness with a focus on time to next treatment (TTNT) and disease progression. Data on 17 patients with SS were obtained from the primary cutaneous lymphoma register in West Sweden between 2012 and 2024. The results revealed that not all patients exhibited the classical triad of symptoms at diagnosis, emphasizing the need for personalized diagnostic approaches. The median survival was only 2.1 years, which reflects the aggressive nature of SS. The longest median TTNT was observed in triple therapy involving retinoids, interferon alpha, and extracorporeal photopheresis (ECP). There was no significant difference in TTNT between various lines of treatment. Early initiation of ECP treatment did not result in improved outcomes. This study highlights the importance of combination therapy for improved outcomes and underscores the need for future studies to identify optimal treatment approaches.

Systematic Review: JAK-STAT Regulation and Its Impact on Inflammation Response in ARDS from COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has had a global impact and resulted in millions of deaths worldwide. The course of the Janus kinase signaling transducers and activators (JAK-STAT) pathway is an important molecular pathway that is involved in the cellular response to various cytokines and growth factors promoting an inflammatory response. The overactivation of the JAK-STAT signaling pathway in coronavirus disease 2019 (COVID-19) and its effect on acute respiratory distress syndrome (ARDS)-induced inflammatory processes was observed in various clinical articles that focused on JAK-STAT regulation regarding angiotensin converting enzyme 2 (ACE2) expression and cytokine storm release. Down-regulation of the JAK-STAT signaling pathway through inhibitors decreases the inflammatory response by decreasing cytokine storm release. However, the increased regulation of JAK-STAT in severe COVID-19 patients caused cytokines such as interferon alpha (IFN-α) to promote the phosphorylation of STATs. This response indicated an imbalance with JAK-STAT regulation and its inability to induce the transcription of interferon stimulated response elements. Furthermore, an increase in ACE2 regulation was noted to also increase JAK-STAT signaling, yet the down-regulation of JAK-STAT signaling can result in the overexpression of ACE2 by binding to SARS-CoV-2 and increasing STAT1 expression. Data suggest that inflammatory cytokines enhance the activation of ACE2 in endothelial cells via JAK-STAT pathway. Increasing the regulation of the JAK-STAT signaling pathway enhances the release of cytokines such as tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), further expressing ACE2. The expression of ACE2 regulates STAT1 and STAT2 expression, leading to the up-regulation of the inflammasomal complexes in hyper-inflammatory responses from the JAK-STAT pathway. Through the review of various clinical reports, the effect of the JAK-STAT signaling pathway on ARDS-induced inflammatory response was observed and correlated with the expression of ACE2 and cytokine storm release in severe COVID-19 cases.

Interferon-induced polarization of M1 macrophages mediates antiviral activity against the hepatitis B virus via the hepcidin-ferroportin axis

Backgrounds & aimsGiven its ability to inhibit HBV replication, Interferon alpha (IFN-α) treatment has been confirmed to be effective in managing Chronic Hepatitis B (CHB). However, its underlying mechanisms are incompletely understood. MethodsHerein, we investigated the antiviral properties of IFN-α by introducing IFN-α expression plasmids into a well-established HBV Hydrodynamic Injection (HDI) mouse model and examined the impact of IFN-α or hepcidin treatment on macrophages derived from THP-1 cells. The cytokine profiles were analyzed using the cytometry microsphere microarray technology, and flow cytometry was used to analyze the polarization of macrophages. Additionally, the IL-6/JAK2/STAT3 signaling pathway and the hepcidin-ferroportin axis were analyzed to better understand the macrophage polarization mechanism. ResultsAs evidenced by the suppression of HBV replication, injection of an IFN-α expression plasmid and supernatants of IFN-α-treated macrophages exerted anti-HBV effects. The IFN-α treatment up-regulated IL-6 in mice with HBV replication, as well as in IFN-α-treated HepG2 cells and macrophages. Furthermore, JAK2/STAT3 signaling and hepcidin expression was promoted, inducing iron accumulation via the hepcidin-ferroportin axis, which caused the polarization of M1 macrophages. Furthermore, under the effect of IFN-α, IL-6 silencing or blockade downregulated the JAK2/STAT3 signaling pathway and hepcidin, implying that increased hepcidin expression under IFN-α treatment was dependent on the IL-6/JAK2/STAT3 pathway. ConclusionThe IL-6/JAK2/STAT3 signaling pathway is activated by IFN-α which induces hepcidin expression. The resulting iron accumulation then induces the polarization of M1 macrophages via the hepcidin-ferroportin axis, yielding an immune response which exerts antiviral effects against HBV replication.

