Explore the vast range of titles available.

Accurate screening of COVID-19 infection status for symptomatic patients is a critical public health task. Although molecular and antigen tests now exist for COVID-19, in resource-limited settings, screening tests are often not available. Furthermore, during the early stages of the pandemic tests were not available in any capacity. We utilized an automated machine learning (ML) approach to train and evaluate thousands of models on a clinical dataset consisting of commonly available clinical and laboratory data, along with cytokine profiles for patients (n = 150). These models were then further tested for generalizability on an out-of-sample secondary dataset (n = 120). We were able to develop a ML model for rapid and reliable screening of patients as COVID-19 positive or negative using three approaches: commonly available clinical and laboratory data, a cytokine profile, and a combination of the common data and cytokine profile. Of the tens of thousands of models automatically tested for the three approaches, all three approaches demonstrated > 92% sensitivity and > 88 specificity while our highest performing model achieved 95.6% sensitivity and 98.1% specificity. These models represent a potential effective deployable solution for COVID-19 status classification for symptomatic patients in resource-limited settings and provide proof-of-concept for rapid development of screening tools for novel emerging infectious diseases.

Maintenance immunotherapy is effective in AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD), but how mechanistically distinct maintenance therapies organize the remission immune landscape and its relationship to neurological disability remains poorly defined. We performed integrated multiparameter flow cytometry and plasma cytokine profiling in serial remission samples (up to three per patient) from 28 patients receiving rituximab (RTX, n = 14) or azathioprine (AZA, n = 14). Between-treatment comparisons, within-treatment coupling analyses, and disability-associated immune analyses were conducted using age-adjusted patient-clustered regression models with prespecified false discovery rate control. RTX showed clear target engagement, characterized by profound B-cell depletion, gradual post-infusion reconstitution, and sustained reduction of natural killer T (NKT)-like cells. Beyond lineage depletion, RTX was associated with regulatory remodeling, including a memory-skewed regulatory T (Treg) phenotype and a lower effector-to-regulatory balance. In B-detectable RTX samples, the reconstituting B-cell compartment was transitional/naive-skewed with marked suppression of memory B cells. Although remission-phase cytokines were broadly low, interferon gamma-induced protein 10/CXC motif chemokine ligand 10 (IP-10/CXCL10) remained selectively elevated under RTX. Importantly, remission immune architecture differed by therapy: AZA showed a T cell immunoreceptor with Ig and ITIM domains (TIGIT)-linked regulatory disability axis, whereas RTX showed disability coupling to soluble inflammatory mediators, particularly interleukin-6 (IL-6) and IP-10. Mechanistically distinct maintenance therapies impose divergent remission immune architectures in NMOSD. These findings support a treatment-aware framework for biomarker interpretation and suggest that remission monitoring should consider therapy-specific immune networks rather than isolated immune markers.

ABSTRACT Several factors are associated with the progression of chronic hepatitis C: comorbidities, lifestyle, and pathogenic factors, including immune response, apoptosis and heredity. Single nucleotide polymorphisms (SNPs) in the PNPLA3 and TM6SF2 genes are more widely studied genetic risk factors, while CXCL9–11 chemokines produced by hepatocytes in the process of infection are less well studied. Our aim was to evaluate the influence of CXCL9 rs10336, CXCL10 rs3921 and CXCL11 rs4619915 in liver fibrosis when analysed together with PNPLA3 rs738409 and TM6SF2 rs58542926. The study included 219 patients with chronic hepatitis C. SNP genotyping was performed by real-time PCR. Univariate and multivariate analyses were used to detect the association between SNPs and advanced fibrosis in a recessive genetic model. All SNPs had a minimum allele frequency >5%, and CXCL9 rs10336, CXCL10 rs3921 and CXCL11 rs4619915 were in high linkage disequilibrium (D′ ≥ 0.84). In the multivariate analysis, we observed that male gender (P = 0.000), older age (P = 0.025), moderate to intense inflammatory activity (P = 0.002), moderate to accentuated hepatic steatosis (P = 0.026) and the CT genotype of the TM6SF2 rs58542926 SNP (P = 0.014) presented significant associations with advanced fibrosis. Overall, the CXCL9 rs10336, CXCL10 rs3921, CXCL11 rs4619915 and PNPLA3 rs738409 SNPs did not influence liver fibrosis among patients with chronic hepatitis C. Exploratory studies comprising possible host biomarkers involved in hepatitis C virus infection are essential to assess and understand the progression of this chronic liver disease.

