Galectin-3 Research Articles

Gene polymorphisms of LGALS2, LGALS3 and LGALS9 in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a complicated rheumatic autoimmune disease. Lectin, galactoside-binding soluble, 2 (LGALS2), LGALS3 and LGALS9, three members of the galectin family, play potential roles in autoimmune diseases, including RA. However, association of genetic polymorphisms of LGALS2, LGALS3 and LGALS9 with RA risk in a Southern Chinese Han population has not been elucidated. A case-control study was conducted herein, including 500 RA patients and 650 healthy individuals of Southern Chinese Han origin. Twelve single nucleotide polymorphisms (SNPs), including rs7291467 for the LGALS2 gene, rs4644, rs4652, rs1009977, rs2274273 and rs17128183 for the LGALS3 gene, and rs4795835, rs3763959, rs4239242, rs3751093, rs732222 and rs4794976 for the LGALS9 gene, were genotyped. Polymorphisms were genotyped using the KASP method. Frequencies of rs1009977 genotype TG and rs3751093 genotype GA of LGALS3 gene were significantly different between RA patients and healthy controls (P = 0.049, P = 0.033). Allele T and genotypes TT and TT + TG of rs4794976 for LGALS9 gene were significantly correlated with RA risk (P = 0.017, P = 0.012, P = 0.041). Subgroup analysis revealed that rs1009977, rs2274273 and rs17128183 polymorphisms of LGALS3 gene and rs4795835 polymorphism of LGALS9 gene were correlated with several RA clinical manifestations (all P < 0.05). In addition, haplotype GCGTT showed an increased risk for RA (OR = 1.216, 95% CI: 1.028–1.438, P = 0.023), whereas haplotype GCGTG showed a reduced risk for RA susceptibility (OR = 0.779, 95% CI: 0.625–0.971, P = 0.026). In conclusion, LGALS3 and LGALS9 gene polymorphisms may associate with RA predisposition in a Southern Chinese Han population.

Transcriptional control of brain tumor stem cells by a carbohydrate binding protein.

Brain tumor stem cells (BTSCs) and intratumoral heterogeneity represent major challenges in glioblastoma therapy. Here, we report that the LGALS1 gene, encoding the carbohydrate binding protein, galectin1, is a key regulator of BTSCs and glioblastoma resistance to therapy. Genetic deletion of LGALS1 alters BTSC gene expression profiles and results in downregulation of gene sets associated with the mesenchymal subtype of glioblastoma. Using a combination of pharmacological and genetic approaches, we establish that inhibition of LGALS1 signaling in BTSCs impairs self-renewal, suppresses tumorigenesis, prolongs lifespan, and improves glioblastoma response to ionizing radiation in preclinical animal models. Mechanistically, we show that LGALS1 is a direct transcriptional target of STAT3 with its expression robustly regulated by the ligand OSM. Importantly, we establish that galectin1 forms a complex with the transcription factor HOXA5 to reprogram the BTSC transcriptional landscape. Our data unravel an oncogenic signaling pathway by which the galectin1/HOXA5 complex maintains BTSCs and promotes glioblastoma.

Relationship of Galectin-3 with hemodynamic parameters of patients with chronic heart failure

Background and Aims: to assess the relationship of aldosterone, galectin-3 (G-3) with structural changes and parameters of central hemodynamics of the heart in hemodynamic phenotypes of chronic heart failure (CHF).

LGALS-3 containing haplotype block tag variants in association with cerebrovascular ischemic events

Background and Aims: Stroke is one of the leading causes of mortality and disability worldwide. Numerous studies have shown galectin-3 (gal-3) as a novel prognostic biomarker with high predictive value for cardiovascular and all-cause mortality. Recently, it was suggested that plasma gal-3 could be a predictive marker for cerebrovascular ischemic events (CVI) in female subjects who have undergone carotid endarterectomy (CEA) due atherosclerotic carotid stenosis. Human gal-3 is encoded by LGALS-3 gene located on 14q21-q22 in a unique 300 kb haplotype block in Caucasians.

