Podoplanin immunoexpression in odontogenic lesions: a systematic review, meta-analysis, and integrated bioinformatic analysis.

BACKGROUND: Podoplanin (PDPN) is a transmembrane glycoprotein implicated in the pathogenesis of odontogenic lesions (OL). It is localized at the membrane and cytoplasmic level, and its interaction with other proteins could trigger cell proliferation, invasion and migration. The main objective of this systematic review is to explore the immunoexpression pattern of podoplanin in OL. In addition, as secondary objectives, we aimed to compare the immunostaining intensity of PDPN in OL, to analyze its interaction networks by bioinformatic analysis and to highlight its importance as a potential diagnostic marker useful in the pathogenesis of OL. METHODS: The protocol was developed following PRISMA and Cochrane guidelines. The digital search was performed in the databases: PubMed/MEDLINE, ScienceDirect, Scopus, Web of Science and Google Schoolar from August 15, 2010 to June 15, 2023. We included cross-sectional and cohort studies that will analyze the pattern of PDPN immunoexpression in OL. Two investigators independently searched for eligible articles, selected titles and abstracts, analyzed full text, conducted data collection, and performed assessment of study quality and risk of bias. In addition, part of the results were summarized through a random-effects meta-analysis. STRING database was used for protein-protein interaction analysis. RESULTS: Twenty-nine relevant studies were included. The ages of the subjects ranged from 2 to 89 years, with a mean age of 33.41 years. Twenty-two point two percent were female, 21.4% were male, and in 56.4% the gender of the participants was not specified. A total of 1,337 OL samples were analyzed for PDPN immunoexpression pattern. Ninety-four (7.03%) were dental follicles and germs, 715 (53.47%) were odontogenic cysts, and 528 (39.49%) were odontogenic tumors. Meta-analysis indicated that the immunostaining intensity was significantly stronger in odontogenic keratocysts compared to dentigerous cysts (SMD=3.3(CI=1.85-4.82, p=0.000*). Furthermore, bioinformatic analysis revealed that PECAM-1, TNFRF10B, MSN, EZR and RDX interact directly with PDPN and their expression in OL was demonstrated. CONCLUSIONS: The results of the present systematic review support the unique immunoexpression of PDPN as a potential useful diagnostic marker in the pathogenesis of OL.

Screening for biomarkers of tuberous sclerosis complex-associated epilepsy: a bioinformatics analysis.

Background: The optimal biomarkers for early diagnosis, treatment, and prognosis of tuberous sclerosis complex (TSC)-associated epilepsy are not yet clear. This study identifies the crucial genes involved in the pathophysiology of TSC-associated epilepsy via a bioinformatics analysis. These genes may serve as novel therapeutic targets. Methods: Gene chip data sets (GSE62019 and GSE16969) comprising the data of patients with TSC-associated epilepsy and healthy control participants were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) in the GEO database were identified using the GEO2R gene expression analysis tool. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene Ontology function, and protein-protein interaction (PPI) network analyses were then conducted. The results were analyzed using R language, and are presented in volcano plots, Venn diagrams, heatmaps, and enrichment pathway bubble charts. A gene set enrichment analysis (GSEA), was conducted to examine the KEGG pathways and crucial genes linked to TSC-associated epilepsy. The potential genes were compared with the genes listed in the Online Mendelian Inheritance in Man (OMIM) database and analyzed against the literature to determine their clinical significance. Finally, the expression of the key genes in the TSC-associated epilepsy mice cerebral cortex was examined through immunohistochemical staining. Results: The intersection of the GSE62019 and GSE16969 data sets revealed 151 commonly upregulated DEGs. The KEGG enrichment analysis indicated that these DEGs affected the occurrence and development of TSC-associated epilepsy by modulating complement and coagulation cascades, glycosaminoglycans in cancer, and extracellular matrix-receptor interactions. Four high-scoring clusters emerged, and podoplanin (PDPN) was identified as a key gene through the construction of a PPI network of the common DEGs using the Cytoscape software. A GSEA of the DEGs revealed that the common DEG PDPN was enriched in both data sets in pathways related to platelet activation, aggregation, and the glycoprotein VI (GPVI)-mediated activation cascade. Immunohistochemical staining revealed a significant elevation in PDPN expression in the cerebral cortex of mice with TSC-associated epilepsy. Conversely, the control group mice did not display any significantly positive neurons. Conclusions: The discovery of these crucial genes and signaling pathways extends understanding of the molecular processes underlying the development of TSC-associated epilepsy. Additionally, our findings may provide a theoretical basis for research into targeted clinical treatments.