IP-10 (also called CXCL10) plays a significant role in leukocyte homing to inflamed tissues, and increased IP-10 levels are associated with the pathologies of various inflammatory disorders, including type 2 diabetes, atherosclerosis, and cancer. TNF-α is a potent activator of immune cells and induces inflammatory cytokine expression in these cells. However, it is unclear whether TNF-α is able to induce IP-10 expression in MCF-7 breast cancer cells. We therefore determined IP-10 expression in TNF-α-treated MCF-7 cells and investigated the mechanism involved. Our data show that TNF-α induced/upregulated the IP-10 expression at both mRNA and protein levels in MCF-7 cells. Inhibition of JNK (SP600125) significantly suppressed the TNF-α-induced IP-10 in MCF-7 cells, while the inhibition of p38 MAPK (SB203580), MEK1/2 (U0126), and ERK1/2 (PD98059) had no significant effect. Furthermore, TNF-α-induced IP-10 expression was abolished in MCF-7 cells deficient in JNK. Similar results were obtained using MCF-7 cells deficient in c-Jun. Moreover, the JNK kinase inhibitor markedly reduced the TNF-α-induced JNK and c-Jun phosphorylation. The kinase activity of JNK induced by TNF-α stimulation of MCF-7 cells was significantly inhibited by SP600125. Altogether, our novel findings provide the evidence that TNF-α induces IP-10 expression in MCF-7 breast cancer cells via activation of the JNK/c-Jun signaling pathway.

Objectives: To identify peripheral blood autoantibody and cytokine profiles that characterise clinically relevant subgroups of patients with early rheumatoid arthritis using arthritis antigen microarrays and a multiplex cytokine assay. Methods: Serum samples from 56 patients with a diagnosis of rheumatoid arthritis of <6 months’ duration were tested. Cytokine profiles were also determined in samples from patients with psoriatic arthritis (PsA) and ankylosing spondylitis (n = 21), and from healthy individuals (n = 19). Data were analysed using Kruskal–Wallis test with Dunn’s adjustment for multiple comparisons, linear correlation tests, significance analysis of microarrays (SAM) and hierarchical clustering software. Results: Distinct antibody profiles were associated with subgroups of patients who exhibited high serum levels of tumour necrosis factor (TNF)α, interleukin (IL)1β, IL6, IL13, IL15 and granulocyte macrophage colony-stimulating factor. Significantly increased autoantibody reactivity against citrullinated epitopes was observed in patients within the cytokine “high” subgroup. Increased levels of TNFα, IL1α, IL12p40 and IL13, and the chemokines eotaxin/CCL11, monocyte chemoattractant protein-1 and interferon-inducible protein 10, were present in early rheumatoid arthritis as compared with controls (p<0.001). Chemokines showed some of the most impressive differences. Only IL8/CXCL8 concentrations were higher in patients with PsA/ankylosing spondylitis (p = 0.02). Conclusions: Increased blood levels of proinflammatory cytokines are associated with autoantibody targeting of citrullinated antigens and surrogate markers of disease activity in patients with early rheumatoid arthritis. Proteomic analysis of serum autoantibodies, cytokines and chemokines enables stratification of patients with early rheumatoid arthritis into molecular subgroups.