Peripheral blood mononuclear cell response to YKL-40 and Galectin-3 in cystic fibrosis

BackgroundElevated circulating levels of YKL-40 correlate with disease severity in Cystic Fibrosis (CF), but the role of YKL-40 in the inflammatory response in CF is still under investigation. Our main goal was to evaluate if YKL-40 can modulate the expression of major cytokines (IL-6, IL-10, IL-13) implicated in the inflammatory response in CF. A secondary goal was to explore the interactions between YKL-40 and other circulating proteins to determine the impacts on cytokine modulation. MethodPeripheral blood mononuclear cells (PBMCs) were isolated from the blood of 83 adult CF patients in stable clinical condition. PBMCs were treated with human YKL-40 followed by the measure of IL-6, IL-10 and IL-13 gene expression. Protein arrays were used to explore the interactions between YKL-40 and circulating proteins. Interaction with Galectin-3 (GAL3) was identified, and confirmed by binding assay. Cytokine gene expressions were again monitored by RT-qPCR after PBMC treatment with GAL3, with or without YKL-40 co-stimulation. ResultsFollowing YKL-40 stimulation, PBMC gene expression of IL-6, IL-10 and IL-13 varies across patients. IL-6 and IL-13 are coexpressed, but this response was different in male and female patients. GAL3 protein was detected in the blood of CF patients, and a molecular interaction with YKL-40 was identified. GAL3 did not interfere with the YKL-40 stimulation of IL-6, IL-10 and IL-13 but may modulate the coexpression. ConclusionWe observed that YKL-40 stimulation had a variable impact on IL-6, IL-10, and IL-13 gene expression in CF PBMCs and uncovered an interaction between GAL3 and YKL-40 in the serum of CF patients. Our findings suggest that YKL-40 is not only a biomarker of disease severity in CF, but it might play an active role in the inflammatory pathophysiology of the disease.

Galectin-3 Possesses Anti-Necroptotic and Anti-Apoptotic Effects in Cisplatin-Induced Acute Tubular Necrosis.

Acute kidney injury (AKI) is a public health burden with increasing morbidity, mortality and health care cost. It is associated with increased risk for the development of chronic kidney disease and death. Acute tubular necrosis (ATN) is the most common cause of AKI. Apoptosis and tissue necrosis play an important role in ATN. Galectin 3 (GAL-3), a beta galactoside binding lectin, is known to have a role in inflammation, apoptosis and oxidative stress but its role in cisplatin induced acute tubular necrosis is not clearly elucidated. Male C57B6-J and C57BL-6 -GAL-3 knock-out mice were used to induce ATN using cisplatin mouse model of acute tubular necrosis. GAL-3 expression, apoptotic, necrotic and necroptotic proteins in kidneys were measured using standard histologic, immunohistochemical, and enzyme-linked immunosorbent assay techniques. Data were presented as mean ± S.E. Statistically significant differences (p<0.05) was calculated between experimental groups and corresponding control groups by one-way analysis of variance. There was a significant increase in GAL-3 in kidneys of cisplatin treated GAL-3 wild mice when compared with its control mice. In addition, there were significant higher percentage of ATN, higher levels of plasma urea and creatinine, and higher levels of cathepsin B and cathepsin D, in kidneys of cisplatin-treated GAL-3 KO mice than cisplatin-treated GAL-3 wild mice. Likewise, there were significant higher levels of necroptosis proteins RIPK1, RIPK3, and MLKL in kidneys of cisplatin-treated GAL-3 KO mice than cisplatin-treated GAL-3 wild mice. Moreover, there were significant higher levels of kidney pro-apoptotic proteins; cleaved caspase-3, cleaved PARP, TRAIL and FAS in cisplatin treated GAL-3 KO mice when compared with cisplatin treated GAL-3 wild mice. GAL-3 can affect cell survival and death through its interaction with necroptotic, apoptotic and pro-survival proteins in renal tubules during cisplatin-induced acute tubular necrosis.