PDPN/CCL2/STAT3 feedback loop alter CAF heterogeneity to promote angiogenesis in colorectal cancer.

Colorectal cancer (CRC) is one of the common clinical malignancies and the fourth leading cause of cancer-related death in the world. The tumor microenvironment (TME) plays a crucial role in promoting tumor angiogenesis, and cancer-associated fibroblasts (CAFs) are one of the key components of the tumor microenvironment. However, due to the high heterogeneity of CAFs, elucidating the molecular mechanism of CAF-mediated tumor angiogenesis remained elusive. In our study, we found that there is pro-angiogenic functional heterogeneity of CAFs in colorectal cancer and we clarified that Podoplanin (PDPN) can specifically label CAF subpopulations with pro-angiogenic functions. We also revealed that PDPN + CAF could maintain CAF heterogeneity by forming a PDPN/CCL2/STAT3 feedback loop through autocrine CCL2, while activate STAT3 signaling pathway in endothelial cells to promote angiogenesis through paracrine CCL2. We demonstrated WP1066 could inhibit colorectal cancer angiogenesis by blocking both the PDPN/CCL2/STAT3 feedback loop in CAFs and the STAT3 signaling pathway in endothelial cells. Altogether, our study suggests that STAT3 could be a potential therapeutic target for blocking angiogenesis in colorectal cancer. We provide theoretical basis and new therapeutic strategies for the clinical treatment of colorectal cancer.

Characterisation of colorectal cancer by hierarchical clustering analyses for five stroma-related markers.

Evidence for the tumour-supporting capacities of the tumour stroma has accumulated rapidly in colorectal cancer (CRC). Tumour stroma is composed of heterogeneous cells and components including cancer-associated fibroblasts (CAFs), small vessels, immune cells, and extracellular matrix proteins. The present study examined the characteristics of CAFs and collagen, major components of cancer stroma, by immunohistochemistry and Sirius red staining. The expression status of five independent CAF-related or stromal markers, decorin (DCN), fibroblast activation protein (FAP), podoplanin (PDPN), alpha-smooth muscle actin (ACTA2), and collagen, and their association with clinicopathological features and clinical outcomes were analysed. Patients with DCN-high tumours had a significantly worse 5-year survival rate (57.3% versus 79.0%; p = 0.044). Furthermore, hierarchical clustering analyses for these five markers identified three groups that showed specific characteristics: a solid group (cancer cell-rich, DCNLowPDPNLow); a PDPN-dominant group (DCNMidPDPNHigh); and a DCN-dominant group (DCNHighPDPNLow), with a significant association with patient survival (p = 0.0085). Cox proportional hazards model identified the PDPN-dominant group (hazard ratio = 0.50, 95% CI = 0.26-0.96, p = 0.037) as a potential favourable factor compared with the DCN-dominant group. Of note, DCN-dominant tumours showed the most advanced pT stage and contained the lowest number of CD8+ and FOXP3+ immune cells. This study has revealed that immunohistochemistry and special staining of five stromal factors with hierarchical clustering analyses could be used for the prognostication of patients with CRC. Cancer stroma-targeting therapies may be candidate treatments for patients with CRC.

Expand available targets for CAR-T therapy to overcome tumor drug resistance based on the "Evolutionary Traps".

Based on the concept of "Evolutionary Traps", targeting survival essential genes obtained during tumor drug resistance can effectively eliminate resistant cells. While, it still faces limitations. In this study, lapatinib-resistant cells were used to test the concept of "Evolutionary Traps" and no suitable target stand out because of the identified genes without accessible drug. However, a membrane protein PDPN, which is low or non-expressed in normal tissues, is identified as highly expressed in lapatinib-resistant tumor cells. PDPN CAR-T cells were developed and showed high cytotoxicity against lapatinib-resistant tumor cells in vitro and in vivo, suggesting that CAR-T may be a feasible route for overcoming drug resistance of tumor based on "Evolutionary Trap". To test whether this concept is cell line or drug dependent, we analyzed 21 drug-resistant tumor cell expression profiles reveal that JAG1, GPC3, and L1CAM, which are suitable targets for CAR-T treatment, are significantly upregulated in various drug-resistant tumor cells. Our findings shed light on the feasibility of utilizing CAR-T therapy to treat drug-resistant tumors and broaden the concept of the "Evolutionary Trap".

