Hongmei Shen

We integrated bulk, single-cell, and spatial transcriptomics to test whether intratumoral heterogeneity (ITH) aggravates CD8⁺ T-cell exhaustion (TEX) in lung adenocarcinoma. In bulk cohorts, ITH and TEX were tightly coupled, with ITH-High tumors preferentially exhibiting deeper TEX phenotypes. This dually adverse (high ITH/high TEX) context was associated with increased antigenicity (higher TMB, predicted neoantigen and cancer/testis antigen scores) but reduced TCR diversity, lower global immune/stromal infiltration, more aggressive clinicogenomic features, and poorer survival. Joint ITH-TEX stratification further revealed an additive prognostic effect, with dual-low (low ITH/low TEX) best and dual-high (high ITH/high TEX) worst outcomes. Single-cell analyses implicated macrophages: ITH-High tumors exhibited coordinated upregulation of classical MHC-I antigen-presentation programs (processing/loading; HLA-A/B/C signaling), stronger macrophage→TEX communication, and enrichment of terminal TEX states. Spatially, in ITH-High tumors, TEX co-localized more closely with MHC-I^high macrophage niches than with macrophages overall, whereas in ITH-Low tumors this proximity was attenuated. B cells showed increased TEX communication but inconsistent MHC-I state spatial coupling, while dendritic cells showed high proximity without ITH-dependent communication increases and weakened colocalization when restricted to MHC-I^high. We also derived a six-gene decision-tree classifier (CDC45, CENPF, PCLAF, SCGB3A1, CDCA8, and NDC80) predicting ITH/TEX phenotypes. These data support a macrophage MHC-I axis linking ITH to terminal TEX and motivate combining checkpoint blockade with macrophage reprogramming or modulation of antigen-processing and presentation.

The cross-sectional survey aimed to characterize the health status of adult endemic cretinism patients in a severely iodine-deficient region, focusing on the prevalence of dyslipidemia, hyperglycemia, and hypertension. The study also sought to provide new epidemiological evidence for the association between endemic cretinism and lipid metabolism disorders, particularly hypercholesterolemia and hypertriglyceridemia. All surviving endemic cretinism patients (n = 31) and matched controls (n = 97) were investigated in December 2020. iodine concentration in urinary and serum, thyroid function parameters, lipid profile [total cholesterol (TC), triglyceride (TRIG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C)], fasting blood glucose (FBG), and blood pressure measurements [systolic blood pressure (SBP), diastolic blood pressure (DBP)] were assessed. Endemic cretinism patients exhibited significantly elevated thyroid-stimulating hormone (TSH) levels and a higher prevalence of hypothyroidism compared to controls. Serum TC and TRIG concentrations were markedly higher in endemic cretinism patients than in controls (5.27 mmol/L vs. 4.73 mmol/L, P = 0.009; and 1.65 mmol/L vs. 1.04 mmol/L, P < 0.001, respectively). The prevalence of hypercholesterolemia and hypertriglyceridemia was significantly higher in endemic cretinism patients (P = 0.001 and P < 0.001, respectively). Multivariate analysis revealed that endemic cretinism was an independent risk factor for both hypercholesterolemia [adjusted odds ratio (AOR) = 2.870, 95% confidence interval (CI): 1.129–7.298] and hypertriglyceridemia (AOR = 5.912, 95% CI: 2.261–15.455). Adult endemic cretinism patients demonstrate significantly elevated serum lipid levels and are more susceptible to hypercholesterolemia and hypertriglyceridemia, conditions closely associated with their underlying hypothyroidism. These findings highlight the importance of monitoring and managing metabolic parameters in adult endemic cretinism patients.

Little is known about the association between iodine nutrition status and bone health. The present study aimed to explore the connection between iodine nutrition status, bone metabolism parameters, and bone disease (osteopenia and osteoporosis). A cross-sectional survey was conducted involving 391, 395, and 421 adults from iodine fortification areas (IFA), iodine adequate areas (IAA), and iodine excess areas (IEA) of China. Iodine nutrition status, bone metabolism parameters and BMD were measured. Our results showed that, in IEA, the urine iodine concentrations (UIC) and serum iodine concentrations (SIC) were significantly higher than in IAA. BMD and Ca²⁺ levels were significantly different under different iodine nutrition levels and the BMD were negatively correlated with UIC and SIC. Univariate linear regression showed that gender, age, BMI, menopausal status, smoking status, alcohol consumption, UIC, SIC, free thyroxine, TSH, and alkaline phosphatase were associated with BMD. The prevalence of osteopenia was significantly increased in IEA, UIC ≥ 300 µg/l and SIC > 90 µg/l groups. UIC ≥ 300 µg/l and SIC > 90 µg/l were risk factors for BMD T value < –1·0 sd. In conclusion, excess iodine can not only lead to changes in bone metabolism parameters and BMD, but is also a risk factor for osteopenia and osteoporosis.