Robust Bioinformatics Approach for Identifying Novel AML LSC Targets: Putative Role of Galectin-1 in the Immune-Microenvironment

Acute Myeloid Leukemia (AML) is a clonal malignancy of the bone marrow derived from and maintained by rare leukemia stem cells (LSC). Conventional chemotherapy results in remission in up to 80% of patients, however, most patients relapse and the 5-year survival rate for those with AML lingers at 25%. Chemoresistant LSCs are an important source of relapse, implicating LSCs as a critical target for curing AML. In this study, we aimed to identify novel LSC markers that can potentially be translated into AML therapy.First, we performed a broad survey of publically available data and identified 3 datasets (Gentles et al., 2010; Goardon et al., 2011; Jung et al., 2015) in which the authors performed gene expression arrays on human AML patient samples sorted by leukemia stem, progenitor, and blast cells. These studies also contained paired normal hematopoietic cell subsets for comparison. While immunophenotyping varied between datasets, all LSC discrimination included Lin-CD34+CD38-CD90-. For each dataset, we performed two-sample t-tests per gene to identify those which were significantly differentially expressed between LSCs and HSCs (p<0.05) and had a directional fold change greater than 2 (LSC/HSC). However, instead of correcting for multiple testing within each analysis using traditional methods, we looked instead at the intersection of genes that met the above criteria in all 3 independently generated datasets. This resulted in a list of 43 genes, 27 of which appear to be novel markers of AML LSCs.From this list, we chose to first investigate galectin-1 (Fig. 1A), which is encoded by the LGALS1 gene. Galectin-1 is a member of the beta-galactoside-binding protein family and plays a functional role in modulating cell-cell interactions. Its presence at the cell surface and in the extracellular matrix makes this protein readily targetable. In fact, OTX 008 is a selective small-molecule inhibitor of galectin-1 already clinically available for solid tumors. Using samples from TCGA, we determined that LGALS1 expression is a marker of poor prognosis AML (Fig. 1B).To examine the role of galectin-1 in AML, we established a stable LGALS1 knockdown in vitro model. The human leukemia derived cell line, THP1, has high basal expression of galectin-1 protein at both mRNA and protein level. We transduced these cells with simple hairpin shRNAs in the pLKO.1 lentiviral vector designed by The RNAi Consortium (Fig. 1C). Interestingly, wild-type (WT) and knockdown (shLGALS1) cells showed no differences in proliferation rate or viability (Fig. 1D).We next investigated the potential role of galectin-1 in the immune microenvironment of the overexpressing AML cells. To look explicitly at the function of the secreted galectin-1 protein, we cultured normal human peripheral blood mononuclear cells (PBMCs) with the supernatant from WT or shLGALS1 THP1 cells. Additionally, some PBMCs were stimulated using either PHA or CD3/CD28 activating beads to characterize the role of galectin-1 in the setting of either a nonspecific or specific T cell response, respectively. Cells were incubated in the culture media for 72 hours before being harvested and measured by flow cytometry. We observed that CD3/CD28-stimulated PBMCs had significantly more cells actively proliferating (Fig.1E) and significantly fewer dead cells (Fig. 1F) when cultured in media produced by shLGALS1 cells. This suggests that excess secreted galectin-1 protein can suppress the proliferation and increase cell death of activated T cells. We also measured the relative abundance of CD4+ and CD8+ T cells. PBMCs cultured in shLGALS supernatant had significantly fewer CD4+ T cells than those cultured in WT supernatant (Fig. 1G). This suggests that secreted galectin-1 may play a role in the recruitment or accumulation of CD4+ T cells.In conclusion, we introduce a novel bioinformatics approach for robustly identifying novel AML LSC targets. Additionally, we have shown that one of these markers, galectin-1, has a potential role in suppressing the immune microenvironment by reducing activated PBMC proliferation and increasing CD4+ T cell prevalence. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Galectin 3 Protein Network Analysis By Reverse Protein Arrays Demonstrates Regulation of MCL-1, PKC Delta and CD74 Associated with Poor Survival in Patients with AML

