Multiple studies have identified that complement becomes activated during inflammation of the intestines yet it is unclear what roles the split complement molecules play. The epithelium, in particular, may be impacted and accordingly, we first discovered that colonic cell lines indeed possess the C5aR. Here we examined whether these cells also possess the C3aR. We determined that T84, HT-29 and Caco2 all possess C3aR mRNA and protein; T84 and HT29 were used to further explore the consequence of C3a binding the C3aR. C3a led to increased mRNA for CXCL2, CXCL8 and CXCL11. Polarized T84 monolayers responded to apically applied C3a with increased CXCL8 mRNA more rapidly than if the C3a was applied basolaterally. Polarized monolayers also increased permeability when treated with C3a. ERK1/2 was activated by C3a and the increase in CXCL8 mRNA was ERK-dependent in both T84 and HT-29. C3a resulted in activation of Gαi, determined by the ERK1/2 signal showing sensitivity to pertussis toxin. The transmembrane signal was further mapped to include Ras and c-Raf. Finally, we show that the C3aR is expressed by primary cells in mouse enteroids. We conclude that complement activation will contribute to the epithelial response during inflammation through C3a binding to the C3aR including by priming the cells to upregulate mRNA for selected chemokines.

Malnutrition, due to low body mass index (LBMI), is considered to be one of the key risk factors for tuberculosis (TB) development. The link between pro and anti-inflammatory cytokines and BMI has been studied in active pulmonary TB. However, the association of BMI with cytokines and chemokines in TB lymphadenitis (TBL) has not been examined. Hence, we wanted to examine the plasma levels of different cytokines and chemokines in TBL individuals with LBMI, normal BMI (NBMI) and high BMI (HBMI). LBMI with TBL disease is associated with enhanced systemic levels of type 1 (tumor necrosis factor alpha [TNFα], interleukin-2 [IL-2]) and type 2 (IL-4, IL-13) cytokines in comparison with NBMI and/or HBMI. However, other pro-inflammatory (IFNγ, IL-1β, IL-17A, IL-6, IL-7, IL-12, G-CSF, and GM-CSF) and anti-inflammatory (IL-5 and IL-10) cytokines were not significantly different among the TBL individuals with different BMI status. Likewise, no significant differences were observed in the CC (CCL-1, CCL-2/MCP-1, CCL3/MIP1α, CCL4/MIP-1β, CCL11/eotaxin) and CXC (CXCL-1/GRO-⍺, CXCL2/GRO-β, CXCL9/MIG, CXCL10/IP-10, CXCL11/ITAC 1) chemokine profile among the TBL individuals with different BMI. Hence, our data implies that TBL individuals with LBMI are characterized by minimal effects on plasma cytokines and chemokines in TBL.

Keywords: BMI; Chemokines; Cytokines; ELISA; TBL.

Background: Yersinia ruckeri is a pathogen that can cause enteric redmouth disease in salmonid species, damaging global production of economically important fish including rainbow trout (Oncorhynchus mykiss). Herein, we conducted the transcriptomic profiling of spleen samples from rainbow trout at 24 h post-Y. ruckeri infection via RNA-seq in an effort to more fully understand their immunological responses.

Results: We identified 2498 differentially expressed genes (DEGs), of which 2083 and 415 were up- and down-regulated, respectively. We then conducted a more in-depth assessment of 78 DEGs associated with the immune system including CCR9, CXCL11, IL-1β, CARD9, IFN, TNF, CASP8, NF-κB, NOD1, TLR8α2, HSP90, and MAPK11, revealing these genes to be associated with 20 different immunological KEGG pathways including the Cytokine-cytokine receptor interaction, Toll-like receptor signaling, RIG-I-like receptor signaling, NOD-like receptor signaling, and MAPK signaling pathways. Additionally, the differential expression of 8 of these DEGs was validated by a qRT-PCR approach and their immunological importance was then discussed.

Conclusions: Our findings provide preliminary insight on molecular mechanism underlying the immune responses of rainbow trout following Y. ruckeri infection and the base for future studies of host-pathogen interactions in rainbow trout.

Keywords: Immune response; Rainbow trout; Spleen; Transcriptome; Yersinia ruckeri.