This study aims to assess the applicability of the serum iodine (SI) standards proposed by the WHO and other renowned laboratories for the Chinese population. Additionally, it seeks to establish reference intervals (RIs) for SI in Chinese adults and conduct a risk assessment between serum iodine concentration (SIC) and the development of thyroid diseases. This study enrolled 3138 adults aged 18–60 years from six provinces in China. A total of 1794 healthy adults with normal thyroid function were selected to assess the applicability of the international standards and establish China’s RI, utilizing five external datasets for validation. Multiple logistic regression analysis was applied to explore the relationship between SIC and thyroid disease. The ratios of adults with normal thyroid function from five provinces whose SI levels fall outside the limits of the international standards are partially greater than 10%. China’s RI was 40.11–97.59 µg/L, and the ratios of individuals in the validation datasets outside this RI were all less than 10%. Adults with low SIC levels (< 40.11 µg/L) were at higher risk of hypothyroxinemia (adjusted OR = 4.715, 95% CI = 1.459–15.235), overt hypothyroidism (adjusted OR = 4.719, 95% CI = 1.583–14.067), and autoimmune thyroiditis (adjusted OR = 2.394, 95% CI = 1.410–4.064). Adults with high SIC levels (> 97.59 µg/L) were at a higher risk of overt hyperthyroidism (adjusted OR = 18.170, 95% CI = 5.940–55.577). These international standards are not fully applicable to the Chinese population. We established RIs for SI in Chinese adults to better accommodate the country’s specific conditions.

AIT (autoimmune thyroiditis) is a complex disease influenced by genetic and environmental factors as well as immune dysregulation. Epigenetics has unveiled potential connections among environmental factors, gene expression and thyroid autoimmunity. Among epigenetic modifications, DNA methylation is the first discovered and the most extensively-studied. Investigations both domestically and internationally indicate that iodine supplementation in areas with either excessive or insufficient iodine levels increases the incidence of AIT. Chemokines also play a crucial role in the pathogenesis of AIT. Therefore, does iodine influence the DNA methylation of chemokine genes of patients with AIT, and what are the potential mechanisms involved?. Healthy controls and patients with AIT were matched at the ratio of 1:1 according to age, sex, BMI and residential address, and a total of 176 patients with AIT together with 176 controls were included from regions with varying iodine levels. DNA methylation and mRNA expression levels were analyzed in whole blood using MethylTarget and qRT-PCR methods. At the same time, the GSE138198 and GSE54958 datasets were downloaded from GEO to obtain transcriptional datasets of thyroid tissues from patients with AIT. AIT patients had lower DNA methylation levels in CCL5_2 and CXCL8_1 target regions than controls, while the mRNA expression of CCL5 and CXCL8 genes was significantly higher. A negative correlation was found between the DNA methylation of CCL5_2 and its CpG sites as well as CCL5 gene expression. Higher CCL5 mRNA expression was validated in the thyroid tissues of patients with AIT using GSE datasets. DNA methylation differences at different iodine levels were mainly observed in CCL5_1, CCL5_2, CXCL8_1 and CXCR5_1. CXCL8_1 showed a positive correlation with UIC (urinary iodine concentration). This study demonstrates an association between the DNA methylation status of CCL5 and CXCL8 genes and AIT. The DNA methylation level of the CCL5 gene can serve as an epigenetic marker and biological indicator for AIT. Additionally, long-term iodine deficiency supplementation has a more pronounced impact on the DNA methylation levels of CCL5 and CXCL8 genes.

Objective: This study aimed to identify differentially methylated genes (DMGs) associated with natural killer cells in patients with autoimmune thyroiditis (AIT), focusing on the influence of varying water iodine exposure levels. Methods: Participants were divided into categories based on median water iodine (MWI) concentrations: iodine-fortified areas (IFA, MWI < 10 g/L), iodine-adequate areas (IAA, 40 <= MWI <= 100 mu g/L), and iodine-excessive areas (IEA, MWI > 300 mu g/L). A total of 176 matched AIT cases and controls were recruited and divided into 89, 40, and 47 pairs for IFA, IAA, and IEA, respectively. DMGs were identified using 850K BeadChip analysis for 10/10 paired samples. Validation of DNA methylation and mRNA expression levels of the DMGs was conducted using MethylTarget (TM) and QRT-PCR for 176/176 paired samples. Results: KLRC1, KLRC3, and SH2D1B were identified as significant DMGs. Validation revealed that KLRC1 was hypomethylated and highly expressed, whereas KLRC3 was hypermethylated and highly expressed in individuals with AIT. Furthermore, KLRC1 was hypomethylated and highly expressed in both IFA and IEA. Conclusion: The DNA methylation status of KLRC1 and KLRC3 may play crucial roles in AIT pathogenesis. Additionally, DNA methylation of KLRC1seems to be influenced by different iodine concentrations in water.

Endemic cretinism (EC) is one of the most severe iodine deficiency disorders, leading to typical symptoms such as neurodevelopmental impairments or mental deficits. In addition to environmental factors, the pathogenesis of its genetic contribution remains unclear. The study revealed the differential expression profiles of long non-coding RNA(lncRNA) and messenger RNA(mRNA) based on high-throughput RNA-seq. GO and KEGG analyses were used to annotate the function and pathway of differentially expressed (DE) mRNA and co-expressed mRNA. The protein–protein interaction(PPI) network was established. The expression levels of three lncRNAs and six mRNAs were validated by quantitative real-time PCR analysis (qRT-PCR) and subjected to correlation analysis. Compared to controls, a total of 864 lncRNAs and 393 mRNAs were differentially expressed. The PPI network had 149 nodes and 238 edges, and three key protein-coding genes were observed. Levels of LINC01220 and target mRNA IDO1 were statistically elevated in EC patients. Differentially expressed lncRNA may be a new potential player in EC. LINC01220 and IDO1 might interact with each other to participate in EC. The biological process of regulation of postsynaptic membrane potential and the Rap1 signaling pathway might exert a regulating role in the pathophysiological process of EC. Our findings could provide more theoretical and experimental evidence for investigating the pathophysiological mechanisms of EC.