Galectin 3 (LGALS3) is a glycan binding protein that positively regulates survival signaling by diverse mechanisms. LGALS3 is involved in trafficking of kinases such as RAS and receptors such as CD44 to membranes. LGALS3 gene expression is associated with poor survival in AML (Cheng et al Blood 2013) but its functional role is not clear. We therefore analyzed protein expression of LGALS3 and 230 other proteins by RPPA in 511 AML patients. LGALS3 was significantly elevated in AML blast cells compared to normal CD34+ counterparts and highest in monocytic AML patients. LGALS3 levels were highest in Intermediate and Unfavorable Cytogenetic groups. Pearson correlation of LGALS3 with the other proteins identified a distinct set of 23 proteins positively and 13 proteins negatively correlated with LGALS3 expression levels. LGALS3 positively correlated with the expression of anti-apoptotic BCL2 family member MCL-1. To validate RPPA results, OCI-AML3 cells were transduced with a lentivirus expressing shRNA against LGALS3 or with a control lentivirus expressing shRNA against a non-human gene (i.e. GFP). Suppression of LGALS3 in the cells results in reduced MCL-1 gene and protein expression. As reduction of LGALS3 by shRNA or inhibition of LGALS3 using GCS-100 suppresses phosphorylation of ERK, the mechanism how LGALS3 supports MCL-1 in the AML cells may involve ERK. OCI-AML3 LGALS3 shRNA cells were more sensitive to ABT-737 compared to control cells. RPPA also revealed that LGALS3 was strongly correlated with phosphorylated PKC delta and suppression of LGALS3 by shRNA reduced PKC delta phosphorylation levels implicating LGALS3 as a positive regulator of the kinase. While PKC delta is viewed foremost as a stress kinase, RPPA analysis of phosphorylated (i.e. active) PKC delta in AML patients reveals that elevated levels of active kinase is a prognostic factor associated with poor survival. The pro-survival role of PKC delta in AML may reflect its function as an AKT kinase or as a suppressor of ROS. RPPA also identified a novel positive association of LGALS3 with CD74. OCI-AML3 cells with LGALS3 shRNA did not exhibit altered CD74 expression suggesting that CD74 is upstream of the galectin or possibly that an as yet unidentified protein serves as a common regulator of both LGALS3 and CD74. Stromal cell derived CD74 has been implicated as important in the AML microenvironment as a regulator of IL-8 production (Abdul-Aziz et al Cancer Research 2016) but the role for CD74 in AML blast cells is not clear. CD74 modulates CD44 function so the protein could participate in signaling cascades involving the receptor. Pearson correlation with the other proteins analyzed identified 23 proteins including CD44 and LGALS3 that were positively correlated with CD74 and 8 proteins that were negatively associated with CD74. Though LGALS3 was not positively correlated with CD44, the galectin could potentially modulate CD44 function by influencing its surface expression as LGALS3 is involved in trafficking CD44 to the cell surface. The protein associations of LGALS3 and CD74 were used to assemble protein clusters that were then used for analysis of patient survival. LGALS3 and CD74 were collectively analyzed as part of a group of T-cell regulating proteins analyzed on this array. Within that group 4 different expression patterns (clusters) were defined by hierarchical clustering with LGALS3 being active in 2 of them. The protein cluster identifying active LGALS3 was prognostic for shorter remission duration. AML patients who exhibited both LGALS3 and CD74 active clusters exhibited very poor survival characteristics. For AML patients with both LGALS3 and CD74 active protein cluster, median overall survival was only 24.3 weeks, median remission duration was 17.8 weeks, and no patient survived beyond one year. These data suggest that LGALS3 supports AML cell survival via diverse pathways including positive regulation of MCL-1 and PKC delta and support of a CD74 protein network that identifies a new high risk AML population. It is our hope that strategies targeting LGALS3 and CD74 can be developed to help this new at risk population. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Is there any relationship between LGALS3 gene variations and histopathological criteria in laryngeal squamous cell carcinoma (LSCC)?

Abstract Objectives Genetic variations of LGALS3 (Galectin-3) were found to be associated with treatment resistance, mortality, recurrence, high tumor volume and multiple tumor involvement in solid organ cancers. The modulators of extracellular matrix (ECM), which is a dynamic factor in the larynx tissue with high biomechanical and regenerating ability, can play an important role. We aimed to investigate the relationship between the genetic variants of LGALS3, one of these modulators, with Laryngeal Squamous Cell Carcinoma (LSCC). Methods LGALS3 gene variations were genotyped by PCR-RFLP method using genomic DNA samples obtained from peripheral blood samples of 74 patients diagnosed with LSCC and 94 healthy controls. Results The C allele carriage for the Rs4652 genetic variant was found to be higher (p=0.017) in patients with LSCC. Statistical relationships were found between homozygous genotypes of this variant (CC/AA) with advanced tumor stage (p=0.017) and presence of reflux (p=0.036). CC genotype for rs4644 was found to be higher in cases with positive family history (p=0.036). Conclusions Our findings of LGALS3 gene variants, which are also found to be associated with other solid cancers, suggest that they may play a role in LSCC pathophysiology similarly.

