Real-world TRAE association between niraparib and platinum-based chemotherapy.

Background: Pre-clinical studies showed the anti-tumor mechanisms of PARP inhibitors (PARPi) and platinum have some crossover and overlap in the DNA damage repair pathway, patients who respond to platinum-based chemotherapy are also more likely to be sensitive to PARPi. This real-world study mainly aimed to evaluate whether TRAE (treatment-related adverse event) between platinum based chemotherapy (PBC) and niraparib are also associated. Methods: Patients received niraparib as maintenance treatment or salvage therapy for advanced ovarian cancer at the First Affiliated Hospital of Gannan Medical University from January 2020 to August 2023 were included. Survival data of niraparib treatment and adverse events occurred during the last platinum-based chemotherapy cycle before starting niraparib treatment and during niraparib treatment are documented. Fisher's exact test were used for correlation analysis. Results: 1. 40 patients treated with niraparib were included in the analysis, including 31 patients treated with niraparib for 1st-line maintenance therapy, 6 patients for PSR (platinum-sensitive recurrence) maintenance therapy, and 3 patients for salvage therapy. The overall median follow-up time was 15.0 months (ranged from 2.2 months to 32.1 months). 2. Overall grade≥3 TRAE (40% vs 70%, p=0.012) including anemia (20% vs 45%, p=0.041) and neutrophil count decreased (17.5% vs 57.5%, p<0.001) was significantly lower during niraparib treatment compared to during chemotherapy. 3. Any grade TRAE (75% vs 100%, p=0.002) including white blood cell count decreased (47.5% vs 87.5%, p<0.001), red blood cell count decreased (57.5% vs 92.5%, p<0.001), anemia (55% vs 87.5%, p<0.001) and neutrophil count decreased (35% vs 85%, p<0.001) were also significantly lower in niraparib treatment group compared with chemotherapy group. No new safety signals were identified. Conclusion: 1. In this real-world practice, we observed that patients with advanced ovarian cancer who experienced any grade and grade ≥3 TRAE during chemotherapy were well tolerated when treated with niraparib, particularly the incidence of any grade and grade ≥3 anemia, and neutrophil count decreased during niraparib treatment were significantly lower compared with that during chemotherapy. 2. For patients with ovarian cancer who have experienced grade ≥3 hematological adverse reactions during prior platinum-based chemotherapy, greater attention should be paid to the monitoring and management of hematological adverse reactions during subsequent treatment with niraparib.

KIF23 promotes cervical cancer progression via inhibiting NLRP3-mediated pyroptosis.

BACKGROUND: Cervical cancer (CC), closely linked to persistent human papillomavirus infection, represents a major health problem for women worldwide. The objective of this study is to elucidate KIF23's role in the development of CC and its regulatory mechanism. METHODS: The bioinformatics methods were utilized to extract pyroptosis-associated differentially expressed genes (DEGs) and pivot genes from the GSE9750 and GSE63678 datasets, followed by immune infiltration analysis and quantification of these genes' expression. The effects of kinesin family member 23 (KIF23) were verified through functional experiments in vitro and a mouse xenograft model. The NLPR3 activator, nigericin, was applied for further analyzing the potential regulatory mechanism of KIF23 in CC. RESULTS: A total of 8 pyroptosis-related DEGs were screened out, among which 4 candidate core genes were identified as candidate hub genes and confirmed upregulation in CC tissues and cells. These genes respectively showed a positive correlation with the infiltration of distinct immune cells or tumor purity. Downregulation of KIF23 could suppress the proliferation, migration, and invasion abilities in CC cells and tumorigenesis through enhancing pyroptosis. Conversely, KIF23 overexpression accelerated the malignant phenotypes of CC cells and inhibited pyroptosis activation, which was blocked by nigericin treatment. CONCLUSIONS: KIF23 may play an oncogenic role in CC progression via inhibition of the NLRP3-mediated pyroptosis pathway.

Knockdown of CENPM activates cGAS-STING pathway to inhibit ovarian cancer by promoting pyroptosis.

