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.

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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 D 3 deficiency, since proteinuria present in pe induces the loss of molecules responsible for renal tubular vitamin D 3 reabsorption for subsequent activation. Combined with other factors, the proteinuria may intensify vitamin D 3 deficiency in PE. Preeclampsia (PE) is a multisystem disorder of pregnancy in which renal damage has a significant contribution. A set level of proteinuria has been used to predict high-risk groups and define treatment for PE. In terms of physiopathology, proteinuria emerges due to processes that disturb the glomerular filtration barrier. Besides the classical mechanisms of glomerular damage such as endotheliosis and loss of podocytes 1,2 , an evidence for tubular injury have also been reported. Markers of proximal tubule injury such as kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and retinol-binding protein (RBP) were higher in the urine of PE patients than in urine of healthy pregnancies 3 In addition, urinary lysosomal enzyme excretion is elevated in patients with PE compared to a pregnant woman with chronic hypertension 4. Burwick et al. demonstrated that pregnancies affected by severe PE have high amounts of KIM-1 in the urine, which was closely correlated with urinary complement activation products, suggesting that tubular injury in PE is intensified by inflammation-activated complement 5. Direct effects of proteinuria on tubular cell damage have been ...

Background Indoleamine 2,3‐dioxygenase (IDO) is an enzyme that acts as an immunomodulatory molecule. It is found in several cancer types where it seems to be associated with tumor escape due to its immunosuppressive mechanisms. Some studies have reported a correlation between carcinogenesis and changes in IDO expression. However, the role of IDO expression in prostate cancer (PC) is unclear. The aim of our study was to evaluate the expression of IDO in localized PC, and to correlate its expression with the classic prognostic factor and recurrence after surgical treatment. Methods For this case‐control study, we retrospectively evaluated surgical specimens from 111 patients with localized PC, who underwent radical prostatectomy. Recurrence was defined as a prostate specific antigen (PSA) level exceeding 0.2 ng/ml postoperatively, and the median follow‐up was 123 months. IDO expression was evaluated by immunohistochemistry in 72 cases of which 42 (58%) had biochemical recurrence. Results We found that lower IDO expression was associated with higher Gleason score (p = 0.022) and PSA levels (p = 0.042). The multivariate analyses revealed that the loss of IDO expression and higher PSA levels were independently associated with biochemical recurrence. The chance of recurrence was increased by 85% in patients with lower IDO expression (OR = 0.15; p = 0.009 CI 95% [0.038–0.633]) and increased by 5.5 times in patients with higher PSA levels (OR = 5.51; p = 0.012 CI 95% [1.435–21.21]). The recurrence‐free survival curve also demonstrates that lower IDO expression (p = 0.0004) was associated with lower time to biochemical recurrence. Conclusion The loss of IDO expression was associated with increased chance of biochemical recurrence, higher PSA, and a Gleason score in localized PC. Support or Funding Information The study was supported by São Paulo Research Foundation (FAPESP) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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.

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Low-cost solar dryers are an alternative for democratizing access to this technology. This work aimed to design a low-cost solar dryer and to evaluate its viability by modeling the drying kinetics of araticum (Annona crassiflora Mart.). The construction of the prototype used low-cost materials. The araticum drying occurred until the samples reached equilibrium moisture. The data were processed to adapt the kinetic models.The araticum pulp, after 420 min of drying, had a constant mass with 2.67% ± 0.28% of moisture. The Midilli, Kucuk & Yapar model was the evaluated model that best fit the drying curve. It was possible to determine three diffusion coefficients associated with the process. It was inferred that the built dryer and the climatic conditions were efficient for drying the product and demanded little expense for its construction. The tested empirical models were able to accurately describe the solar drying of this fruit. Novelty impact statement:The designed dryer showed efficacy in the drying process of araticum pulp. It was possible to mathematically model the solar drying process kinetics for araticum. The equipment requests low investment and can democratize access to the drying process.

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