Targeting folate receptor beta on monocytes/macrophages renders rapid inflammation resolution independent of root causes.

Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled monocyte/macrophage activation can pose imminent or impending harm to the affected organs. Curiously, folate receptor beta (FRβ), with subnanomolar affinity for the vitamin folic acid (FA), is upregulated during immune activation in hematopoietic cells of the myeloid lineage. This phenomenon has inspired a strong interest in exploring FRβ-directed diagnostics/therapeutics.

Effect of thread depth and thread pitch on the primary stability of miniscrews receiving a torque load : A finite element analysis.

Purpose: We have been developing a new type of miniscrew to specifically withstand orthodontic torque load. This study aimed to investigate the effect of thread depth and thread pitch on the primary stability of these miniscrews if stressed with torque load.

Methods: Finite element analysis (FEA) was used to evaluate the primary stability of the miniscrews.

A Novel Treatment for Glomerular Disease: Targeting the Activated Macrophage Folate Receptor with a Trojan Horse Therapy in Rats.

Since activated macrophages express a functional folate receptor β (FRβ), targeting this macrophage population with folate-linked drugs could increase selectivity to treat inflammatory diseases. Using a macrophage-mediated anti-glomerular basement membrane (anti-GBM) glomerulonephritis (GN) in WKY rats, we investigated the effect of a novel folic acid-aminopterin (AMT) conjugate (EC2319) designed to intracellularly deliver AMT via the FR. We found that treatment with EC2319 significantly attenuated kidney injury and preserved renal function.

A Novel Prognostic Model for Oral Squamous Cell Carcinoma: The Functions and Prognostic Values of RNA-Binding Proteins.

Purpose: The biological roles and clinical significance of RNA-binding proteins (RBPs) in oral squamous cell carcinoma (OSCC) are not fully understood. We investigated the prognostic value of RBPs in OSCC using several bioinformatic strategies.

Materials And Methods: OSCC data were obtained from a public online database, the Limma R package was used to identify differentially expressed RBPs, and functional enrichment analysis was performed to elucidate the biological functions of the above RBPs in OSCC.

Efficacy and tolerability of folate-aminopterin therapy in a rat focal model of multiple sclerosis.

Background: Activated macrophages in the experimental model of multiple sclerosis (MS) express folate receptor-β (FR-β), representing a promising target for the treatment of MS. Here, we both evaluated the efficacy of a novel folate-aminopterin construct (EC2319) in a rat focal model of multiple sclerosis (MS) and investigated the utility of Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate (Ga-FOL) for assessing inflammatory lesions. In addition, we investigated whether FR-β is expressed in the brain of patients with MS.

Thread shape affects the stress distribution of torque force on miniscrews: a finite element analysis.

This study aimed to investigate the effect of miniscrews thread shape on the stress distribution receiving a torque load. Seven thread shapes (S,V1,V2,B1,B2,R1,R2) models were constructed and a 6 Nmm-torque load was applied. The order of maximum equivalent stress (EQV) value was V1 > V2 > B1 > R1 > R2 > B2 > S.

HBx/ERα complex-mediated LINC01352 downregulation promotes HBV-related hepatocellular carcinoma via the miR-135b-APC axis.

Hepatitis B virus (HBV) infection plays an important role in hepatocarcinogenesis, especially in hepatocellular carcinoma (HCC). Long non-coding RNAs (lncRNAs) have emerged as crucial biomarkers and regulators in many cancers. Novel lncRNAs involved in the initiation and progression of HBV-related hepatocellular carcinoma (HCC) need to be investigated.

Pulmonary Lymphomatoid Granulomatosis With Hemophagocytic Lymphohistiocytosis as the Initial Manifestation.

Lymphomatoid granulomatosis (LYG) is an extremely rare angio-centric and angio-destructive B-cell lymphoproliferative disease. Driven by Epstein-Barr virus (EBV), LYG predominantly involves the bilateral lungs. Commonly presenting as multiple nodules in the lung, pulmonary LYG can masquerade as various infectious diseases, vasculitis, lung cancer, or other metastatic neoplasm.

[MiR-30b Regulates the Cisplatin-Resistance of Human NK/T Cell Lypnphoma Cell Lines SNK-6 and YTS by Targeting the CCL22].