OBJECTIVE: We aimed to screen novel gene signatures for ovarian cancer (OC) and explore the role of biomarkers in OC via regulating pyroptosis using bioinformatics analysis. METHODS: Differentially expressed genes (DEGs) of OC were screened from GSE12470 and GSE16709 datasets. Hub genes were determined from protein-protein interaction networks after bioinformatics analysis. The role of Centromeric protein M (CENPM) in OC was assessed by subcutaneous tumor experiment using hematoxylin-eosin and immunohistochemical staining. Tumor metastasis was evaluated by detecting epithelial-mesenchymal transition-related proteins. The proliferation, migration, and invasion were determined using cell counting kit and transwell assay. Enzyme-linked immunosorbent assay was applied to measure inflammatory factors. The mRNA and protein expression were detected using real-time quantitative PCR and western blot. RESULTS: We determined 9 hub genes (KIFC1, PCLAF, CDCA5, KNTC1, MCM3, OIP5, CENPM, KIF15, and ASF1B) with high prediction value for OC. In SKOV3 and A2780 cells, the expression levels of hub genes were significantly up-regulated, compared with normal ovarian cells. CENPM was selected as a key gene. Knockdown of CENPM suppressed proliferation, migration, and invasion of OC cells. Subcutaneous tumor experiment revealed that CENPM knockdown significantly suppressed tumor growth and metastasis. Additionally, pyroptosis was promoted in OC cells and xenograft tumors after CENPM knockdown. Furthermore, CENPM knockdown activated cGAS-STING pathway and the pathway inhibitor reversed the inhibitory effect of CENPM knockdown on viability, migration, and invasion of OC cells. CONCLUSION: CENPM was a novel biomarker of OC, and knockdown of CENPM inhibited OC progression by promoting pyroptosis and activating cGAS-STING pathway.

Cmtm4 deficiency exacerbates colitis by inducing gut dysbiosis and S100A8/9 expression.

The dysfunction of innate immunity components is one of the major drivers for ulcerative colitis (UC), and increasing reports indicate that the gut microbiome serves as an intermediate between genetic mutations and UC development. Here, we find that the IL-17 receptor subunit, CMTM4, is reduced in UC patients and dextran sulfate sodium (DSS)-induced colitis. The deletion of CMTM4 (Cmtm4-/-) in mice leads to a higher susceptibility to DSS-induced colitis than in wild-type, and the gut microbiome significantly changes in composition. The causal role of the gut microbiome is confirmed with a cohousing experiment. We further identify that S100a8/9 is significantly up-regulated in Cmtm4-/- colitis, with the block of its receptor RAGE that reverses the phenotype associated with the CMTM4 deficiency. CMTM4 deficiency rather suppresses S100a8/9 expression in vitro via the IL17 pathway, further supporting that the elevation of S100a8/9 in vivo is most likely a result of microbial dysbiosis. Taken together, the results suggest that CMTM4 is involved in the maintenance of intestinal homeostasis, suppression of S100a8/9, and prevention of colitis development. Our study further shows CMTM4 as a crucial innate immunity component, confirming its important role in the UC development and providing insights into potential targets for the development of future therapies.

Protocol to examine immune subpopulations in murine conjunctiva and lacrimal gland using flow cytometry.

Here, we present a protocol for the examination of immune cells in the murine conjunctiva and lacrimal gland using flow cytometry. We describe steps for dissection, preparation of high-quality single-cell suspensions, utilization of comprehensive staining panels, and optimization of flow cytometry voltage. We then detail procedures for compensation adjustments and the implementation of effective gating strategies. For complete details on the use and execution of this protocol, please refer to Ma et al.1.

Identification of rat Vstm1 with conservative anti-inflammatory effect between rat and human homologs.

