Although stressful events are known to trigger Graves’ disease (GD), the mechanisms involved in this process are not well understood. The NR3C1 gene, encoding for the glucocorticoid receptor (GR), presents single nucleotide polymorphisms (SNPs) that are associated with stress-related diseases. To investigate the relationship between NR3C1 SNPs, GD susceptibility, and clinical features, we studied 792 individuals, including 384 patients, among which 209 presented with Graves’ orbitopathy (GO), and 408 paired healthy controls. Stressful life events were evaluated in a subset of 59 patients and 66 controls using the IES-R self-report questionnaire. SNPs rs104893913, rs104893909, and rs104893911 appeared at low frequencies and presented similar profiles in patients and controls. However, variant forms of rs6198 were rarer in GD patients, suggesting a protective effect. Stressful events were more common in patients than controls, and were reported to have clearly occurred immediately before the onset of GD symptoms in 23 cases. However, no association was found between these events and rs6198 genotypes or GD/GO characteristics. We suggest that the NR3C1 rs6198 polymorphism may be an important protective factor against GD, but its relationship with stressful events needs further investigation.

Objective: Abnormalities involving the TGFB1 gene and its receptors are common in several types of cancer and often related to tumor progression. We investigated the role of single nucleotide polymorphisms (SNP) in the susceptibility to cancer, their impact on its features, as well as the role of mRNA expression of these genes in thyroid malignancy. Materials and methods: We genotyped TGFB1, TGFBR1, and TGFBR2 SNPs in 157 papillary thyroid cancer (PTC) patients and 200 healthy controls. Further, we investigated RNA samples of 47 PTC and 80 benign nodules, searching for differential mRNA expression. Results: SNPs rs1800472 and rs1800469 were associated with characteristics of PTC aggressiveness. Effect predictor software analysis of nonsynonymous SNP rs1800472 indicated increasing protein stability and post-translational changes. TGFB1 mRNA expression was upregulated in PTC and downregulated in benign samples, differentiating malignant from benign nodules (p<0.0001); PTC from goiter (p<0.0001); and PTC from FA (p<0.0001). TGFBR1 mRNA expression was upregulated in goiter and PTC, but downregulated in FA, distinguishing PTC from goiter (p=0.0049); PTC from FA (p<0.0001); and goiter from FA (p=0.0267). On the other hand, TGFBR2 was downregulated in all histological types analyzed and was not able to differentiate thyroid nodules. Conclusion: TGFB1 polymorphism rs1800472 may confer greater activity to TGF-beta 1 in the tumor microenvironment, favoring PTC aggressiveness. Evaluation of TGFB1 and TGFBR1 mRNA levels may be useful to identify malignancy in thyroid nodules.

To better understand the relationship among cell adhesion molecules (CAM) and investigate the clinical diagnostic and prognostic application of ICAM-1 (ICAM1), LFA-1 (ITGAL), and L-selectin (SELL) proteins and mRNA corresponding expression in thyroid cancer. Gene expression was evaluated by RT–qPCR, and protein expression was evaluated by immunohistochemistry. We evaluated 275 patients (218 women, 57 men, 48.4 ± 14.5 years old), including 102 benign and 173 malignant nodules. The 143 papillary thyroid carcinoma (PTC) and 30 follicular thyroid carcinoma (FTC) patients were managed according to current guidelines and followed-up for 78.7 ± 54.2 months. Malignant and benign nodules differed concerning mRNA (p = 0.0027) and protein (p = 0.0020 for nuclear) expression of L-selectin and ICAM-1 (mRNA: p = 0.0001 and protein: p = 0.0014) and protein expression of LFA-1 (p = 0.0168), but not mRNA expression of LFA-1 (p = 0.2131). SELL expression was more intense in malignant tumors (p = 0.0027). ICAM1 (p = 0.0064) and ITGAL (p = 0.0244) mRNA expression was higher in tumors with lymphocyte infiltrate. ICAM-1 expression correlated with younger age at diagnosis (p = 0.0312) and smaller tumor size (p = 0.0443). Also, LFA-1 expression correlated with higher age at diagnosis (p = 0.0376) and was more intense at stage III and IV (p = 0.0077). In general, the protein expression of the 3 CAM decreased as the process of cellular dedifferentiation occurred. We suggest that the SELL and ICAM1 genes and L-selectin and LFA-1 protein expression may help confirm malignancy and assist in the histological characterization of follicular patterned lesions, but we were unable to correlate these CAMs with patient outcomes.

Understanding the complex mechanisms involved in diseases caused by or related to important genetic variants has led to the development of clinically useful biomarkers. However, the increasing number of described variants makes it difficult to identify variants worthy of investigation, and poses challenges to their validation. We combined publicly available datasets and open source robust bioinformatics tools with molecular quantum chemistry methods to investigate the involvement of selectins, important molecules in the cell adhesion process that play a fundamental role in the cancer metastasis process. We applied this strategy to investigate single nucleotide variants (SNPs) in the intronic and UTR regions and missense SNPs with amino acid changes in the SELL, SELP, SELE, and SELPLG genes. We then focused on thyroid cancer, seeking these SNPs potential to identify biomarkers for susceptibility, diagnosis, prognosis, and therapeutic targets. We demonstrated that SELL gene polymorphisms rs2229569, rs1131498, rs4987360, rs4987301 and rs2205849; SELE gene polymorphisms rs1534904 and rs5368; rs3917777, rs2205894 and rs2205893 of SELP gene; and rs7138370, rs7300972 and rs2228315 variants of SELPLG gene may produce important alterations in the DNA structure and consequent changes in the morphology and function of the corresponding proteins. In conclusion, we developed a strategy that may save valuable time and resources in future investigations, as we were able to provide a solid foundation for the selection of selectin gene variants that may become important biomarkers and deserve further investigation in cancer patients. Large-scale clinical studies in different ethnic populations and laboratory experiments are needed to validate our results.

Sickle cell anemia is a hereditary disease caused by sickle-shaped red blood cells that can lead to vaso-occlusive crises. Treatment options are currently limited, highlighting the need to develop new clinical approaches. Studies demonstrated that elevated levels of fetal hemoglobin (Hb F) are associated with a reduction of mortality and morbidity in sickle cell anemia patients. In light of this, researchers have been trying to elucidate the transcriptional regulation of Hb F to develop new therapeutic interventions. The present study aimed to present the main transcription factors of Hb F and discuss the clinical feasibility of these molecular targets. Two search strategies were used in the PubMed, SciELO, and LILACS databases between July and August 2023 to conduct this review. Manual searches were also conducted by checking references of potentially eligible studies. Eligibility criteria consisted of clinical trials and cohort studies from the last five years that investigated transcription factors associated with Hb F. The transcription factors investigated in at least four eligible studies were included in this review. As a result, 56 eligible studies provided data on the BCL11A, LRF, NF-Y, GATA1, KLF1, HRI, ATF4, and MYB factors. The studies demonstrated that Hb F is cooperatively regulated by transcription factors with the BCL11A factor appearing to be the most specific target gene for γ-globin induction. Although these data are promising, there are still significant gaps and intervention limitations due to the adverse functions of the target genes. New studies that clarify the aspects and functionalities of Hb F regulators may enable new clinical approaches for sickle cell anemia patients.