Objective: To explore the effect and mechanism of miR-30b on cisplatin-resistance of human NK/T cell lymphoma lines SNK-6 and YTS cells.

Methods: Normal NK cells, SNK-6 and YTS cells were cultured, the expression levels of miR-30b and macrophage-derived chemokine (CCL22) were detected by real-time PCR assay, and the CCL22 expression was detected by Western blot. The SNK-6 and YTS cells were transfected with miR-30b mimics and inhibitor respectively, then the effect of cisplatin resistance in SNK-6 and YTS cells was measured by MTT assay, the activity of caspase-3 was detected by caspase-3 assay kit, and the cell apoptosis was analyzed by flow cytometry.

Decreased expression of mitochondrial miR-5787 contributes to chemoresistance by reprogramming glucose metabolism and inhibiting MT-CO3 translation.

MicroRNAs (miRNAs) have been recently found in the mitochondria, and were named "mitomiRs", but their function has remained elusive. Here, we aimed to assess the presence and function(s) of mitomiRs in tongue squamous cell carcinoma (TSCC). miRNA microarray was performed in paired TSCC cell lines, Cal27 and its chemoresistant counterpart, Cal27-re.

Detecting Functional and Accessible Folate Receptor Expression in Cancer and Polycystic Kidneys.

Folate-based small molecule drug conjugates (SMDCs) are currently under development and have shown promising preclinical and clinical results against various cancers and polycystic kidney disease. Two requisites for response to a folate-based SMDC are (i) folate receptor alpha (FRα) protein is expressed in the diseased tissues, and (ii) FRα in those tissues is accessible and functionally competent to bind systemically administered SMDCs. Here we report on the development of a small molecule reporter conjugate (SMRC), called EC2220, which is composed of a folate ligand for FRα binding, a multilysine containing linker that can cross-link to FRα in the presence of formaldehyde fixation, and a small hapten (fluorescein) used for immunohistochemical detection.

Identification and validation of a prognostic four-genes signature for hepatocellular carcinoma: integrated ceRNA network analysis.

Background: Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, with a poor long-term prognosis worldwide. The functional deregulations of global transcriptome were associated with the genesis and development of HCC, but lacks systematic research and validation.

Methods: A total of 519 postoperative HCC patients were included.

Regulation of CAR T cell-mediated cytokine release syndrome-like toxicity using low molecular weight adapters.

Although chimeric antigen receptor (CAR) T cell therapies have demonstrated considerable success in treating hematologic malignancies, they have simultaneously been plagued by a cytokine release syndrome (CRS) that can harm or even kill the cancer patient. We describe a CAR T cell strategy in which CAR T cell activation and cancer cell killing can be sensitively regulated by adjusting the dose of a low molecular weight adapter that must bridge between the CAR T cell and cancer cell to initiate tumor eradication. By controlling the concentration and dosing schedule of adapter administration, we document two methods that can rapidly terminate (<3 h) a pre-existing CRS-like toxicity and two unrelated methods that can pre-emptively prevent a CRS-like toxicity that would have otherwise occurred.

Preclinical Evaluation of Bispecific Adaptor Molecule Controlled Folate Receptor CAR-T Cell Therapy With Special Focus on Pediatric Malignancies.

Chimeric antigen receptor (CAR)-T cell therapy has transformed pediatric oncology by producing high remission rates and potent effects in CD19+ B-cell malignancies. This scenario is ideal as CD19 expression is homogeneous and human blood provides a favorable environment for CAR-T cells to thrive and destroy cancer cells (along with normal B cells). Yet, CAR-T cell therapies for solid tumors remain challenged by fewer tumor targets and poor CAR-T cell performances in a hostile tumor microenvironment.

Long Noncoding RNA MPRL Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via Disruption of Pre-miRNA Processing.

Purpose: The overall biological roles and clinical significance of most long noncoding RNAs (lncRNA) in chemosensitivity are not fully understood. We investigated the biological function, mechanism, and clinical significance of lncRNA NR_034085, which we termed miRNA processing-related lncRNA (MPRL), in tongue squamous cell carcinoma (TSCC).

Experimental Design: LncRNA expression in TSCC cell lines with cisplatin treatment was measured by lncRNA microarray and confirmed in TSCC tissues.

Downregulation of RGMA by HIF-1A/miR-210-3p axis promotes cell proliferation in oral squamous cell carcinoma.