Cytokine-induced killer (CIK) cells are a group of heterogeneous immune cells which can be isolated from human peripheral blood mononuclear cells and have demonstrated therapeutic benefit both in hematologic malignancies and solid tumors, including colorectal cancer. However, poor tumor-targeted migration has limited the clinical efficacy of CIK cell treatment. The chemokine-chemokine receptor (CK-CKR) axis serves a role in the tumor-directed trafficking capacity of immune cells. Investigating the relationship between CKR profiles on the surface of CIK cells and chemokine expression levels in the tumor microenvironment may improve CIK cell therapy. In the present study, the spectrum of chemokine expression levels in tumor tissues from patients with colorectal cancer (CRC) and CKR expression profiles in CIK cells obtained from the same individuals with CRC were investigated. The results showed that chemokine expression levels in tumor tissues exhibited variability and cell line heterogeneity. However, the expression levels of a number of chemokines were similar in different CRC donors and cell lines. Expression levels of CXCLL10, CXCL11 and CCL3 were significantly higher in most tumor tissues compared with adjacent normal tissues and highly expressed in most CRC cell lines. In accordance with chemokine expression levels, CKR profiles on the surface of CIK cells also showed donor-to-donor variability. However, concordant expression profiles of CKRs were identified in different patients with CRC. CXCR3 and CXCR4 were highly expressed on the surface of CIK cells through the culture process. Importantly, the expression levels of all CKRs, especially CCR4, CXCR4 and CXCR3, were notably decreased during the course of CIK cell expansion. The changing trend of CKR profiles were not correlated with the chemokine expression profiles in CRC tissues (CCL3, CXCL12 and CXCL10/CXCL11 were highly expressed in CRC tissue). Re-stimulating CIK cells using chemokines (CCL21 and CXCL11) at the proper time point increased corresponding CKR expression levels on the surface of CIK cells and enhance tumor-targeted trafficking in vitro. These results demonstrated that modification of the CK-CKR axis using exogenous recombinant chemokines at the proper time point enhanced CIK cell trafficking ability and improved CIK antitumor effects.

Keywords: chemokine; chemokine receptors; colorectal cancer; cytokine induce killer cells; immunotherapy.

Mayaro virus (MAYV) and chikungunya virus (CHIKV) are known for their arthrotropism, but accumulating evidence shows that CHIKV infections are occasionally associated with serious neurological complications. However, little is known about the capacity of MAYV to invade the central nervous system (CNS). We show that human neural progenitors (hNPCs), pericytes and astrocytes are susceptible to MAYV infection, resulting in the production of infectious viral particles. In primary astrocytes, MAYV, and to a lesser extent CHIKV, elicited a strong antiviral response, as demonstrated by an increased expression of several interferon-stimulated genes, including ISG15, MX1 and OAS2. Infection with either virus led to an enhanced expression of inflammatory chemokines, such as CCL5, CXCL10 and CXCL11, whereas MAYV induced higher levels of IL-6, IL-12 and IL-15 in these cells. Moreover, MAYV was more susceptible than CHIKV to the antiviral effects of both type I and type II interferons. Taken together, this study shows that although MAYV and CHIKV are phylogenetically related, they induce different types of antiviral responses in astrocytes. This work is the first to evaluate the potential neurotropism of MAYV and shows that brain cells and particularly astrocytes and hNPCs are permissive to MAYV, which, consequently, could lead to MAYV-induced neuropathology.

Keywords: alphavirus; arbovirus; astrocytes; chikungunya; mayaro; neural progenitors; neurotropism; pericytes.

Objective: Transcriptomic Profile Analysis Related to Inflammation in Nasopharyngeal Carcinoma Cases.

Methods: This study used 2 control samples taken using the brushing technique and 7 cancer samples with tissue biopsy. Isolate total RNA using Rneasy® RNA Extraction Mini Kit. Measurement of total RNA concentration and purity using a fluorometer and nanodrop Qubit. Synthesis of cDNA library uses TruSeq® RNA Library Preparation Kit V2 and concentration is measured using qPCR. Sequencing samples using NGS Illumina NextSeq 550 platform engine. Quality control results of sequencing using FASTQC, and raw data processing using HISAT2. Differential analysis of gene expression (DEGs) using edgeR and pathway analysis using DAVID and PANTHER.