The Tim3-galectin-9 interactions in the tumor microenvironment of nasopharyngeal cancer.

2629 Background: The complex cell interactions within the tumor microenvironment (TME) have become a crucial point in cancer research. Yet, the cell interactions might not only depend on the frequency of immune cells, but also on the inter-individual distances as cells might interact via soluble factors and/or cell-cell contact. Accordingly, the mapping of TME has recently gained importance. The aim of this study is to investigate the alternations between galectin-9 (G9) and its natural immunosuppressive receptor, T cell immunoglobulin and mucin domain 3 (Tim3) in nasopharyngeal cancer (NPC). Methods: Using multiplexed quantitative immunofluorescence, we measured the levels of G9 and Tim3 in 95 NPC patients cancerous and 8 normal specimens in tissue microarray format. Cell densities and cell-to-cell distances were quantified. The interaction between G9-expressing tumor cell lines and T cells were also studied. Results: G9-expressing tumor cells were detected in all NPC cases and were significantly higher than normal tissue. Elevated G9 was associated with shorter overall survival (OS: 89% vs 70.5% at 7 years, p: 0.019). Incremental percentages of Tim3+ cells were shown in top 10% cases strongly positive for G9-expressing tumor cells. The number of Tim3+ cells was calculated at 15µm intervals from the nearest G9-expressing tumor cells, of which a significant difference of Tim3+ cells was observed at the 0-15µm distance from G9-expressing cell in cancerous compared to normal tissues. Epithelial short distances were associated with a unfavourable prognosis. Observed short distance were hypothesized to represent Tim3+ cells actively interacting with G9-expressing tumor cells. Accordingly, In vitro cocultured of G9-ovexpressing NPC cell lines induced Tim3 expression on T cells which suppressed the T-cell mediate cytotoxicity on tumor cells. Conclusions: Our findings indicate a specific preexisting profile of Tim3+ and G9-expressing tumor cells and demonstrated that Tim3+ cells were mainly found intratumorally within 15µm of a NPC cell. The relevance of Tim3+ and G9+ distances reflect a potential marker of their functional interaction. Our results could have important implications for clinical therapeutic strategies. Since high G9 expression have poorer OS, they would deserve a different therapeutic strategy.[Table: see text]

P144: Lack of maternal‐derived gal‐3 prevents proper placentation increasing the risk of FGR

P144: Lack of maternal‐derived gal‐3 prevents proper placentation increasing the risk of FGR

Novel pathogenic role for galectin-3 in early disease stages of arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (AC) is a myocardial disease due to desmosomal mutations whose pathogenesis is incompletely understood. The purpose of this study was to identify molecular pathways underlying early AC by gene expression profiling in both humans and animal models. RNA sequencing for differentially expressed genes (DEGs) was performed on the myocardium of transgenic mice overexpressing the Desmoglein2-N271S mutation before phenotype onset. Zebrafish signaling reporters were used for invivo validation. Whole exome sequencing was undertaken in 10 genotype-negative AC patients and subsequent direct sequencing in 140 AC index cases. Among 29 DEGs identified at early disease stages, Lgals3/GAL3 (lectin, galactoside-binding, soluble, 3) showed reduced cardiac expression in transgenic mice and in 3 AC patients who suffered sudden cardiac death without overt structural remodeling. Four rare missense variants of LGALS3 were identified in 5 human AC probands. Pharmacologic inhibition of Lgals3 in zebrafish reduced Wnt and transforming growth factor-β signaling, increased Hippo/YAP-TAZ signaling, and induced alterations in desmoplakin membrane localization, desmosome integrity and stability. Increased LGALS3 plasma expression in genotype-positive AC patients and CD98 activation supported the galectin-3 (GAL3) release by circulating macrophages pointing toward the stabilization of desmosomal assembly at the injured regions. GAL3 plays a crucial role in early AC onset through regulation of Wnt/β-catenin signaling and intercellular adhesion.