Comparison of the efficacy of spinal cord stimulation and dorsal root ganglion stimulation in the treatment of painful diabetic peripheral neuropathy: a prospective, cohort-controlled study.

Objective: The aim of this study was to compare the clinical outcomes of spinal cord stimulation (SCS) and dorsal root ganglion stimulation (DRG-S) in the treatment of painful diabetic peripheral neuropathy (PDPN). Methods: In this prospective cohort study, 55 patients received dorsal column spinal cord stimulation (SCS group) and 51 patients received dorsal root spinal cord stimulation (DRG-S group). The primary outcome was a Numerical Rating Scale (NRS) remission rate of ≥50%, and secondary outcomes included the effects of SCS and DRG-S on quality of life scores (EQ-5D-3L), nerve conduction velocity, and HbA1c, respectively. Results: The percentage of NRS remission rate ≥ 50% at 6 months was 80.43 vs. 79.55%, OR (95% CI): 1.06 (0.38-2.97) in the SCS and DRG-S groups, respectively, and the percentage of VAS remission rate ≥ 50% at 12 months was 79.07 vs. 80.95%, OR (95% CI): 0.89 (0.31-2.58). Compared with baseline, there were significant improvements in EQ-5D and EQ-VAS at 6 and 12 months (p < 0.05), but there was no difference in improvement between the SCS and DRG-S groups (p > 0.05). Nerve conduction velocities of the common peroneal, peroneal, superficial peroneal, and tibial nerves were significantly improved at 6 and 12 months compared with the preoperative period in both the SCS and PND groups (p < 0.05). However, at 6 and 12 months, there was no difference in HbA1c between the two groups (p > 0.05). Conclusion: Both SCS and DRG-S significantly improved pain, quality of life, and lower extremity nerve conduction velocity in patients with PDPN, and there was no difference between the two treatments at 12 months.

Maackia amurensis seed lectin (MASL) and soluble human podoplanin (shPDPN) sequence analysis and effects on human oral squamous cell carcinoma (OSCC) cell migration and viability.

Maackia amurensis lectins serve as research and botanical agents that bind to sialic residues on proteins. For example, M. amurensis seed lectin (MASL) targets the sialic acid modified podoplanin (PDPN) receptor to suppress arthritic chondrocyte inflammation, and inhibit tumor cell growth and motility. However, M. amurensis lectin nomenclature and composition are not clearly defined. Here, we sought to definitively characterize MASL and its effects on tumor cell behavior. We utilized SDS-PAGE and LC-MS/MS to find that M. amurensis lectins can be divided into two groups. MASL is a member of one group which is composed of subunits that form dimers, evidently mediated by a cysteine residue in the carboxy region of the protein. In contrast to MASL, members of the other group do not dimerize under nonreducing conditions. These data also indicate that MASL is composed of 4 isoforms with an identical amino acid sequence, but unique glycosylation sites. We also produced a novel recombinant soluble human PDPN receptor (shPDPN) with 17 threonine residues glycosylated with sialic acid moieties with potential to act as a ligand trap that inhibits OSCC cell growth and motility. In addition, we report here that MASL targets PDPN with very strong binding kinetics in the nanomolar range. Moreover, we confirm that MASL can inhibit the growth and motility of human oral squamous cell carcinoma (OSCC) cells that express the PDPN receptor. Taken together, these data characterize M. amurensis lectins into two major groups based on their intrinsic properties, clarify the composition of MASL and its subunit isoform sequence and glycosylation sites, define sialic acid modifications on the PDPN receptor and its ability to act as a ligand trap, quantitate MASL binding to PDPN with KD in the nanomolar range, and verify the ability of MASL to serve as a potential anticancer agent.

Exosome-transmitted podoplanin promotes tumor-associated macrophage-mediated immune tolerance in glioblastoma.