Results: From the 25,493 genes that experienced a significant change in expression level (P <0.05) from DEG analysis there were 13 genes that play a role in the inflammatory process. Based on DAVID pathway analysis software, there are 8 genes detected based on the KEGG pathway database found in 2 pathways, namely Inflammatory Mediator Regulation of TRP Channels pathway with genes that play HTR2A, NGF, TRPA1, PRKCG, and ADCY8. CXCL9, CXCL10, and CXCL11 genes are found in the Toll-Like Receptor Signaling pathway. Based on PANTHER pathway analysis software, 6 genes were found, namely CXCL10, MYLK2, COL20A1, MYH2, ACTC1, and ALOX15 in the Inflammation Mediated by Chemokine and Cytokine Signaling pathways. Almost all genes found from DEGs are upregulated, except the ALOX15 gene that is downregulated.

Conclusion: There are 13 genes that play a role in the inflammatory process in Nasopharyngeal Carcinomafrom a sample of the Indonesian population. Genes CXCL9, CXCL10, CXCL11, MYLK2, COL20A1, MYH2, ACTC1, HTR2A, NGF, TRPA1, PRKCG, and ADCY8 have been upregulated and ALOX15 has been downregulated. These genes play a role in the Inflammation Mediated by Chemokine and Cytokine Signaling pathways, Inflammatory Mediator Regulation of TRP Channels, and Toll-Like Receptor Signaling.

Keywords: Inflammation; Nasopharyngeal cancer; Transcriptome profile analysis; next generation sequencing.

Dengue virus (DENV) infection causes dengue fever, dengue hemorrhagic fever, or dengue shock syndrome. Interferons (IFNs), and IFN-γ dependent chemokines, chemokine (C-X-C motif) ligand (CXCL)10/IFN-γ-induced protein 10 (IP-10), CXCL9/MIG and CXCL11/I-TAC, and their common receptor chemokine (C-X-C motif) receptor (CXCR)3 are induced by DENV infection; however it has been shown that the latter two could not compensate for the absence of IP-10. This paper reviews studies about DENV and IP-10. Evidences show the importance of IP-10 induction during DENV infection, in macrophages, lymphocytes, hepatic cells, denritic cells, in skin and in the brain. Furthermore it has been shown that chemokines IP-10, I-TAC and their receptor CXCR3 are involved in severity of dengue; in fact, pulmonary effusion or ascites, painful hepatomegaly or aspartate aminotransferase increase, are correlated with IP-10 levels. It has been also demonstrated that IP-10 was more elevated in subjects who subsequently developed dengue hemorrhagic fever or dengue shock syndrome. It has been also shown that IP-10 has a direct action in control of dengue viral replication. Furthermore IP-10 circulating levels may be used to discriminate dengue fever from other febbrile diseases. This is of particular importance in certain situations, for example to discriminate occupationally acquired dengue, in patients with febbrile disorders coming from endemic countries. These studies suggested that these chemokines can be used as potential biomarkers for differential diagnosis and the disease progression, while others can be used to control dengue viral replication, thus representing a viable targets for drug therapy.

Ovarian cancer patients with homologous recombination deficiency (HRD) tumors would benefit from PARP inhibitor (PARPi) therapy. However, patients with HRD tumors account for less than 50% of the whole cohort, so new biomarkers still need to be developed. Based on the data from the SNP array and somatic mutation profiles in the ovarian cancer genome, we found that high frequency of actionable mutations existed in patients with non-HRD tumors. Through transcriptome analysis, we identified that a downstream target of the cGAS-STING pathway, CXCL11, was upregulated in HRD tumors and could be used as a predictor of survival outcome. Further comprehensive analysis of the tumor immune microenvironment (TIME) revealed that CXCL11 expression signature was closely correlated with cytotoxic cells, neoantigen load and immune checkpoint blockade (ICB). Clinical trial data confirmed that the expression of CXCL11 could be used as a biomarker for anti-PD-1/PD-L1 therapy. Finally, in vivo and in vitro experiments showed that cancer cells with PARPi treatment increased the expression of CXCL11. Collectively, our study not only provides biomarkers of ovarian cancer complementary to the HRD score but also introduces a potential new perspective for identifying prognostic biomarkers of immunotherapy.

Keywords: CXCL11; HRD; PARPi; TIME; cGAS-STING; ovarian cancer.

