1-Methyl-D-tryptophan activates aryl hydrocarbon receptor, a pathway associated with bladder cancer progression.

BACKGROUND: Indoleamine 2, 3-dioxygenase-1 (IDO1) is a promising target for immunotherapy in bladder cancer (BC). IDO1 breaks-down tryptophan to generate kynurenine derivatives, which may activate the aryl hydrocarbon receptor (AHR). AHR is an important target for carcinogens, but its association with BC progression was unknown. Two IDO1 inhibitors used in clinical trials are 1-methyl-D-tryptophan (MT) and INCB240360. Because MT is an aromatic hydrocarbon, it may be a ligand for AHR. We hypothesized that AHR could be associated with BC progression and that MT could activate AHR in BC. METHODS: BC patients (n = 165) were selected from the Gene Expression Omnibus database. A cut-off point for relative expression of AHR and cytochrome 450 enzymes (CYP1A1, CYP1A2, and CYP1B1; markers of AHR activation) was determined to compare with the grade, stage, and tumor progression. For in vitro experiments, RT4 (grade 1) and T24 (grade 3) BC cells were incubated with MT and INCB240360 to evaluate the expression of AHR and CYP1A1. RESULTS: AHR activation was associated with grade, stage, and progression of BC. T24 cells express more CYP1A1 than RT4 cells. Although IDO1 expression and kynurenine production are elevated in T24 cells concomitantly to CYP1A1 expression, IDO1 inhibitors were not able to decrease CYP1A1 expression, in contrast, MT significantly increased it in both cell lines. CONCLUSION: In conclusion, it is rational to inhibit IDO1 in BC, among other factors because it contributes to AHR activation. However, MT needs to be carefully evaluated for BC because it is an AHR pathway agonist independently of its effects on IDO1.

Similar hypothyroid and sepsis circulating mRNA expression could be useful as a biomarker in onthyroidal illness syndrome: a pilot study.

Objective: Based on hypothetical hypothyroidism and nonthyroidal illness syndrome (NTIS) gene expression similarities, we decided to compare the patterns of expression of both as models of NTIS. The concordant profile between them may enlighten new biomarkers for NTIS challenging scenarios. Materials and methods: We used Ion Proton System next-generation sequencing to build the hypothyroidism transcriptome. We selected two databanks in GEO2 platform datasets to find the differentially expressed genes (DEGs) in adults and children with sepsis. The ROC curve was constructed to calculate the area under the curve (AUC). The AUC, chi-square, sensitivity, specificity, accuracy, kappa and likelihood were calculated. We performed Cox regression and Kaplan-Meier analyses for the survival analysis. Results: Concerning hypothyroidism DEGs, 70.42% were shared with sepsis survivors and 61.94% with sepsis nonsurvivors. Some of them were mitochondrial gene types (mitGenes), and 95 and 88 were related to sepsis survivors and nonsurvivors, respectively. BLOC1S1, ROMO1, SLIRP and TIMM8B mitGenes showed the capability to distinguish sepsis survivors and nonsurvivors. Conclusion: We matched our hypothyroidism DEGs with those in adults and children with sepsis. Additionally, we observed different patterns of hypothyroid-related genes among sepsis survivors and nonsurvivors. Finally, we demonstrated that ROMO1, SLIRP and TIMM8B could be predictive biomarkers in children´s sepsis.

Circulating RNA Transcriptome of Pregnant Women with TSH Just Above the Trimester-Specific Reference and its Correlation with the Hypertensive Phenotype.

During gestation, a woman's body undergoes physiological changes that alter thyroid function. Pregnant women with hypothyroidism may exhibit gestational complications, including hypertension and preeclampsia. We investigated differentially expressed genes (DEGs) in circulating RNAs from pregnant women with TSH levels just above the normal range to determine the impact of a mild elevation of TSH in pregnancy. We selected three women with healthy thyroid pregnancy (HTP), three pregnant women with gestational hypothyroidism (GHT), and three nonpregnant women (NPG) to construct transcriptome libraries. We also compared our results with data from the GEO dataset and DisGeNET. We identified 1500 DEG in GHT and 1656 DEG in HTP. From GEO dataset, we recognized 453 DEGs in trimester-specific plasma RNA, 1263 DEGs in placental tissues from healthy women, 1031 DEGs from preeclamptic uteroplacental tissues and 1657 DEGs from placental tissues from severely preeclamptic women. In this scenario, 12.26% and 12.86% genes were shared between these datasets in GHT and HTP, respectively. We stablished 62 genes in GHT DEGs related to hypertensive phenotype hallmarks. In conclusion, even in women with a mild TSH increment, we were able to detect some DEGs that could be associated with a hypertensive phenotype.

