Endocrine, Metabolic & Immune Disorders-Drug Targets - Online First

This study aimed to explore the differential expression of the co-stimulatory molecule CD226 in lymphocytes from patients with New-Onset Graves' Disease (NOGD) and its correlation with clinical indicators.

Sixty-eight participants were recruited for the discovery experiment (NOGD: healthy control (HC) = 39:29). Peripheral Blood Mononuclear Cells (PBMCs) were isolated. Flow cytometry was performed to detect CD226 expression on multiple lymphocyte subtypes. CD226 mRNA expression in PBMCs was detected by qPCR. Fifty-eight participants were recruited for the validation experiment (NOGD: HC=35:23). CD4+ T cells were isolated, and the level of CD226 mRNA in CD4+ T cells was detected. Five cases of each of Graves' disease (GD) thyroid and control thyroid were collected for CD226 immunohistochemical staining.

CD226 expression was the highest in monocytes (NOGD: 94.1% vs. HC: 94.8%) and the lowest in CD8+ T cells (NOGD: 65.3% vs. HC: 64.9%). Compared with HC, CD226 expression on the CD4+ T cells increased in the peripheral blood of NOGD patients and correlated with TPO-Ab. Meanwhile, CD226 mRNA levels were elevated in CD4+ T cells and positively correlated with TR-Ab. CD226 expression was significantly increased in the thyroid tissues of GD patients.

This study demonstrates for the first time the elevated expression of CD226 in CD4+ T cells and thyroid tissue of NOGD. The abnormal elevation of CD226 is correlated with clinical indicators. It suggests that the co-stimulatory molecule CD226 is involved in the pathogenesis of GD.

TAP-1 and TAP-2 are crucial proteins for loading antigenic peptides after proteasome-mediated endogenous processing of the MHC-I (Major Histocompatibility Complex-I) pathway. Our study aimed to explore the Transporter Associated with Antigen Processing proteins (TAP-1 and TAP-2) in oral squamous cell carcinoma and premalignant oral lesions.

We recruited a total of 135 subjects from the outpatient department of the ENT unit of our institute. Real-time Polymerase Chain Reaction (PCR) was used to evaluate the levels of TAP-1 and TAP-2 gene expression in pre-cancerous and oral squamous carcinoma samples. Additionally, we measured the circulating levels of inflammatory markers using an automated biochemistry analyzer.

In the current study, we found that the subjects with oral squamous cell carcinoma had lower expressions of the TAP 1 and TAP 2 genes than precancerous oral subjects of OSMF, leukoplakia, and OLP. In oral squamous carcinoma subjects, we found a 1.7- and 2.1-fold change in gene expression of TAP-1 and TAP-2, respectively, compared to control subjects. Furthermore, we observed an increase in levels of metabolic inflammatory biomarkers of CRP, ESR, and ferritin in oral squamous carcinoma subjects compared to premalignant cases and controls, indicating the presence and aggravation of systemic inflammation.

The study revealed that subjects with oral squamous cell carcinoma have lower TAP 1 and TAP 2 gene expression than premalignant control subjects, thus affecting MHC-I processing, which ultimately affects the functioning of the immune system. These results have the potential to improve our understanding of disease pathophysiology and provide more targeted treatment options.

Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer, and myocardial infarction (MI) is an acute cardiovascular disease resulting from the disruption of coronary blood supply. Recent studies have suggested that these two diseases may share common molecular mechanisms.

The aim of this study was to discover common diagnostic genes for LUAD and MI and analyze their molecular functions and potential drug values by applying bioinformatics analysis.

The objective was to provide a theoretical basis for further research on the pathological mechanisms of LUAD and MI, contributing to the development of novel diagnostic and therapeutic strategies for the two diseases.

In this study, the datasets of LUAD and MI were obtained from TCGA and GEO databases, and differential expression analysis was performed to screen significantly differentially expressed genes (DEGs). Subsequently, disease-related genes were identified using WGCNA analysis, and the biological functions of these genes were explored by functional enrichment analysis. After screening key genes using the protein-protein interaction (PPI) network and the cytoHubba algorithm, biomarkers were determined by LASSO and SVM-RFE machine-learning methods. Finally, immune infiltration analysis and drug prediction were performed, and biomarker expression was verified by single-cell sequencing analysis.

A total of 158 differentially upregulated genes were identified between LUAD and MI. WGCNA analysis screened 86 genes that were significantly associated with both diseases and were enriched in an inflammatory response and immune regulation-related pathways, such as the IL-17 signaling pathway. Ten significant genes were identified by the PPI network and cytoHubba and then reduced to 4 using LASSO and SVM-RFE. Noticeably, MMP9 was significantly overexpressed in both diseases. Immune infiltration analysis showed that MMP9 was significantly related to multiple immune cell infiltration. Drug prediction and molecular docking analysis predicted Ilomastat and Osthole as the potential target drugs. Single-cell sequencing analysis revealed that MMP9 was high-expressed in the macrophages in LUAD tissues.