A minigene DNA vaccine encoding peptide epitopes derived from Galectin-1 has protective antitumoral effects in a model of neuroblastoma.

We recently identified Galectin-1 (Gal-1), a β-galactoside-binding lectin, as a novel immune regulator in neuroblastoma (NB). Here, we characterized the tolerogenic function of Gal-1 within the CD8+ T cell compartment and further evaluated its relevance as an antigen for effective DNA vaccination against NB in a mouse model. NB cells with Gal-1 knockdown (NXS-2L) exhibited significantly reduced tumor growth compared to NXS-2 NB cells. Administration of anti-CD8 antibodies prevented this antitumor effect, with primary tumor growth comparable to that from Gal-1 (G1)-sufficient NB cells. Peptide epitope screening with online databases and in silico docking experiments predicted the sequences "FDQADLTI" (#1), "GDFKIKCV" (#2), and "AHGDANTI" (#3) to have superior H2-KK binding affinities and "KFPNRLNM" (#4), "DGDFKIKCV" (#5), and "LGKDSNNL" (#6) to have superior H2-DD binding affinities. Minigenes encoding G1-KK (#1-#2-#3), G1-DD (#4-#5-#6) and the triplet with the highest affinity, G1-H (#1-#2-#4), were generated and cloned into a ubiquitin-containing plasmid (pU). Mice receiving pU-G1-KK or pU-G-1H presented a reduction in the s.c. tumor volume and weight of up to 80% compared to control mice; this reduction was associated with increased cytotoxicity of isolated splenocytes from vaccinated animals. Vaccination with pUG1-DD showed a lower capability to suppress primary tumor progression. In conclusion, Gal-1 expression by NB negatively regulates CD8+ T cells. Vaccination with DNA plasmids encoding Gal-1 epitopes overcomes immune escape, enhances CD8+ T cell-dependent immunity and displays effective antitumor activity against NB.

Prognostic significance of galectin-3 expression in patients with resected NSCLC treated with platinum-based adjuvant chemotherapy.

BackgroundGalectin‐3 (GAL3), a protein encoded by the LGALS3 gene, plays diverse roles in cancer initiation, progression, and drug resistance. Accordingly, high GAL3 expression in tumor cells is associated with poor prognosis in non‐small cell lung cancer (NSCLC). However, the prognostic impact of GAL3 expression on patients with resected NSCLC receiving platinum‐based adjuvant chemotherapy (AC) remains unclear.This study aimed to determine the prognostic significance of GAL3 expression in NSCLC patients receiving platinum‐based AC.MethodsThe study included 111 patients with completely resected stages II and IIIA NSCLC who were receiving platinum‐based AC. GAL3 expression in cancer cells was evaluated immunohistochemically according to H‐score (“histo score), with a score of ≥170 considered as high expression. The correlation of GAL3 expression with clinicopathological characteristics and survival was subsequently evaluated.ResultsIn survival analysis, GAL3 expression was significantly associated with recurrence‐free survival (RFS) and overall survival (OS). In multivariate analysis, GAL3 expression was an independent predictive factor of RFS rather than OS.ConclusionsGAL3 expression is a reliable biomarker to predict the prognosis of completely resected NSCLC patients receiving platinum‐based AC.

The Immune Checkpoint Inhibitor LAG-3 and Its Ligand GAL-3 in Vulvar Squamous Neoplasia.