Dysregulation of the kynurenine pathway has been regarded as a mechanism of tumor immune escape by the enzymatic activity of indoleamine 2, 3 dioxygenase and kynurenine production. However, the immune-modulatory properties of other kynurenine metabolites such as kynurenic acid, 3-hydroxykynurenine, and anthranilic acid are poorly understood. In this study, plasma from patients diagnosed with metastatic cutaneous malignant melanoma (CMM) was obtained before (PRE) and during treatment (TRM) with inhibitors of mitogen-activated protein kinase pathway (MAPKIs). Immuno-oncology related protein profile and kynurenine metabolites were analyzed by proximity extension assay (PEA) and LC/MS-MS, respectively. Correlation network analyses of the data derived from PEA and LC/MS-MS identified a set of proteins that modulate the differentiation of Th1 cells, which is linked to 3-hydroxykynurenine levels. Moreover, MAPKIs treatments are associated with alteration of 3-hydroxykynurenine and 3hydroxyanthranilic acid (3HAA) concentrations and led to higher "CXCL11," and "KLRD1" expression that are involved in T and NK cells activation. These findings imply that the kynurenine pathway is pathologically relevant in patients with CMM.

Tumor tissue includes cancer cells and normal stromal cells such as vascular endothelial cells, connective tissue cells (cancer associated fibroblast, mesenchymal stem cell), and immune cells (tumor-infiltrating lymphocytes or TIL, dendritic cells, eosinophils, basophils, mast cells, tumor-associated macrophages or TAM, myeloid-derived suppressor cells or MDSC). Anti-tumor activity is mainly mediated by infiltration of NK cells, Th1 and CD8⁺ T cells, and correlates with expression of NK cell and T cell attracting chemokines. Nevertheless, cancer cells hijack tissue homeostasis through secretion of cytokines and chemokines that mediate not only the induction of an inflamed status that supports cancer cell survival and growth, but also the recruitment and/or activation of immune suppressive cells. CXCL9, CXCL10, and CXCL11 are known for their tumor-inhibiting properties, but their overexpression in several hematologic and solid tumors correlates with disease severity, suggesting a role in tumor promotion. The dichotomous nature of CXCR3 ligands activity mainly depends on several molecular mechanisms induced by cancer cells themselves able to divert immune responses and to alter the whole local environment. A deep understanding of the nature of such phenomenon may provide a rationale to build up a CXCR3/ligand axis targeting strategy. In this review, we will discuss the role of CXCR3 in cancer progression and in regulation of anti-tumor immune response and immunotherapy.

Keywords: CXCL10; anti-tumor immunity; cancer immunotherapy; chemokines; immune suppression; lymphocyte migration.

Carnosic acid, which is a bioactive compound isolated from rosemary, has various pharmacological effects. However, the anti-inflammatory effect of carnosic acid on periodontitis is still unknown. The aim of this study was to investigate the effect of carnosic acid on CXC chemokine receptor 3 (CXCR3) ligands, which are involved in Th1 cells migration and accumulation, production in interleukin (IL)-27-stimulated human oral epithelial cells (TR146 cells). Carnosic acid decreased CXC chemokine ligand (CXCL)9, CXCL10, and CXCL11 production in IL-27-stimulated TR146 cells in a dose-dependent fashion. Moreover, we disclosed that carnosic acid could suppress signal transducer and activator of transcription (STAT)1, STAT3, and protein kinase B (Akt) phosphorylation in IL-27-stimulated TR146 cells. Furthermore, STAT1, STAT3, and Akt inhibitors could suppress CXCR3 ligands production in IL-27-treated TR146 cells. In summary, carnosic acid could reduce CXCR3 ligands production in human oral epithelial cell by inhibiting STAT1, STAT3, and Akt activation.

Background. Despite considerable interest in the search for a spinal cord injury (SCI) therapy, there is a critical need to develop a panel of diagnostic biomarkers to determine injury severity. In this regard, there is a requirement for continuing research into the fundamental processes of neuroinflammatory and autoimmune reactions in SCI, identifying changes in the expression of cytokines. Methods. In this pilot study, an extended multiplex analysis of the cytokine profiles in the serum of patients at 2 weeks post-SCI (n = 28) was carried out, together with an additional assessment of neuron-specific enolase (NSE) and vascular endothelial growth factor (VEGF) levels by enzyme-linked immunosorbent assay. A total of 16 uninjured subjects were enrolled as controls. Results. The data obtained showed a large elevation of IFNγ (>52 fold), CCL27 (>13 fold), and CCL26 (>8 fold) 2 weeks after SCI. The levels of cytokines CXCL5, CCL11, CXCL11, IL10, TNFα, and MIF were different between patients with baseline American Spinal Injury Association Impairment Scale (AIS) grades of A or B, whilst IL2 (>2 fold) and MIP-3a (>6 fold) were significantly expressed in the cervical and thoracic regions. There was a trend towards increasing levels of NSE. However, the difference in NSE was lost when the patient set was segregated based on AIS group. Conclusions. Our pilot research demonstrates that serum concentrations of cytokines can be used as an affordable and rapid detection tool to accurately stratify SCI severity in patients.