Human VSTM1 (also known as SIRL1) is an inhibitory immune checkpoint receptor involved in leukocyte activation. Identification of the homologous genes in other species, such as mice and rats, will undoubtedly contribute to functional studies and clinical applications. Here, we successfully cloned the Vstm1 gene in rats, as supported by high-throughput sequencing data. However, Vstm1 is degenerated to a pseudogene in the mouse genome. Rat Vstm1 mRNA contains a complete open reading frame (ORF) of 630 nucleotides encoding 209 amino acids. Rat Vstm1 is highly expressed in bone marrow, especially in granulocytes. The expression levels of Vstm1 gradually increase with the development of granulocytes in bone marrow but are downregulated in response to inflammatory stimuli. Rat VSTM1 does not have an immunoreceptor tyrosine-based inhibitory motif (ITIM), however, it shows a conservative function of inflammatory inhibition with human VSTM1, and both are anti-correlated with many inflammatory cytokines, such as IL-1α and TNF-α. In bone marrow-derived macrophages (BMDMs), either rat or human VSTM1 suppressed the secretion of inflammatory cytokines in response to LPS stimulation. Further analysis in lung cancer microenvironment revealed that VSTM1 is mainly expressed in myeloid cells, anti-correlated with inflammatory cytokines and associated with tumor development and metastasis.

Transmembrane Protein CMTM6 Alleviates Ocular Inflammatory Response and Improves Corneal Epithelial Barrier Function in Experimental Dry Eye.

Purpose: To investigate the impact of transmembrane protein CMTM6 on the pathogenesis of dry eye disease (DED) and elucidate its potential mechanisms. Methods: CMTM6 expression was confirmed by database analysis, real-time polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry. Tear secretion was measured using the phenol red thread test. Immune cell infiltration was assessed through flow cytometry. Barrier function was evaluated by fluorescein sodium staining, immunofluorescence staining of zonula occludens 1 (ZO-1), and electric cell-substrate impedance sensing (ECIS) assessment. For silencing CMTM6 expression, siRNA and shRNA were employed, along with lentiviral vector-mediated overexpression of CMTM6. Proinflammatory cytokine levels were analyzed by RT-PCR and cytometric bead array (CBA) analysis. Results: CMTM6 showed high expression in healthy human and mouse corneal and conjunctival epithelium but was notably reduced in DED. Notably, this downregulation was correlated with disease severity. Cmtm6-/- dry eye (DE) mice displayed reduced tear secretion, severe corneal epithelial defects, decreased conjunctival goblet cell density, and upregulated inflammatory response. Additionally, Cmtm6-/- DE mice and CMTM6 knockdown human corneal epithelial cell-transformed (HCE-T) cells showed more severe barrier disruption and reduced expression of ZO-1. Knockdown of CMTM6 in HCE-T cells increased inflammatory responses induced by hyperosmotic stress, which was significantly mitigated by CMTM6 overexpression. Moreover, the level of phospho-p65 in hyperosmolarity-stimulated HCE-T cells increased after silencing CMTM6. Nuclear factor kappa B (NF-κB) p65 inhibition (JSH-23) reversed the excessive inflammatory responses caused by hyperosmolarity in CMTM6 knockdown HCE-T cells. Conclusions: The reduction in CMTM6 expression on the ocular surface contributes to the pathogenesis of DED. The CMTM6-NF-κB p65 signaling pathway may serve as a promising therapeutic target for DED.

CMTM6 promotes hepatocellular carcinoma progression through stabilizing ß-catenin.

CMTM6, a regulator of PD-L1 stability, has been implicated in the development of various cancers. However, the expression and role of CMTM6 in hepatocellular carcinoma (HCC) remains controversial. Our study revealed a negative correlation between CMTM6 expression and HCC prognosis through bioinformatics analysis and immunofluorescence staining. CMTM6 expression was also positively associated with alpha-fetoprotein (AFP) levels, supporting its potential as a prognostic marker for HCC. Using Cmtm6 knockout mice, we found that Cmtm6 deficiency inhibited HCC formation and cell proliferation in primary liver cancer models induced by DEN and DEN/CCl4. In HCC cell lines, CMTM6 promoted cell proliferation and interacted with ß-catenin, stabilizing it by preventing ubiquitination. In conclusion, our study suggested that CMTM6 upregulation promotes HCC cell proliferation through the ß-catenin pathway, making it a potential therapeutic target for HCC treatment.