Evaluation of intralesional 5-fluorouracil versus intralesional interferon alpha in treatment of warts

Background: Warts are non-malignant growth of the skin and mucous membranes resulting from infection with human papillomavirus (HPV). It can significantly impact the quality of life for patients and elicit feeling of embarrassment. Aim and objectives: A comparative analysis of the efficacy of intralesional 5-FU and intralesional interferon alpha among distinct groups of patients diagnosed with warts. Patients and methods: This is a cohort of sixty individuals diagnosed with warts were selected from the period of early April 2022 to the end of April 2023. Results: There was a statistically significant difference (P-value=0.005) seen between the two groups, namely group A and group B, in relation to the final response. In group A (5-Fluorouracil)), complete clearance was achieved by 23 patients (76.7%), with 7 patients (23.3%) showing partial response. No instances of resistance were observed in this group. Conversely, in group B (Interferon alpha), only 11 patients (36.7%) attained complete clearance, while 16 patients (53.3%) exhibited partial response, and resistance was evident in 3 cases (10%). Conclusion: Intralesional 5-Fluorouracil (5-FU) is highly effective, cheaper, and easily available in treating warts. The combination of the both treatments may deliver a greater benefit to patients with resistant warts.

A novel vaccine strategy against Brucellosis using Brucella abortus multi-epitope OMPs vaccine based on Lactococcus lactis live bacterial vectors

Brucella infections typically occur in mucosal membranes, emphasizing the need for mucosal vaccinations. This study evaluated the effectiveness of orally administering Lactococcus lactis (L. lactis) for producing the Brucella abortus multi-epitope OMPs peptide. A multi-epitope plasmid was generated through a reverse vaccinology method, and mice were administered the genetically modified L. lactis orally as a vaccine. The plasmid underwent digestion, synthesizing a 39 kDa-sized protein known as OMPs by the target group. The sera of mice that were administered the pNZ8124-OMPs-L. lactis vaccine exhibited a notable presence of IgG1 antibodies specific to outer membrane proteins (OMPs), heightened levels of interferon (IFN-λ) and tumor necrosis factor alpha (TNF-α), and enhanced transcription rates of interleukin 4 (IL-4) and interleukin 10 (IL-10). The spleen sections from the pNZ8124-OMPs-L. lactis and IRIBA group had less morphological damage associated with inflammation, infiltration of lymphocytes, and lesions to the spleen. The findings present a novel approach to utilizing the food-grade, non-pathogenic L. lactis as a protein cell factory to synthesize innovative immunological candidate OMPs. This approach offers a distinctive way to evaluate experimental medicinal items' practicality, safety, affordability, and long-term sustainability.

Abstract PO5-15-09: DNA damage induced necroptosis predicts response to radioimmunotherapy

Abstract Background: More than half of all cancer patients receive radiotherapy (RT) during their cancer experience. DNA damage induced by RT can initiate a pro-inflammatory immune response within the tumor microenvironment (TME), yet this response is not uniformly observed across all tumors. Mre11 is one of the first responders to double stranded breaks and coordinates the DNA damage response. Recent work in our lab reveals that Mre11 is required for cGAS mediated detection of cytoplasmic DNA, in turn activating STING to engage the type I interferon signaling pathway, downstream of which can activate ZBP1/RIPK3/MLKL mediated necroptosis. The purpose of this study is to determine if expression of the necroptotic pathway may predict whether breast tumors benefit from RT to overcome ICI resistance and induce systemic anti-tumor immunity in the form of an abscopal response. Methods: Four Trp53-/- Balb/c breast cancer syngeneic allograft models with low tumor mutational burden and resistance to dual ICI (anti-PD1 and anti-CTLA4, BioXcell) were used. Mice were implanted with bilateral tumors and randomly divided into four treatment cohorts: untreated, RT, ICI, or RT+ICI, where RT (8Gyx3) was administered to one tumor. Two lines exhibited abscopal responses to RT+ICI (i.e., “abscopal models”), whereas the other two did not (i.e., “non-abscopal models”). To identify gene expression patterns associated with abscopal responding breast tumors, we performed spatial transcriptomic analysis of tumors 10 days after initiating treatment using the GeoMx whole transcriptome assay targeting panCK+ tumor cells and tumor adjacent CD45+ immune cells (N >5 for each treatment group and tumor type). Unsupervised hierarchical clustering was performed to identify gene expression patterns across areas of interest. Genes selectively induced by RT+ICI in abscopal models that were not induced in non-abscopal models were identified using two-tailed t-test and FDR correction for multiple testing (FDR< 5%). DeSEQ2 and GSEA analysis were performed using publicly available mouse gene sets (Broad Institute). Results: The TME in untreated tumors in the abscopal models demonstrate upregulation in the B cell survival pathway and apoptotic pathways compared to untreated tumors in non-abscopal models. Hierarchical clustering of immune related genes in CD45+ segments of RT+ICI treated tumors exhibiting an abscopal response revealed a global shift in gene expression profiles after treatment. GSEA analysis of CD45+ segments from abscopal models shows that RT+ICI treatment results in enrichment of the interferon mediated signaling pathway including interferon alpha (p< 0.0001), interferon beta (p< 0.0001), type II interferon response (p< 0.0001), and antigen processing and presentation (p< 0.0001). In tumor cells of breast cancers demonstrating the abscopal response, Isg15 and Zbp1 are highly induced by RT+ICI. The necroptotic pathway, including Zbp1, Ripk3, and Mlkl, are significantly higher expressed in the panCK+ tumors known to demonstrate the abscopal response. Conclusion: Breast cancer models with an abscopal response to RT+ICI demonstrate higher expression of Isg15 and Zbp1, both of which are involved in secreted inflammatory signaling. The TME in these models have increased interferon signaling and antigen presentation in response to RT+ICI. The role of DNA damage induced necroptosis in generating an abscopal response in breast cancer warrants further investigation as a potential biomarker for response to RT+ICI combination therapy. Citation Format: Anna Goddard, Qinhong Wang, Minguk Cho, Lynn Lerner, Gaorav Gupta. DNA damage induced necroptosis predicts response to radioimmunotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-15-09.