This study identified MMP9 as a common diagnostic gene and potential therapeutic target for both LUAD and MI and revealed its role in inflammation and immune regulation through comprehensive bioinformatics analysis. These findings provided a theoretical basis for further research on the pathological mechanisms of LUAD and MI, contributing to the development of novel diagnostic and therapeutic strategies.

Immune Checkpoint Inhibitor (ICPi) therapy has revolutionized cancer treatment but can lead to immune-related adverse events (irAE), including thyroid dysfunction. The impact of ICPi on patients with pre-existing autoimmune thyroid diseases (PATD), particularly the development of Graves' disease, remains poorly understood.

We provide the first complete case of Graves' disease with ICPi therapy in a patient who already had Hashimoto's thyroiditis.. The patient, a 52-year-old male, was diagnosed with lung adenocarcinoma and received Atezolizumab. Clinical evaluation revealed hyperthyroidism, confirmed by elevated thyroid hormones and autoantibodies (TRAb and TSAb). The patient was managed with methimazole and demonstrated a transient hyperthyroid phase followed by persistent hypothyroidism. Only 16 confirmed cases of Graves' disease induced by ICPi were reported. We conducted a review to investigate the clinical characteristics, risk factors, and prognosis trends associated with ICPi-induced Graves disease in PTAD patients. Additionally, changes in thyroid function and autoantibodies during and after ICPi treatment are examined.

This case underscores the importance of monitoring thyroid function and autoantibodies in patients with PATD undergoing ICPi therapy. The findings suggest distinct differences in the humoral immune response between ICPi-induced and spontaneous Graves' disease, necessitating further research into autoantibody dynamics and their relationship with cellular immunity in these patients.

Combination therapy with levothyroxine (L-T4) and slow-release T3 (SRT3) in the treatment of hypothyroidism results in a normal triiodothyronine/thyroxine (T3/T4) ratio above that of L-T4 monotherapy. No clinical study has been reported on SRT3 monotherapy for hypothyroidism.

This study was conducted in two parts. In the first part, 20 patients with primary hypothyroidism and serum thyrotropin (TSH) >30 mU/L were randomized into three groups receiving 1.6 μg/kg L-T4, equivalent doses of SRT3 or L-T3 of 0.55 μg/kg for 4 weeks. Their fasting serum-free T4 [fT4], T3, and TSH were measured weekly before taking medication for up to 4 weeks. In the second part, in 9 hypothyroid patients on L-T4 therapy and normal serum TSH, L-T4 therapy was discontinued, and a once-daily dose of SRT3 of 0.55 μg/kg was replaced. Serum fT4, T3, and TSH were measured weekly.

In part one, in patients treated with L-T3 and L-T4, serum TSH decreased to normal values after 4 weeks of intervention. In 7 patients on SRT3, serum T3 increased from 47±12 at baseline to 110±16 ng/dL, and serum TSH decreased from 60±11 at baseline to 24±10 and 26±7 mU/L, respectively, at 14 and 21 days after intervention. At the end of 28 days, mean serum T3 was 110±16, 168±74, and 96±18 ng/dL in SRT3, L-T3, and L-T4 groups, respectively (p < 0.001). In part two, serum fT4 decreased from 1.43±0.7 to 0.41±0.14 ng/dl, and serum T3 increased from 86±21 to 113±27 ng/dL by 21 days. Mean serum TSH remained normal until 14 days but increased to 15.1±7.6 mU/L at 21 days. In the end, mean serum fT4, T3, and TSH were 0.35±0.17 ng/dl, 77.4±8.9 ng/dL, and 35±11 mU/L, respectively.

In patients with primary hypothyroidism, SRT3 monotherapy with an equivalent dose to L-T4 maintained normal serum T3 but could not sustain normal serum TSH concentration.

IRCT20100922004794N12.

There is still no conclusive understanding of whether the glucokinase regulator (GCKR) gene rs780094 and rs1260326 polymorphisms predispose to gestational diabetes mellitus (GDM).

This systematic review and meta-analysis aimed to determine the effect of the GCKR polymorphisms on GDM susceptibility.

Seven literature databases were searched (from inception to February 17, 2024) to locate relevant studies included in further meta-analysis. Odds ratio (OR) and 95% confidence intervals (CI) in the pooled population were estimated to assess the effects of the variant allele on GDM risk.

For the rs780094 polymorphism, 13 datasets with 3443 GDM cases and 5930 nondiabetic controls were included. The pooled estimates in the allele model (OR: 1.19, 95% CI: 1.07~1.32), homozygote model (OR: 1.27, 95% CI: 1.10~1.47), dominant model (OR: 1.16, 95% CI: 1.03~1.31), and recessive model (OR: 1.31, 95% CI: 1.09~1.57) suggested that the C allele carriers were prone to GDM. For the rs1260326 polymorphism, five datasets with 1495 cases and 2678 controls were integrated. The statistically significant effect of the C allele was evident in the allele model (OR: 1.12, 95% CI: 1.01~1.24) and the homozygote model (OR: 1.26, 95% CI: 1.03~1.54).

This meta-analysis suggested that the C allele of the rs780094 and rs1260326 polymorphisms in the GCKR gene are significantly associated with increased risk of GDM.