AIMS: Glioblastoma is the most frequent and aggressive primary brain tumor, characterized by rapid disease course and poor treatment responsiveness. The abundance of immunosuppressive macrophages in glioblastoma challenges the efficacy of novel immunotherapy. METHODS: Bulk RNA-seq and single-cell RNA-seq of glioma patients from public databases were comprehensively analyzed to illustrate macrophage infiltration patterns and molecular characteristics of podoplanin (PDPN). Multiplexed fluorescence immunohistochemistry staining of PDPN, GFAP, CD68, and CD163 were performed in glioma tissue microarray. The impact of PDPN on macrophage immunosuppressive polarization was investigated using a co-culture system. Bone marrow-derived macrophages (BMDMs) and OT-II T cells isolated from BALB/c and OT-II mice respectively were co-cultured to determine T-cell adherence. Pathway alterations were probed through RNA sequencing and western blot analyses. RESULTS: Our findings demonstrated that PDPN is notably correlated with the expression of CD68 and CD163 in glioma tissues. Additionally, macrophages phagocytosing PDPN-containing EVs (EVsPDPN ) from GBM cells presented increased CD163 expression and augmented secretion of immunoregulatory cytokine (IL-6, IL-10, TNF-α, and TGF-ß1). PDPN within EVs was also associated with enhanced phagocytic activity and reduced MHC II expression in macrophages, compromising CD4+ T-cell activation. CONCLUSIONS: This investigation underscores that EVsPDPN derived from glioblastoma cells contributes to M2 macrophage-mediated immunosuppression and is a potential prognostic marker and therapeutic target in glioblastoma.

A novel PDPN antagonist peptide CY12-RP2 inhibits melanoma growth via Wnt/ß-catenin and modulates the immune cells.

BACKGROUND: Podoplanin (PDPN) is a highly conserved, mucin-type protein specific to the lymphatic system. Overexpression of PDPN is associated with the progression of various solid tumors, and plays an important roles in the tumor microenvironment by regulating the immune system. However, the role of PDPN-mediated signal activation in the progression of melanoma is still unknown. METHODS: PDPN expression was first analyzed in 112 human melanoma tissue microarrays and melanoma cell lines. Functional experiments including proliferation, clone formation, migration, and metastasis were utilized to identify the suppressive effects of PDPN. The Ph.D.TM-12 Phage Display Peptide Library was used to obtain a PDPN antagonist peptide, named CY12-RP2. The immunofluorescence, SPR assay, and flow cytometry were used to identify the binding specificity of CY12-RP2 with PDPN in melanoma cells. Functional and mechanistic assays in vivo and in vitro were performed for discriminating the antitumor and immune activation effects of CY12-RP2. RESULTS: PDPN was overexpressed in melanoma tissue and cells, and inhibited melanoma cells proliferation, migration, and metastasis by blocking the EMT and Wnt/ß-catenin pathway. PDPN antagonistic peptide, CY12-RP2, could specifically bind with PDPN, suppressing melanoma various functions inducing apoptosis in both melanoma cells and 3D spheroids. CY12-RP2 also enhanced the anti-tumor capacity of PBMC, and inhibited melanoma cells growth both in xenografts and allogeneic mice model. Moreover, CY12-RP2 could inhibit melanoma lung metastasis, and abrogated the immunosuppressive effects of PDPN by increasing the proportion of CD3 + CD4 + T cells, CD3 + CD8 + T cells, CD49b + Granzyme B + NK cells, and CD11b + CD86 + M1-like macrophages and the levels of IL-1ß, TNF-α, and IFN-γ. CONCLUSIONS: This study has demonstrated the important role of PDPN in the progression of melanoma and formation of immunosuppressive environment, and provided a potential approach of treating melanoma using the novel CY12-RP2 peptide. In melanoma, PDPN is overexpressed in the cancer cells, and promotes melanoma cells growth and metastasis through activating the Wnt/ß-catenin pathway. Treatment with the PDPN antagonistic peptide CY12-RP2 could not only inhibit the melanoma growth and metastasis both in vitro and in vivo through Wnt/ß-catenin pathway blockade, but also abrogate the immunosuppressive effects of PDPN through modulating immune cells.