Keywords: blood serum; clinical trial; cytokine profile; inflammation; traumatic spinal cord injury.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease characterized by irreversible airflow limitation. The current medications show limited effects on the decline of pulmonary function in COPD. Our multicenter clinical trial found that Bu-Shen-Fang-Chuan fomula (BSFCF), a Chinese herbal formula, markedly reduced the frequencies of acute exacerbation of COPD and delayed lung function decline. However, the underlying mechanisms are still unclear. In this study, we established a COPD rat model through a 6-month exposure to cigarette smoke (CS) and found that BSFCF (7.2 g/kg) effectively improved CS-induced reduction in pulmonary function and remarkably decreased the numbers of inflammatory cells in bronchoalveolar lavage fluid (BALF). Importantly, BSFCF treatment notably prevented the accumulation of T-lymphocytes (especially CD8⁺ T-cells) in the lung of COPD rats. RNA sequencing analysis of lung tissue demonstrated that CXCL9/CXCL10/CXCL11-CXCR3 chemokine axis in the lung of CS-exposed rats was significantly suppressed by BSFCF. Moreover, our Real-time PCR data verified that BSFCF evidently inhibited the mRNA expressions of CXCL9, CXCL10, CXCL11 and CXCR3. Conclusively, BSFCF markedly improved pulmonary function and attenuated CD8⁺ T-cells recruitment in the lung of CS-exposed rats, which were partially through inhibition of CXCL9/CXCL10/CXCL11-CXCR3 axis.

Neutrophils are recognized as important circulating effector cells in the pathophysiology of severe coronavirus disease 2019 (COVID-19). However, their role within the inflamed lungs is incompletely understood. Here, we collected broncho-alveolar lavage (BAL) fluids and parallel blood samples of critically ill COVID-19 patients requiring invasive mechanical ventilation and compared BAL fluid parameters with those of mechanically ventilated influenza patients, as a non-COVID-19 viral pneumonia cohort. Compared to influenza, BAL fluids of COVID-19 patients contained increased numbers of hyperactivated degranulating neutrophils and elevated concentrations of the cytokines IL-1β, IL-1RA, IL-17A, TNF-α and G-CSF, the chemokines CCL7, CXCL1, CXCL8, CXCL11 and CXCL12α, and the protease inhibitors elafin, secretory leukocyte protease inhibitor (SLPI) and tissue inhibitor of metalloproteinases 1 (TIMP-1). In contrast, α-1 antitrypsin levels and net proteolytic activity were comparable in COVID-19 and influenza BAL fluids. During antibiotics treatment for bacterial co-infections, increased BAL fluid levels of several activating and chemotactic factors for monocytes, lymphocytes and NK cells were detected in COVID-19 patients whereas concentrations tended to decrease in influenza patients, highlighting the persistent immunological response to co-infections in COVID-19. Finally, the high proteolytic activity in COVID-19 lungs suggests considering protease inhibitors as a treatment option.

Keywords: COVID-19; Cytokines; Immunology; Influenza; Neutrophils.