Vulvar squamous cell carcinoma (vSCC), although rare, carries significant morbidity and a high rate of recurrence. Treatment options beyond surgical excision remain limited. Lymphocyte activation gene-3 (LAG-3) and its binding partner galectin-3 (GAL-3) are an immuno-inhibitory checkpoint pair that represent potential immunotherapy targets for the treatment of vSCC. This study examined the expression of LAG-3 and GAL-3 alongside programmed cell death ligand-1 expression in invasive SCC and vulvar intraepithelial neoplasia (VIN) by immunohistochemical analysis of formalin-fixed paraffin-embedded tissue. A total of 35 cases were selected for evaluation: 13 VIN3 [human papillomavirus (HPV)-associated VIN/usual-type VIN], 2 differentiated VIN (dVIN), 16 HPV-associated vSCC, and 4 dVIN-associated vSCC. LAG-3+ tumor-infiltrating lymphocytes were identified in 91% (32/35) of cases of vulvar squamous neoplasia. Tumor cells were positive for GAL-3 in 71% of the vulvar neoplasia cases. HPV-associated vSCC was more likely to demonstrate GAL-3 tumoral positivity when compared with dVIN-associated vSCC (24/29 vs. 1/6, P=0.004). We observed co-expression of all 3 immunomarkers in 40% (14/35) of cases evaluated. In light of these findings, use of immunomodulatory drugs that target the LAG-3/GAL-3 pathway may be potentially beneficial in vSCC and efficacy may be increased when combined with anti-programmed cell death ligand-1 therapy.

Evaluation of Galectin-3 Plasma Concentration in Adolescents with Ventricular Arrhythmia.

Galectin-3 (G3) is a biomarker known as an inflammatory state exponent. The aim of this paper was to analyze the G3 in adolescents with ventricular arrhythmia (VES) in order to evaluate its impact on myocardial tissue preservation. The study group (SG) consisted of 25 VES adolescents. The control group (CG) was 21 healthy children. G3 was assessed in the SG and CG. In the SG electrocardiography, Holter monitoring, echocardiography and CMR were performed. The G3 in SG was 13.45 ± 11.4 ng/mL and in CG 7.2 ± 2.0 ng/mL, p < 0.001. Moderate positive correlation between the G3 and z-score of the left ventricular diameter (r = 0.47, p = 0.041) and moderate negative correlation between the G3 and the left ventricular ejection fraction in cardiac magnetic resonance (CMR EF) (−0.49, p = 0.032) were found. According to the multiple linear regression analysis, CMR EF and VES were independent predictors for G3 elevation. Conclusion: Galectin-3 plasma concentration is elevated and correlates with the chosen left ventricular dysfunction parameters in adolescents suffering from ventricular arrhythmia. Further investigation is necessary to establish if elevated G3 is a useful biomarker for screening young individuals with ventricular arrhythmia who are at risk of structural cardiovascular pathology.

Pro64His (rs4644) Polymorphism Within Galectin-3 Is a Risk Factor of Differentiated Thyroid Carcinoma and Affects the Transcriptome of Thyrocytes Engineered via CRISPR/Cas9 System.

Background: Galectin-3 (LGALS3) is an important glycoprotein involved in the malignant transformation of thyrocytes acting in the extracellular matrix, cytoplasm, and nucleus where it regulates TTF-1 and TCF4 transcription factors. Within LGALS3 gene, a common single-nucleotide polymorphism (SNP) (c.191C>A, p.Pro64His; rs4644) encoding for the variant Proline to Histidine at codon 64 has been extensively studied. However, data on rs4644 in the context of thyroid cancer are lacking. Thus, the aim of the present work was to evaluate the role of the rs4644 SNP as risk factor for differentiated thyroid cancer (DTC) and to determine the effect on the transcriptome in thyrocytes. Methods: A case/control association study in 1223 controls and 1142 unrelated consecutive DTC patients was carried out to evaluate the association between rs4644-P64H and the risk of DTC. We used the nonmalignant cell line Nthy-Ori (rs4644-C/A) and the CRISPR/Cas9 technique to generate isogenic cells carrying either the rs4644-A/A or rs4644-C/C homozygosis. Then, the transcriptome of the derivative and unmodified parental cells was analyzed by RNA-seq. Genes differentially expressed were validated by quantitative reverse transcription PCR and further tested in the parental Nthy-Ori cells after LGALS3 gene silencing, to investigate whether the expression of target genes was dependent on galectin-3 levels. Results: rs4644 AA genotype was associated with a reduced risk of DTC (compared with CC, ORadj = 0.66; 95% confidence interval = 0.46-0.93; Pass = 0.02). We found that rs4644 affects galectin-3 as a transcriptional coregulator. Among 34 genes affected by rs4644, HES1, HSPA6, SPC24, and NHS were of particular interest since their expression was rs4644-dependent (CC>AA for the first and AA>CC for the others), also in 574 thyroid tissues of Genotype-Tissue Expression (GTEx) biobank. Moreover, the expression of these genes was regulated by LGALS3-silencing. Using the proximity ligation assay in Nthy-Ori cells, we found that the TTF-1 interaction was genotype dependent. Conclusions: Our data show that in thyroid, rs4644 is a trans-expression quantitative trait locus that can modify the transcriptional expression of downstream genes, through the modulation of TTF-1.