PMab-301: An Anti-Giraffe Podoplanin Monoclonal Antibody for Immunohistochemistry.

Immunohistochemistry staining is an essential method in pathological diagnoses. Podoplanin (PDPN) is a specific maker of alveolar epithelium, lymphatic vessels, and glomeruli. In this study, we established a novel anti-giraffe PDPN (girPDPN) mAb, PMab-301, using the Cell-Based Immunization and Screening (CBIS) method. PMab-301 (mouse IgG1, kappa) detected girPDPN in various applications, such as flow cytometry, western blot, and immunohistochemistry. PMab-301 specifically stained type-I alveolar cells using formalin-fixed paraffin-embedded giraffe lung tissues. Our findings suggest the potential usefulness of PMab-301 for the pathophysiological analyses of giraffe tissues.

A Humanized and Defucosylated Antibody against Podoplanin (humLpMab-23-f) Exerts Antitumor Activities in Human Lung Cancer and Glioblastoma Xenograft Models.

A cancer-specific anti-PDPN mAb, LpMab-23 (mouse IgG1, kappa), was established in our previous study. We herein produced a humanized IgG1 version (humLpMab-23) and defucosylated form (humLpMab-23-f) of an anti-PDPN mAb to increase ADCC activity. humLpMab-23 recognized PDPN-overexpressed Chinese hamster ovary (CHO)-K1 (CHO/PDPN), PDPN-positive PC-10 (human lung squamous cell carcinoma), and LN319 (human glioblastoma) cells via flow cytometry. We then demonstrated that humLpMab-23-f induced ADCC and complement-dependent cytotoxicity against CHO/PDPN, PC-10, and LN319 cells in vitro and exerted high antitumor activity in mouse xenograft models, indicating that humLpMab-23-f could be useful as an antibody therapy against PDPN-positive lung squamous cell carcinomas and glioblastomas.

Impact of Hemostasis on the Lymphatic System in Development and Disease.

Lymphatic vessels form a systemic network that maintains interstitial fluid homeostasis and regulates immune responses and is strictly separated from the circulatory system. During embryonic development, lymphatic endothelial cells originate from blood vascular endothelial cells in the cardinal veins and form lymph sacs. Platelets are critical for separating lymph sacs from the cardinal veins through interactions between CLEC-2 (C-type lectin-like receptor-2) and PDPN (podoplanin) in lymphatic endothelial cells. Therefore, deficiencies of these genes cause blood-filled lymphatic vessels, leading to abnormal lymphatic vessel maturation. The junction between the thoracic duct and the subclavian vein has valves and forms physiological thrombi dependent on CLEC-2/PDPN signaling to prevent blood backflow into the thoracic duct. In addition, platelets regulate lymphangiogenesis and maintain blood/lymphatic separation in pathological conditions, such as wound healing and inflammatory diseases. More recently, it was reported that the entire hemostatic system is involved in lymphangiogenesis. Thus, the hemostatic system plays a crucial role in the establishment, maintenance, and rearrangement of lymphatic networks and contributes to body fluid homeostasis, which suggests that the hemostatic system is a potential target for treating lymphatic disorders. This review comprehensively summarizes the role of the hemostatic system in lymphangiogenesis and lymphatic vessel function and discusses challenges and future perspectives.

Co-Expression of Podoplanin and CD44 in Proliferative Vitreoretinopathy Epiretinal Membranes.

Epiretinal membranes (ERMs) are sheets of tissue that pathologically develop in the vitreoretinal interface leading to progressive vision loss. They are formed by different cell types and by an exuberant deposition of extracellular matrix proteins. Recently, we reviewed ERMs' extracellular matrix components to better understand molecular dysfunctions that trigger and fuel the onset and development of this disease. The bioinformatics approach we applied delineated a comprehensive overview on this fibrocellular tissue and on critical proteins that could really impact ERM physiopathology. Our interactomic analysis proposed the hyaluronic-acid-receptor cluster of differentiation 44 (CD44) as a central regulator of ERM aberrant dynamics and progression. Interestingly, the interaction between CD44 and podoplanin (PDPN) was shown to promote directional migration in epithelial cells. PDPN is a glycoprotein overexpressed in various cancers and a growing body of evidence indicates its relevant function in several fibrotic and inflammatory pathologies. The binding of PDPN to partner proteins and/or its ligand results in the modulation of signaling pathways regulating proliferation, contractility, migration, epithelial-mesenchymal transition, and extracellular matrix remodeling, all processes that are vital in ERM formation. In this context, the understanding of the PDPN role can help to modulate signaling during fibrosis, hence opening a new line of therapy.