Aberrant expression of long non-coding RNA (lncRNA) H19 is tightly linked to multiple steps of tumorigenesis via the modulation of cell proliferation and apoptosis; however, the pathological significance and regulatory mechanisms of lncRNA H19 in macrophages remain obscure. To investigate whether lncRNA H19 modulates macrophage activation in rheumatoid arthritis (RA), lncRNA H19 levels in PMA-induced PBMC from patients with RA and healthy volunteers were assessed. In addition, the distribution of macrophage subsets, macrophage phenotypic characteristics, and pro-inflammatory gene expression were examined in lncRNA H19 smart silencer- or pcDNA 3.1- H19-transfected macrophages and AAV8-mediated H19 overexpression in a Freund' s complete adjuvant-induced arthritis mouse model. The level of lncRNA H19 was higher in RA patients than in healthy volunteers. Silencing of lncRNA H19 altered lipopolysaccharide plus interferon-induced M1 macrophage polarization and decreased IL-6, CD80, CCL8, and CXCL10 expression in macrophages of RA patients. LncRNA H19 overexpression markedly induced IL-6, CD80, HLA-DR, KDM6A, STAT1, IRF5, CCL8, CXCL9, CXCL10, and CXCL11 expression in macrophages and promoted macrophage migration. AAV8-mediated H19 overexpression aggravated arthritis in mice by promoting M1 macrophage polarization along with iNOS, IL-6, CCL8, CXCL9, CXCL10, CXCL11, MMP3, MMP13 and COX-2 expression in mononuclear cells isolated from the swollen ankle. GSK-J4, an inhibitor of KDM6A, suppressed the activity of lncRNA H19 in macrophages and ameliorated lncRNA H19-aggravated arthritis. In summary, the current study demonstrated that lncRNA H19 is upregulated in RA patients and arthritic mice. LncRNA H19 promotes M1 macrophage polarization and aggravates arthritis by upregulating KDM6A expression.

Keywords: Arthritis; KDM6A; LncRNA H19; Macrophage.

HTLV-1 infection is endemic in Brazil. About 1 to 2% of the Brazilian population is estimated to be infected, but most infected HTLV-1 individuals do not know about their own infection, which favors the continuity of sexual and vertical virus transmission. In addition, HTLV-1 associated central nervous system diseases and their pathophysiologic mechanisms are not fully understood. This study aimed to evaluate the correlation of spinal cord metabolism, viral and inflammatory profiles with features of neurological presentation in HTLV-1 infected individuals.

This is a cross-sectional study of a cohort including 48 HTLV-1 infected individuals clinically classified as asymptomatic-AG (N = 21), symptomatic-SG (N = 11) and HAM/TSP-HG (N = 16) and a nested case-control study with HTLV-1 infected individuals-HIG (N = 48) and HTLV-1 non infected controls-CG (N = 30) that had their spinal cord analysed by Positron Emission Tomography with 18F-Fluordeoxyglucose (18F-FDG PET/CT). HTLV-1 infected individuals had 18F-FDG PET/CT results analyzed with clinical and demographic data, proviral load, cytokines and chemokines in the blood and cerebrospinal fluid (CSF).

18F-FDG PET/CT showed hypometabolism in the thoracic spinal cord in HTLV-1 infected individuals. The method had an accuracy of 94.4% to identify HAM/TSP. A greater involvement of the thoracic spinal cord was observed, although hypometabolism was also observed in the cervical spinal cord segment in HTLV-1 infected individuals. Individuals with HAM/TSP showed a pro-inflammatory profile in comparison to asymptomatic and symptomatic groups, with a higher level of Interferon-inducible T-cell alpha chemoattractant (ITAC/CXCL11), IL-6, IL-12p70 in the plasma; and ITAC, IL-4, IL-5, IL-8 (CXCL8) and TNF-alpha in the CSF. Using regression, thoracic spinal cord SUV (standardized uptake value) and CSF ITAC level were identified as the HAM/TSP predictors in the multivariate model.

18F-FDG PET/CT imaging showed spinal cord hypometabolism in most HTLV-1 infected individuals, even in the asymptomatic HTLV-1 group. Thoracic spinal cord hypometabolism and CSF-ITAC levels were identified predictors of HAM/TSP.

Our findings suggested that in most HTLV-1 infected individuals there was compromise of central nervous system (CNS) structures despite of the lack of clinical symptoms. To explain the found hypometabolism, the role of microcirculatory and metabolic factors in the pathogenesis of neurological diseases associated with HTLV-1 infection must be further investigated. It is paramount to evaluate the central nervous function and to compare the performance among HTLV-1 infected individuals considered asymptomatic to the uninfected controls.