DNA methylation of ICAM4 and NOXO1 participate in the formation of uterine fibroids via regulating immune cell infiltration.

This atudy aimed to reveal the effect of DNA methylation on immune infiltration of uterine fibroids (UFs) and to further classify UFs based on transcriptomic characteristics. The transcriptome and DNA methylation data of UFs were collected from the GEO database. After taking the intersection of the differentially expressed genes in these two types of data, the intersection gene was used to draw ROC curves and to filtrate the candidate genes with AUC≥0.8. Immune infiltration analysis was performed in the online tool EPIC. The correlation between gene with AUC≥0.8 and the abundance of each immune cell type was calculated with |R|>0.3 and P<0.05. ConsensusClusterPlus package in R software was used to further cluster the samples of UFs. In this study, a total of 41 RNA-seq data (10 normal uterine samples and 31 UFs samples) and 34 DNA methylation data (10 from normal subjects and 24 from patients with UFs) were involved. The significantly down-regulated ICAM4, SPECC1L, and NOXO1 were the top three methylated drive genes of UFs. Therefore, NOXO1 and ICAM4 present an intimate correlation to immune cell infiltration. Besides, UFs could be clustered into two subtypes, including a TSAB1 up-regulated subtype and a FOSB up-regulated subtype. DNA methylation of ICAM4 and NOXO1 are involved in the pathogenesis of UFs via regulating immune cell infiltration. Further classification based on transcriptomic characteristics could divide UFs into sexual steroids-related and biomechanics-related subtypes, which would promote its non-invasive treatment.

Omic horizon expression: a database of gene expression based on RNA sequencing data.

BACKGROUND: Gene expression profiles have important significance for gene expression characteristics and further functional studies. More attention has been given to the expression databases in humans and mice, but less attention has been given to rats, while rat models also play an irreplaceable role in biomedical experiments. RESULTS: To depict the rat gene expression profiles in mRNA expression levels, we analyzed over 2,700 RNA sequencing (RNA-Seq) samples from 48 tissues, 40 primary cell types and 25 cell lines; and then mapped them to the latest version of the rat genome reference, mRatBN7.2. Based on these datasets and reanalysis, we constructed a new database, the Omic Horizon Expression Database ( http://immudb.bjmu.edu.cn/expression.html ), which allows expressional profile query of over 25,000 rat genes based on non-redundant gene symbols. The database supports requests using gene symbols (or alias), Ensemble and Entrez gene IDs. Gene expression profiles can be queried in three categories: tissues, primary cells and cell lines. Application examples including expression profiling and comparison, as well as identification of novel rat genes, were illustrated to show the utility of the database. CONCLUSIONS: As an omic resource, the Omic Horizon Expression Database provides horizons of gene expression profiles across various tissues and cells, which greatly facilitates the identification of rat genes as well as functional clues.

Loss of the Novel Myelin Protein CMTM5 in Multiple Sclerosis Lesions and Its Involvement in Oligodendroglial Stress Responses.

This study comprehensively addresses the involvement of the protein CKLF-like Marvel transmembrane domain-containing family member 5 (CMTM5) in the context of demyelination and cytodegenerative autoimmune diseases, particularly multiple Sclerosis (MS). An observed reduction in CMTM5 expression in post-mortem MS lesions prompted further investigations in both in vitro and in vivo animal models. In the cuprizone animal model, we detected a decrease in CMTM5 expression in oligodendrocytes that is absent in other members of the CMTM protein family. Our findings also confirm these results in the experimental autoimmune encephalomyelitis (EAE) model with decreased CMTM5 expression in both cerebellum and spinal cord white matter. We also examined the effects of a Cmtm5 knockdown in vitro in the oligodendroglial Oli-neu mouse cell line using the CRISPR interference technique. Interestingly, we found no effects on cell response to thapsigargin-induced endoplasmic reticulum (ER) stress as determined by Atf4 activity, an indicator of cellular stress responses. Overall, these results substantiate previous findings suggesting that CMTM5, rather than contributing to myelin biogenesis, is involved in maintaining axonal integrity. Our study further demonstrates that the knockdown of Cmtm5 in vitro does not modulate oligodendroglial responses to ER stress. These results warrant further investigation into the functional role of CMTM5 during axonal degeneration in the context of demyelinating conditions.