Research Progress on the Abnormal Expression of Galectin-3 and p16 in Cervical Cancer

Research Progress on the Abnormal Expression of Galectin-3 and p16 in Cervical Cancer

Circulating multimarker approach to identify patients with preclinical left ventricular remodelling and/or diastolic dysfunction

AimsBiomarkers reflecting myocardial fibrosis and inflammation have been individually associated with left ventricular hypertrophy (LVH) and diastolic dysfunction (DD). However, the added value of a fibrosis‐inflammation multimarker approach in a populational setting is yet to be studied. We evaluated the value of a multimarker approach to detect LVH and DD in a large population‐based cohort.Methods and resultsIn a prespecified analysis (BioSe‐PreIC study) of the 4th visit of the STANISLAS cohort (1705 subjects, 47 ± 14 years, 47.4% men), we evaluated the ability of brain natriuretic peptide (BNP), Galectin‐3 (GAL3), N‐terminal propeptide of procollagen type III (P3NP), and soluble ST2 to predict LVH (LV mass > 116/100 g/m2 for men/women) and DD using discrimination (C‐index) and reclassification analysis (NRI).Participants with LVH and/or DD had significantly higher levels of BNP, GAL3, and ST2. Overall, the predictive value of clinical variables for LVH and/or DD was good (C‐index ranging from 0.76 to 0.82) and the addition of BNP, Gal3, P3NP, and ST2 moderately but significantly improved predictive value (delta C‐index = 0.03, P = 0.03 for LVH and 0.01, P = 0.01 for DD) and reclassification (NRI = 25.3, P = 0.02 for LVH and NRI = 32.7 for DD, P < 0.0001). Gal3, P3NP, and ST2 significantly improved predictive value (delta C‐index = 0.01, P = 0.01) and reclassification (NRI = 31.3, P < 0.0001) for DD of top of clinical variables and BNP.ConclusionsAs the measurement of Gal3, P3NP, and ST2 results in marginal (even if significant) increase in the prediction of DD/LVH on top of routine evaluation, their systematic use should not be promoted in unselected healthy individuals to screen for preclinical DD. Further research is needed to determine whether a more personalized medicine approach combing proteomic and clinical scoring can amplify the added value of biomarkers to identify preclinical DD.

The landscape of immune checkpoints expression in non-small cell lung cancer: a narrative review.

With the increasing clinical potential of tumor immunotherapy, more and more clinical trials are undergoing with immune checkpoint inhibitors (ICIs). Immune checkpoints (ICs) have been identified as crucial regulators of the immune response and have improved ICIs-inhibitor therapeutic strategies. The most important ICs in lung cancer include programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), lymphocyte activation gene-3 (LAG-3), major histocompatibility complex class II (MHC II), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), and Galectin-9 (GAL-9), OX-40, OX40L. However, the expression and prognostic value of these ICs are still controversial. Among them, high expression of PD-L1 on tumor cells (>50%) predicts a better therapeutic effect of anti-PD-1 monoclonal antibody compared to patients with low PD-L1 expression. However, only 20–30% of non-small cell lung cancer (NSCLC) patients seem to get benefit from immunotherapy. In order to improve the immunotherapy outcomes, more and more attention is paid to combination immunotherapy. Analyzing the co-expression of ICs can give us a more comprehensive basis for combination immunotherapy. This review article summarized our comprehensive expression of ICs based on our previous research, and analyzed their correlation with prognosis in NSCLC patients. We also provided suggestions for potentially personalized combination immunotherapy in NSCLC.