Complication of the use of bleomycin in the management of cystic craniopharyngioma: case report

Complication of the use of bleomycin in the management of cystic craniopharyngioma: case report

Regulation of interferon alpha production by MAGUK-family protein CASK in H5N1-infected Macrophage

Regulation of interferon alpha production by MAGUK-family protein CASK in H5N1-infected Macrophage

Targeted siRNA Therapy for Psoriasis: Translating Preclinical Potential into Clinical Treatments.

Psoriasis is a chronic inflammatory skin disease characterized by the excessive proliferation of keratinocytes and heightened immune activation. Targeting pathogenic genes through small interfering RNA (siRNA) therapy represents a promising strategy for the treatment of psoriasis. This mini-review provides a comprehensive summary of siRNA research targeting the pathogenesis of psoriasis, covering aspects such as keratinocyte function, inflammatory cell roles, preclinical animal studies, and siRNA delivery mechanisms. It details recent advancements in RNA interference that modulate key factors including keratinocyte proliferation (Fibroblast Growth Factor Receptor 2, FGFR2), apoptosis (Interferon Alpha Inducible Protein 6, G1P3), differentiation (Grainyhead Like Transcription Factor 2, GRHL2), and angiogenesis (Vascular Endothelial Growth Factor, VEGF); immune cell infiltration and inflammation (Tumor Necrosis Factor-Alpha, TNF-α; Interleukin-17, IL-17); and signaling pathways (JAK-STAT, Nuclear Factor Kappa B, NF-κB) that govern immunopathology. Despite significant advances in siRNA-targeted treatments for psoriasis, several challenges persist. Continued scientific developments promise the creation of more effective and safer siRNA medications, potentially enhancing the quality of life for psoriasis patients and revolutionizing treatments for other diseases. This article focuses on the most recent research advancements in targeting the pathogenesis of psoriasis with siRNA and explores its future therapeutic prospects.

Homeostatic Type I IFN Response at the Placenta Contributes to Sex-biased Neurodevelopmental Outcome

Abstract The maternal-fetal interface, placenta, plays pivotal roles in fetal development. Recent evidence shows that the placenta contributes to the sex-biased prevalence of some developmental disorders such as neurodevelopmental disorders. Commencing an exploration into the molecular intricacies of fetal sex-specific transcriptional changes within the placenta, our study leveraged single-cell RNA sequencing. We uncovered a diminished expression of interferon (IFN)-responsive genes (ISGs) in male fetus-associated trophoblasts compared to female, which have pivotal roles in the process of spiral artery remodeling. We further found maternal NK cells associated with male fetus placenta showed a reduction in the interferon production pathway. The introduction of maternal immune activation (MIA), which induces neurodevelopmental abnormalities in male offspring, it reversed these sex-specific disparities in the placenta. In pursuit of unraveling the potential link between sex-specific ISGs expression and neurodevelopmental outcomes in MIA offspring, we selectively removed IFN alpha and beta receptor subunit 1 (IFNAR1) in a trophoblast-specific manner. Blunting IFNAR1 in the placenta protected male offspring from MIA-induced behavioral abnormalities. Our data suggests the intricate landscape of sex-specific IFN response at the maternal-fetal interface and underscore its role in shaping the sex-bias observed in MIA-induced neurodevelopmental phenotypes.