Corrigendum: A theoretical framework of immune cell phenotypic classification and discovery.

[This corrects the article DOI: 10.3389/fimmu.2023.1128423.].

Comparing the clinical efficacy of three surgical methods for cesarean scar pregnancy.

BACKGROUND: We aimed to compare the clinical efficacy of three surgical methods in the treatment of various types of cesarean scar pregnancy (CSP). METHODS: Herein, 314 cases of CSP were treated in the department of Obstetrics and Gynecology of the First Affiliated Hospital of Gannan Medical University between June 2017 and June 2020. The patients were divided into three groups based on the treatment received: group A (n = 146; curettage by pituitrin combined with ultrasonic monitoring and hysteroscopy-guided surgery), group B [n = 90; curettage after methotrexate (MTX) injection into the local gestational sac], and group C (n = 78; laparoscopic, transvaginal, and transabdominal cesarean scar resection). These groups were divided into three subgroups (type I, type II, and type III) according to the CSP type of the patients. RESULTS: The intraoperative blood loss, length of hospital stay, hospitalization cost, menstrual recovery time, and serum ß-HCG normalization time were lower in groups A than in groups B or C with type I, II and III CSP (P < 0.05). Operative efficiency and Successful second pregnancy rate were higher in groups A than in groups B or C with type I and II CSP (P < 0.05). But in type III CSP, the complications were more serious in group A than group C. CONCLUSIONS: Curettage by pituitrin combined with ultrasonic monitoring and hysteroscopy-guided surgery is an effective and relatively safe treatment for patients with type I and II CSP. Laparoscopic surgery is more suitable for type III CSP.

Mapping Resident Immune Cells in the Murine Ocular Surface and Lacrimal Gland by Flow Cytometry.

BACKGROUND: The ocular surface and lacrimal gland have a frontline position in mucosal immunology. However, there have been few updates to the immune cell atlas of these tissues in recent years. PURPOSE: To map the immune cells in murine ocular surface tissues and lacrimal gland. METHODS: Central and peripheral corneas, conjunctiva, and lacrimal gland were dissociated into single cell suspensions, followed by flow cytometry. Discrepancy of immune cells between the central and peripheral corneas was compared. In the conjunctiva and lacrimal gland, myeloid cells were clustered by tSNE and FlowSOM based on the expression of F4/80, Ly6C, Ly6G, and MHC II. ILCs, type 1 immune cells, and type 3 immune cells were analyzed. RESULTS: The number of immune cells in peripheral corneas was about 16 folds of that in central corneas. B cells accounted for 8.74% of immune cells in murine peripheral corneas. In the conjunctiva and lacrimal gland, most myeloid cells tended out to be monocytes, macrophages, and classical dendritic cells (cDCs). ILC3 were 6.28% and 3.63% of ILCs in the conjunctiva and lacrimal gland, respectively. Th1, Tc1, and NK cells were predominant type 1 immune cells. γδ T17 cells and ILC3 outnumbered Th17 cells among type 3 T cells. CONCLUSION: B cells resident in murine corneas were reported for the first time. Additionally, we proposed a strategy of clustering myeloid cells to better understand their heterogeneity in the conjunctiva and lacrimal gland based on tSNE and FlowSOM. Furthermore, we identified the ILC3 in the conjunctiva and lacrimal gland for the first time. Compositions of type 1 and type 3 immune cells were summarized. Our study provides a fundamental reference and novel insights for ocular surface immune homeostasis and diseases.

A theoretical framework of immune cell phenotypic classification and discovery.