Podoplanin promotes the carcinogenicity of gastric cancer by activating ezrin and mediating the crosstalk between tumour cells and cancer-associated fibroblasts.

NEW FINDINGS: What is the central question of this study? To reveal the role and biological mechanism of PDPN in the progression of gastric cancer. What is the main finding and its importance? This study focused on a prognostic predictor, PDPN, which acted as a promoter in the progression of gastric cancer through the activation of Ezrin expression and CAFs. This finding may expand a new route for the gene-targeted therapy in gastric cancer. ABSTRACT: Gastric cancer (GC) is a frequent malignant disease and the main cause of cancer-related death in the world. Podoplanin (PDPN) has been proved to be involved in the progression of various cancers. However, the role and biological mechanism of PDPN in GC are still vague. In our study, we detected the expression of PDPN in GC tissues and cell lines using RT-qPCR, western blot and datasets. The overall survival of GC patients was analysed with a Kaplan-Meier plot. The effects of PDPN overexpression and silencing on GC cell progression were assessed by Cell Counting Kit-8, flow cytometry and a wound healing assay. Besides, the modulation of PDPN on ezrin activation was investigated. We further explored the role of PDPN in the crosstalk between GC cells and cancer associated fibroblasts (CAFs). Results showed that PDPN was upregulated in GC tissues and cell lines. High expression of PDPN was correlated with poor prognosis of GC patients. PDPN positively regulated the viability, migration and invasion, but inhibited apoptosis, of GC cells by mediating the activation of ezrin. Meanwhile, the change in PDPN in GC cells activated CAFs and promoted the production of cytokines secreted by CAFs, which induced the progression of GC cells. These findings may provide a novel target for GC therapy.

From structure to function - Ligand recognition by myeloid C-type lectin receptors.

The relevance of protein-glycan interactions in immunity has long been underestimated. Yet, the immune system possesses numerous classes of glycan-binding proteins, so-called lectins. Of specific interest is the group of myeloid C-type lectin receptors (CLRs) as they are mainly expressed by myeloid cells and play an important role in the initiation of an immune response. Myeloid CLRs represent a major group amongst pattern recognition receptors (PRRs), placing them at the center of the rapidly growing field of glycoimmunology. CLRs have evolved to encompass a wide range of structures and functions and to recognize a large number of glycans and many other ligands from different classes of biopolymers. This review aims at providing the reader with an overview of myeloid CLRs and selected ligands, while highlighting recent insights into CLR-ligand interactions. Subsequently, methodological approaches in CLR-ligand research will be presented. Finally, this review will discuss how CLR-ligand interactions culminate in immunological functions, how glycan mimicry favors immune escape by pathogens, and in which way immune responses can be affected by CLR-ligand interactions in the long term.

PDPN marks a subset of aggressive and radiation-resistant glioblastoma cells.

Treatment-resistant glioma stem cells are thought to propagate and drive growth of malignant gliomas, but their markers and our ability to target them specifically are not well understood. We demonstrate that podoplanin (PDPN) expression is an independent prognostic marker in gliomas across multiple independent patient cohorts comprising both high- and low-grade gliomas. Knockdown of PDPN radiosensitized glioma cell lines and glioma-stem-like cells (GSCs). Clonogenic assays and xenograft experiments revealed that PDPN expression was associated with radiotherapy resistance and tumor aggressiveness. We further demonstrate that knockdown of PDPN in GSCs in vivo is sufficient to improve overall survival in an intracranial xenograft mouse model. PDPN therefore identifies a subset of aggressive, treatment-resistant glioma cells responsible for radiation resistance and may serve as a novel therapeutic target.

Podoplanin could be a predictive biomarker of the risk of patients with oral leukoplakia to develop oral cancer: A systematic review and meta-analysis.