The chemokine receptor CXCR7, also known as ACKR3, is a seven-transmembrane G-protein-coupled receptor (GPCR) involved in various pathologies such as neurological diseases, autoimmune diseases, and cancers. By binding and scavenging the chemokines <em>CXCL11</em> and CXCL12, CXCR7 regulates their extracellular levels. From an original high-throughput screening campaign emerged hit <b>3</b> among others. The hit-to-lead optimization led to the discovery of a novel chemotype series exemplified by the trans racemic compound <b>11i</b>. This series provided CXCR7 antagonists that block <em>CXCL11</em>- and CXCL12-induced ß-arrestin recruitment. Further structural modifications on the trisubstituted piperidine scaffold of <b>11i</b> yielded compounds with high CXCR7 antagonistic activities and balanced ADMET properties. The effort described herein culminated in the discovery of ACT-1004-1239 (<b>28f</b>). Biological characterization of ACT-1004-1239 demonstrated that it is a potent, insurmountable antagonist. Oral administration of ACT-1004-1239 in mice up to 100 mg/kg led to a dose-dependent increase of plasma CXCL12 concentration.

The high mortality of colorectal cancer (CRC) patients and the limitations of conventional tumor-node-metastasis (TNM) stage emphasized the necessity of exploring hub genes closely related to carcinogenesis and prognosis in CRC. The study is aimed at identifying hub genes associated with carcinogenesis and prognosis for CRC. We identified and validated 212 differentially expressed genes (DEGs) from six Gene Expression Omnibus (GEO) datasets and the Cancer Genome Atlas (TCGA) database. We investigated functional enrichment analysis for DEGs. The protein-protein interaction (PPI) network was constructed, and hub modules and genes in CRC carcinogenesis were extracted. A prognostic signature was developed and validated based on Cox proportional hazards regression analysis. The DEGs mainly regulated biological processes covering response to stimulus, metabolic process, and affected molecular functions containing protein binding and catalytic activity. The DEGs played important roles in CRC-related pathways involving in preneoplastic lesions, carcinogenesis, metastasis, and poor prognosis. Hub genes closely related to CRC carcinogenesis were extracted including six genes in model 1 (CXCL1, CXCL3, CXCL8, CXCL11, NMU, and PPBP) and two genes and Metallothioneins (MTs) in model 2 (SLC26A3 and SLC30A10). Among them, CXCL8 was also related to prognosis. An eight-gene signature was proposed comprising AMH, WBSCR28, SFTA2, MYH2, POU4F1, SIX4, PGPEP1L, and PAX5. The study identified hub genes in CRC carcinogenesis and proposed an eight-gene signature with good reproducibility and robustness at the molecular level for CRC, which might provide directive significance for treatment selection and survival prediction.

Context: Primary Sjögren's syndrome (pSS) is a complex heterogeneous autoimmune disease (AID) which can mimic rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Our exploratory study investigated serum biomarkers that may discriminate pSS from RA and SLE.

Methods: Serum concentrations of 63 biomarkers involved in immune cell trafficking, inflammatory response, cellular movement, and cell-to-cell signaling were measured in AID patients, included prospectively into the study at the Montpellier University Hospital. A multivariate analysis by multiple logistic regression was performed, and discriminative power assessed using logistic regression adjusted on significant demographic factors.

Results: Among the 95 patients enrolled, 42 suffered from pSS, 28 from RA, and 25 from SLE. Statistical analysis showed that concentrations of BDNF (OR = 0.493 with 95% CI [0.273-0.891]; p = 0.0193) and I-TAC/CXCL11 (OR = 1.344 with 95% CI [1.027-1.76]; p = 0.0314) can significantly discriminate pSS from RA. Similarly, greater concentrations of sCD163 (OR = 0.803 with 95% CI [0.649-0.994]; p = 0.0436), Fractalkine/CX3CL1 (OR = 0.534 with 95% CI [0.287-0. 991]; p = 0.0466), MCP-1/CCL2 (OR = 0.839 with 95% CI [0.732-0.962]; p = 0.0121), and TNFa (OR = 0.479 with 95% CI [0.247-0.928]; p = 0.0292) were associated with SLE diagnosis compared to pSS. In addition, the combination of low concentrations of BDNF and Fractalkine/CX3CL1 was highly specific for pSS (specificity 96.2%; positive predictive value 80%) compared to RA and SLE, as well as the combination of high concentrations of I-TAC/CXCL11 and low concentrations of sCD163 (specificity 98.1%; positive predictive value 75%).

Conclusion: Our study highlights biomarkers potentially involved in pSS, RA, and SLE pathophysiology that could be useful for developing a pSS-specific diagnostic tool.

Keywords: biomarkers; primary Sjögren syndrome; proteomics; rheumatoid arthritis; systemic lupus erythematosus.