Immune cells are highly heterogeneous and show diverse phenotypes, but the underlying mechanism remains to be elucidated. In this study, we proposed a theoretical framework for immune cell phenotypic classification based on gene plasticity, which herein refers to expressional change or variability in response to conditions. The system contains two core points. One is that the functional subsets of immune cells can be further divided into subdivisions based on their highly plastic genes, and the other is that loss of phenotype accompanies gain of phenotype during phenotypic conversion. The first point suggests phenotypic stratification or layerability according to gene plasticity, while the second point reveals expressional compatibility and mutual exclusion during the change in gene plasticity states. Abundant transcriptome data analysis in this study from both microarray and RNA sequencing in human CD4 and CD8 single-positive T cells, B cells, natural killer cells and monocytes supports the logical rationality and generality, as well as expansibility, across immune cells. A collection of thousands of known immunophenotypes reported in the literature further supports that highly plastic genes play an important role in maintaining immune cell phenotypes and reveals that the current classification model is compatible with the traditionally defined functional subsets. The system provides a new perspective to understand the characteristics of dynamic, diversified immune cell phenotypes and intrinsic regulation in the immune system. Moreover, the current substantial results based on plasticitomics analysis of bulk and single-cell sequencing data provide a useful resource for big-data-driven experimental studies and knowledge discoveries.

hsa_circ_0017842 acts as a competing endogenous RNA to enhance the malignancy of gastric cancer.

BACKGROUND: Circular RNAs (circRNAs) have been shown to act as competing endogenous RNAs (ceRNAs) participating in the progression of gastric cancer (GC). OBJECTIVES: Our study aimed to investigate whether hsa_circ_0017842 can affect the malignancy of GC in a ceRNA manner. MATERIAL AND METHODS: Gene expression microarrays from GEO DataSets database, quantitative real-time polymerase chain reaction (qPCR) and western blotting were used to identify the expression levels of hsa_circ_0017842, miR-1294, and secreted protein, acidic and rich in cysteine (SPARC) in GC. The function of hsa_circ_0017842/miR-1294/SPARC axis in GC cells was confirmed using gainand loss-of-function assays. In addition, luciferase and RNA pulldown assays were performed to demonstrate the ceRNA mechanism of hsa_circ_0017842 involving miR-1294 and SPARC. RESULTS: The upregulation of hsa_circ_0017842 and SPARC, and downregulation of miR-1294 were observed in GC. Upregulating hsa_circ_0017842 in GC cells led to an increase in their proliferation, migration and invasion, and hsa_circ_0017842 knockdown showed the opposite effects on GC cells. Moreover, hsa_circ_0017842 was shown to be a sponge for miR-1294, thereby regulating SPARC expression. Due to the targeting relationship among hsa_circ_0017842, miR-1294 and SPARC, SPARC knockdown could relieve the effect of hsa_circ_0017842 overexpression on GC cells. CONCLUSIONS: Overall, this study confirmed that hsa_circ_0017842 acted as a ceRNA to promote the malignancy of GC cells through regulating the miR-1294/SPARC axis. Our findings might help better elucidate the molecular mechanism of GC tumorigenesis, and as a result improve the overall survival of GC patients.

The Water Transport System in Astrocytes-Aquaporins.

Astrocytes have distinctive morphological and functional characteristics, and are found throughout the central nervous system. Astrocytes are now known to be far more than just housekeeping cells in the brain. Their functions include contributing to the formation of the blood-brain barrier, physically and metabolically supporting and communicating with neurons, regulating the formation and functions of synapses, and maintaining water homeostasis and the microenvironment in the brain. Aquaporins (AQPs) are transmembrane proteins responsible for fast water movement across cell membranes. Various subtypes of AQPs (AQP1, AQP3, AQP4, AQP5, AQP8 and AQP9) have been reported to be expressed in astrocytes, and the expressions and subcellular localizations of AQPs in astrocytes are highly correlated with both their physiological and pathophysiological functions. This review describes and summarizes the recent advances in our understanding of astrocytes and AQPs in regard to controlling water homeostasis in the brain. Findings regarding the features of different AQP subtypes, such as their expression, subcellular localization, physiological functions, and the pathophysiological roles of astrocytes are presented, with brain edema and glioma serving as two representative AQP-associated pathological conditions. The aim is to provide a better insight into the elaborate "water distribution" system in cells, exemplified by astrocytes, under normal and pathological conditions.