OBJECTIVES: The aim of this study is to identify and analyze the existing literature on the utility of podoplanin to predict the risk of malignancy development (MD) in patients previously diagnosed with oral leukoplakia (OL). METHODS: A systematic review and meta-analysis (SRMA) was performed though a search strategy using several electronic databases and a combination of keywords related to podoplanin and MD of OL, until 15 May, 2022 (PROSPERO CRD42022329326). Evaluation of the risk of bias (ROB) was performed using the Quality in Prognosis Studies Tool. The meta-analyses were estimated using fixed-effect models. RESULTS: From 421 articles, 6 studies were finally included, that enrolled 546 patients with OL, of whom 125 presented with an oral cancer during follow-up (32 to 90 months). Some limitations regarding the ROB were identified mostly related to small sample sizes, short follow-up times, lack of information on covariables in the included studies and lack of accuracy (including sensitivity and specificity). Meta-analysis of 6 studies reveal that high expression of podoplanin carries a pooled hazard ratio (HR) of 3.72 (95% CI, 2.40-5.76; p < 0.00001) for MD without statistical heterogeneity (I2  = 0%, p = 0.53). CONCLUSION: The results of this SRMA support the role of podoplanin immunohistochemical expression as a potential predictive biomarker to assess the risk of malignancy development in oral leukoplakia.

In Vitro Characterization of the Human Skeletal Stem Cell-like Properties of Primary Bone-Derived Mesenchymal Stem/Stromal Cells in Patients with Late and Early Hip Osteoarthritis.

Human skeletal stem cells (hSSCs) were recently identified as podoplanin (PDPN)/CD73/CD164-positive and CD146-negative cells that decline with age, and play a role in the pathogenesis of osteoarthritis (OA). The aim of this study was to identify the hSSC-like properties of bone-derived mesenchymal stem/stromal cells (MSCs) of patients with late and early OA. Methods: First, we performed gene expression profiling for the hSSC markers in 32 patients with late and early OA, and donors without OA. Having identified the low expression of hSSC markers in late OA patients, we further performed trilineage differentiation and immunophenotyping for hSSC makers in the selected subsets from each donor group. Results: Our results show no differences in osteogenesis, chondrogenesis, and adipogenesis between the MSCs from the three groups. However, the immunophenotyping shows lower CD164 in MSCs from early OA patients in comparison with late and no OA subjects (p = 0.002 and p = 0.017). Conclusions: Our study shows that the in vitro hSSC-like properties of bone-derived MSCs are similar in patients with early and late OA, and in donors without OA. However, the lower percentage of CD164-positive MSCs in early OA patients indicates the potential of CD164 as a marker of the onset of OA.

Uterus globulin associated protein 1 (UGRP1) binds podoplanin (PDPN) to promote a novel inflammation pathway during Streptococcus pneumoniae infection.

BACKGROUND: Streptococcus pneumoniae is the major cause of life-threatening infections. Toll-like receptors (TLRs) and NOD-like receptors (NLRs) could recognise S. pneumoniae and regulate the production of pro-inflammatory cytokines. UGRP1, highly expressed in lung, is predominantly secreted in airways. However, the function of UGRP1 in pneumonia is mainly unknown. METHODS AND RESULTS: We showed that upon TLR2/TLR4/NOD2 agonists stimulation or S. pneumoniae infection, treatment with UGRP1 could promote phosphorylation of p65 and enhance IL-6, IL-1ß and TNFα production in macrophages. We further elucidated that after binding with cell-surface receptor PDPN, UGRP1 could activate RhoA to enhance interaction of IKKγ and IKKß, which slightly activated NF-κB to improve expression of TLR2, MyD88, NOD2 and NLRP3. Deletion of UGRP1 or blocking UGRP1 interaction with PDPN protected mice against S. pneumoniae-induced severe pneumococcal pneumonia, and activating RhoA with agonist in UGRP1-deficient mice restored the reduced IL-6 production. CONCLUSION: We demonstrated that UGRP1-PDPN-RhoA signaling could activate NF-κB to promote expression of TLR2, MyD88, NOD2 and NLRP3, which enhanced inflammatory cytokines secretion during S. pneumoniae infection. Antibodies, which could interrupt interaction of UGRP1 and PDPN, are potential therapeutics against S. pneumoniae.