Proteinuria is Associated with Urinary Loss of Cubilin and Vitamin D-Binding Protein in Patients with Preeclampsia.

Women with preeclampsia (PE) form a vulnerable group for vitamin D3 deficiency. Reabsorption of vitamin D3 occurs in the proximal tubule after being endocytosed in combination with DBP (vitamin D binding protein) by the megalin/cubilin receptor. Because proteinuria promotes tubule injury and dysfunction, we hypothesized that the proteinuria present in PE could promote the loss of these components into the urine. Twenty preeclamptic patients and ten normal pregnant women with a gestational age greater than 20 weeks composed three groups: NC, normotensive control pregnant patients; PE, non-proteinuric preeclamptic patients; and PPE, preeclamptic patients with proteinuria. When proteinuria was absent, preeclampsia was diagnosed accordingly to the American College of Obstetricians and Gynecologists' (ACOG) guideline. The presence of 24-hour proteinuria equal to or greater than 300 mg was considered to form the PPE group. Urinary cubilin, megalin, and DBP were measured by ELISA and normalized by urinary creatinine. Regarding gestational age, there was no difference between the groups. NC group had arterial pressure within normal values, whereas PE and PPE groups had a significant increase (p < 0.01). As expected, PPE group presented elevated ACR (p < 0.05), accompanied by large amounts of cubilin and DBP in the urine (p < 0.05 vs. NC and PE). No difference was found in urinary megalin. PPE patients showed more chance of shedding cubilin into the urine compared to non-proteinuric patients (odds ratio 12.7 (1.2-136.3). In conclusion, this study further tightens the relationship between PE and vitamin D3 deficiency, since proteinuria present in PE induces the loss of molecules responsible for renal tubular vitamin D3 reabsorption for subsequent activation. Combined with other factors, the proteinuria may intensify vitamin D3 deficiency in PE.

Two Thyroid Stimulating Hormone assays correlated in clinical practice show disagreement in subclinical hypothyroidism patients.

Thyroid Stimulating Hormone (TSH) levels are related to the pituitary gland's ability to detect thyroid hormone concentration. Many studies have analyzed the correlation between TSH and T4, demonstrating a complex system correlation. This complex system may vary among different TSH levels and patients. OBJECTIVES: The main purpose of this study is to assess the correlation and agreement of serum TSH measured with two assays in different settings. DESIGN & METHODS: We evaluated healthy individuals as well as subclinical or overt hypothyroid patients. Eighty participants had TSH levels measured by Cobas Roche Elecsys 600 (Roche Diagnostics) and Abbott Architect I 2000 (Abbott Diagnostics). The TSH methods correlations were established with Pearson's correlation, and the strength of the agreement was determined by the McBride scale. The paired Student's t-test was applied to evaluate TSH values from both methods. The one-sample t-test was used to evaluate the difference between TSH values. The agreement was also assessed by a Bland-Altman plot. A regression analysis was applied to the correlation between TSH and T4. RESULTS: There was a significant difference in TSH values measured by the two methods (p<0.01). Our results demonstrated a poor correlation for TSH in the euthyroid (r: 0.888, p<0.01) and the subclinical hypothyroid (r:0.886, p<0.01) range. The Bland-Altman plot demonstrates that the majority of the TSH values fell between the lines of equality. There were few differences in the values in the normal upper range and slightly above that range (from a TSH: 3.25 to 6.36mUI/L). The level of correlation between TSH assays remains high in all scenarios for age (r≥0.951), BMI (r≥0.962), anti-TPO antibodies (r: 0.977) or levothyroxine use (r: 0.970). CONCLUSIONS: TSH measurement is essential to access thyroid function. Although the overall agreement between the methods is substantial, there was a poor agreement in the normal upper range and close above. The disagreement observed reinforces the difficulty in using different assays in clinical practice. The better correlation with fT4 and the reference range used by Cobas assay allowed the best clinical performance.