Long non-coding RNA TTTY15 silencing inhibits gastric cancer progression by sponging microRNA-98-5p to down-regulate cyclin D2 expression.

Gastric cancer is the most common malignant tumor in the digestive system. However, the detection rate of early gastric cancer is low, resulting in delayed prognosis and poor outcomes. The identification of effective therapeutic targets for gastric cancer is, therefore, of profound significance. Recently, various lncRNAs have been shown to be biomarkers for different cancers. This study investigated the role of long non-coding RNA (lncRNA) TTTY15 in gastric cancer. The expression level of TTTY15, miR-98-5p, and cyclin D2 (CCND2) were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot assay using tumor and non-tumor tissues collected from 30 patients with gastric cancer, gastric cancer cell lines (AGS, SNU-5, and NCI-N87), and the normal gastric epithelial cell line GES-1. The interaction between TTTY15 and miR-98-5p and between miR-98-5p and CCND2 were predicted by bioinformatics and then further verified by dual-luciferase and RNA pull-down analyses. Cell proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2 H-tetrazolium bromide (MTT) assay, and apoptosis was measured using flow cytometry and caspase-3 assay. The results indicate that TTTY15 and CCND2 expression increased and miR-98-5p expression decreased in gastric cancer tumor tissues and cell lines. TTTY15 knockdown inhibited gastric cancer cell proliferation but promoted apoptosis by sponging miR-98-5p, which acted as a tumor suppressor gene by reducing the expression of its target gene CCND2 in gastric cancer. In conclusion, lncRNA TTTY15 is a potential oncogene involved in gastric cancer and may be a novel therapeutic target for gastric cancer treatment.

Ectopic lymphoid follicles in progressive multiple sclerosis: From patients to animal models.

Ectopic lymphoid follicles (ELFs), resembling germinal centre-like structures, emerge in a variety of infectious and autoimmune and neoplastic diseases. ELFs can be found in the meninges of around 40% of the investigated progressive multiple sclerosis (MS) post-mortem brain tissues and are associated with the severity of cortical degeneration and clinical disease progression. Of predominant importance for progressive neuronal damage during the progressive MS phase appears to be meningeal inflammation, comprising diffuse meningeal infiltrates, B-cell aggregates and compartmentalized ELFs. However, the absence of a uniform definition of ELFs impedes reproducible and comparable neuropathological research in this field. In this review article, we will first highlight historical aspects and milestones around the discovery of ELFs in the meninges of progressive MS patients. In the next step, we discuss how animal models may contribute to an understanding of the mechanisms underlying ELF formation. Finally, we summarize challenges in investigating ELFs and propose potential directions for future research.

Single-cell immune checkpoint landscape of PBMCs stimulated with Candida albicans.

Immune checkpoints play various important roles in tumour immunity, which usually contribute to T cells' exhaustion, leading to immunosuppression in the tumour microenvironment. However, the roles of immune checkpoints in infectious diseases, especially fungal infection, remain elusive. Here, we reanalyzed a recent published single-cell RNA-sequencing (scRNA-seq) data of peripheral blood mononuclear cells (PBMCs) stimulated with Candida albicans (C. albicans), to explore the expression patterns of immune checkpoints after C. albicans bloodstream infection. We characterized the heterogeneous pathway activities among different immune cell subpopulations after C. albicans infection. The CTLA-4 pathway was up-regulated in stimulated CD4+ and CD8+ T cells, while the PD-1 pathway showed high activity in stimulated plasmacytoid dendritic cell (pDC) and monocytes. Importantly, we found that immunosuppressive checkpoints HAVCR2 and LAG3 were only expressed in stimulated NK and CD8+ T cells, respectively. Their viabilities were validated by flow cytometry. We also identified three overexpressed genes (ISG20, LY6E, ISG15) across all stimulated cells. Also, two monocyte-specific overexpressed genes (SNX10, IDO1) were screened out in this study. Together, these results supplemented the landscape of immune checkpoints in fungal infection, which may serve as potential therapeutic targets for C. albicans infection. Moreover, the genes with the most relevant for C. albicans infection were identified in this study.