Repulsive guidance molecules comprise a group of proteins that play an important role in carcinogenesis through interactions with their receptors, but their function in oral squamous cell carcinoma (OSCC) is unclear. Here, we investigated the potential role of the RGM family members in oral cancer pathogenesis. Our study showed that only RGMA was significantly downregulated in the OSCC tissues analyzed by TCGA and validated this finding in OSCC cells.

MEG3 modulates TIGIT expression and CD4 + T cell activation through absorbing miR-23a.

T cells are involved in bone marrow failure in aplastic anemia (AA). MEG3 is a long, non-coding RNA that can modulate target gene expression and T cell differentiation by acting as a microRNA sponge. Our previous study showed that T cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif (ITIM) domain (TIGIT) plays a critical role in regulating CD4 + T cell functions.

Tumor necrosis factor receptor-associated factor 6 mediated the promotion of salivary adenoid cystic carcinoma progression through Smad-p38-JNK signaling pathway induced by TGF-β.

Background: Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) has been proved to play an important role in tumorigenesis, invasion, and metastasis. However, its precise role salivary adenoid cystic carcinoma (SACC) has not been determined. The aim of this study was to explore the role of TRAF6 in SACC including invasion and metastasis of SACC cells.

Down-regulation of miR-125a-5p is associated with salivary adenoid cystic carcinoma progression via targeting p38/JNK/ERK signal pathway.

Salivary adenoid cystic carcinoma (SACC) is a relatively uncommon epithelial-like malignancy that can occur in the head and neck region. Despite its slow growth, this aggressive salivary gland tumor frequently recurs and metastasizes to distant organs since lacking effective chemotherapy treatment. MicroRNAs are key regulators in tumor metastasis and progression, but their roles during SACC progression have not been illustrated.

Folate-Hapten-Mediated Immunotherapy Synergizes with Vascular Endothelial Growth Factor Receptor Inhibitors in Treating Murine Models of Cancer.

The overexpression of folate receptors (FR) on many human cancers has led to the development of folate-linked drugs for the imaging and therapy of FR-expressing cancers. In a recent phase I clinical trial of late-stage renal cell carcinoma patients, folate was exploited to deliver an immunogenic hapten, fluorescein, to FR tumor cells in an effort to render the cancer cells more immunogenic. Although >50% of the patients showed prolonged stable disease, all patients eventually progressed, suggesting that the folate-hapten immunotherapy was insufficient by itself to treat the cancer.

Finite Element Analysis of Bone Stress around Micro-Implants of Different Diameters and Lengths with Application of a Single or Composite Torque Force.

Background: Stress on the bone surrounding dental micro-implants affects implant success.

Purpose: To compare the stress on the bone surrounding a micro-implant after application of a single force (SF) of 200 g or a composite force (CF) of 200 g and 6 N.mm torque.

Analysis on the stress of the bone surrounding mini-implant with different diameters and lengths under torque.

The purpose of this study is to compare the stress of the bone around the mini-implant under the two kinds of force: the composite force which contains torque and traditional single force. There were 96 finite element models formed by the combination of mini-implant and bone, with diameters of 1.2 mm, 1.

Antiinflammatory Activity of a Novel Folic Acid Targeted Conjugate of the mTOR Inhibitor Everolimus.

Folate receptor (FR)-β has been identified as a promising target for antimacrophage and antiinflammatory therapies. In the present study, we investigated EC0565, a folic acid-derivative of everolimus, as a FR-specific inhibitor of the mammalian target of rapamycin (mTOR). Because of its amphiphilic nature, EC0565 was first evaluated for water solubility, critical micelle formation, stability in culture and FR-binding specificity.

A Phase I/Ib study of folate immune (EC90 vaccine administered with GPI-0100 adjuvant followed by EC17) with interferon-α and interleukin-2 in patients with renal cell carcinoma.

Folate immune (EC90 vaccine with GPI-0100 adjuvant followed by EC17) is a novel folate-targeted hapten immunotherapy designed to exploit the overexpression of folate receptors on renal cell carcinoma (RCC) cells. In this open-label, phase I/II clinical study, we report the safety, pharmacokinetics, and antitumor activity of folate immune with concurrent interleukin-2 (IL-2) and interferon-α (IFN-α) in patients with recurrent or metastatic RCC. Twenty-four patients were enrolled.