Interferon-γ-inducible protein 10 is a potent chemoattractant for natural killer cells and activated T lymphocytes. It also displays angiostatic properties and some antitumor activity. Tumor necrosis factor-α (TNF-α) is a powerful immunomodulating cytokine with demonstrated tumoricidal activity in various tumor models and the ability to induce strong immune responses. This prompted us to evaluate the antitumor effects of recombinant parvoviruses designed to deliver IP-10 or TNF-α into a glioblastoma. When Gl261 murine glioma cells were infected in vitro with an IP-10- or TNF-α-transducing parvoviral vector and were subcutaneously implanted in mice, tumor growth was significantly delayed. Complete tumor regression was observed when the glioma cells were coinfected with both the vectors, demonstrating synergistic antitumor activity. In an established in vivo glioma model, however, repeated simultaneous peritumoral injection of the IP-10- and TNF-α-delivering parvoviruses failed to improve the therapeutic effect as compared with the use of a single cytokine-delivering vector. In this tumor model, cytokine-mediated immunostimulation, rather than inhibition of vascularization, is likely responsible for the therapeutic efficacy.

Chemokines are chemotactic cytokines controlling the recruitment of leukocytes from the blood by regulating integrin adhesiveness. It has been shown that the migration of CD4+Th1 and CD4+Th2 cells is governed by specific chemokines. Increasing evidence suggests that the CD4+Th1 cheomoattractant chemokine CXCL10, also termed Interferon (IFN)-gamma -inducible protein (IP)-10 is pathogenetically involved in several immunoinflammatory and autoimmune diseases. IFN-gamma and IP-10 were quantified by solid-phase ELISA in sera of patients with either newly diagnosed or long-term Type I (insulin-dependent) diabetes mellitus, and in sera of their healthy first degree relatives. The latter were subdivided into \"low\" and \"high\" risk prediabetic subjects depending on whether they were negative or positive for the anti-beta-cell autoantibodies ICA and GAD. Compared with healthy control subjects (18%, 9/50), those with a low risk of disease (21%, 5/24) and the group of patients with long-term Type I diabetes (24%, 12/50), IP-10 was found more frequently and at increased concentrations in both newly diagnosed Type I diabetic patients (84%, 42/50) and in those with a high risk of disease (73%, 16/22); in the latter, the IP-10 concentrations correlated with those of IFN-gamma. Circulating IP-10 concentrations is increased in patients with Type I diabetes, but only during the early and subclinical stage of the disease.

Objective This study investigates the effects of dipyrithione (PTS2) on the expression of IP-10/CXCL10, which has been observed in a wide variety of chronic inflammatory disorders and autoimmune conditions. Methods RAW264.7 cells (a murine macrophage-like cell line) were cultured in the absence or in the presence of PTS2 (3-10 μM) together with or without IFN-γ (10 ng/ml). IP-10/CXCL10 expression was measured by specific enzyme-amplified immunoassays and reverse transcriptase-PCR (RT-PCR). Phosphorylation of JAK1, JAK2 and STAT1 were detected by Western blot analysis. Results We found that PTS2 inhibited IFN-γ-induced up-regulation of IP-10/CXCL10 protein level in a dose- and time-dependent manner in RAW264.7 cells. RT-PCR experiments showed that PTS2 suppressed IFN-γ-induced IP-10/CXCL10 expression at mRNA levels. Mechanistically, PTS2 prevented phosphorylation of JAK1, JAK2 and STAT1, but did not interfere with the p38 pathway. Furthermore, the inhibitory effect of PTS2 on IP-10/CXCL10 up-regulation was slightly stronger than JAK2 inhibitor AG490. Conclusion PTS2 inhibits IFN-γ-induced IP-10/CXCL10 expression in RAW264.7 cells by targeting the JAK/STAT1 signaling pathway, suggesting that PTS2 could exert anti-inflammatory effects through attenuating the formation of chemokine IP-10/CXCL10.