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The expression of inflammation-related miRs bound to high-density lipoproteins (HDLs), the anti-inflammatory activity of HDLs isolated from individuals with breast cancer, and controls were determined. Forty newly diagnosed women with breast cancer naïve of treatment and 10 control participants were included. Cholesterol-loaded bone-marrow-derived macrophages were incubated with HDL from both groups and challenged with lipopolysaccharide (LPS). Interleukin 6 (IL6) and tumor necrosis factor (TNF) in the medium were quantified. The miRs in HDLs were determined by RT-qPCR. Age, body mass index, menopausal status, plasma lipids, and HDL composition were similar between groups. The ability of HDL to inhibit IL6 and TNF production was higher in breast cancer compared to controls, especially in advanced stages of the disease. The miR-223-3p and 375-3p were higher in the HDLs of breast cancer independent of the histological type of the tumor and had a high discriminatory power between breast cancer and controls. The miR-375-3p was greater in the advanced stages of the disease and was inversely correlated with the secretion of inflammatory cytokines. Inflammation-related miRs and the anti-inflammatory role of HDLs may have a significant impact on breast cancer pathophysiology.
Assuntos
Neoplasias da Mama , MicroRNAs , Humanos , Feminino , Neoplasias da Mama/genética , Interleucina-6 , MicroRNAs/genética , Anti-Inflamatórios/farmacologia , Inflamação/genética , Lipoproteínas HDL , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND: The diagnosis of cancer in Bethesda III/IV thyroid nodules is challenging as fine-needle aspiration (FNA) has limitations, and these cases usually require diagnostic surgery. As approximately 77% of these nodules are not malignant, a diagnostic test accurately identifying benign thyroid nodules can reduce "potentially unnecessary" surgery rates. We have previously reported the development and validation of a microRNA-based thyroid classifier (mir-THYpe) with high sensitivity and specificity, which could be performed directly from FNA smear slides. We sought to evaluate the performance of this test in real-world clinical routine to support clinical decisions and to reduce surgery rates. METHODS: We designed a real-world, prospective, multicentre study. Molecular tests were performed with FNA samples prepared at 128 cytopathology laboratories. Patients were followed-up from March 2018 until surgery or until March 2020 (patients with no indication for surgery). The final diagnosis of thyroid tissue samples was retrieved from postsurgical anatomopathological reports. FINDINGS: A total of 435 patients (440 nodules) classified as Bethesda III/IV were followed-up. The rate of avoided surgeries was 52·5% for all surgeries and 74·6% for "potentially unnecessary" surgeries. The test achieved 89·3% sensitivity, 81·65% specificity, 66·2% positive predictive value, and 95% negative predictive value. The test supported 92·3% of clinical decisions. INTERPRETATION: The reported data demonstrate that the use of the microRNA-based classifier in the real-world can reduce the rate of thyroid surgeries with robust performance and support clinical decision-making. FUNDING: The São Paulo Research-Foundation (FAPESP) and Onkos.
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Sistemas de Apoio a Decisões Clínicas , MicroRNAs , Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Brasil , Humanos , MicroRNAs/genética , Estudos Prospectivos , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/cirurgia , Nódulo da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/patologiaRESUMO
Thyroid cancer is the most common endocrine malignancy, and papillary thyroid carcinoma (PTC) is the main subtype. The cribriform morular variant is a histological phenotype of PTC characterized by its relationship with familial adenomatous polyposis (FAP). Description of the case: We report the genetic assessment of a 20-year-old female patient diagnosed with a cribriform-morular variant of PTC and FAP. We aimed to assess the genetic background of the reported patient, looking for variants that would help us explain the predisposition to tumorigenesis. Genomic DNA was extracted from peripheral blood lymphocytes, and whole exome sequencing was performed. We applied an overrepresentation and gene-set enrichment analysis to look for an accumulation of effects of variants in multiple genes at the genome. We found an overrepresentation of single nucleotide variants (SNVs) in extracellular matrix interactions and cell adhesion genes. Underrepresentation of SNVs in genes related to the regulation of autophagy and cell cycle control was also observed. We hypothesize that the package of alterations of our patient may help to explain why she presented colonic manifestations and thyroid cancer. Our findings suggest that multiple variants with minor impact, when considered together, may be helpful to characterize one particular clinical condition.
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Polipose Adenomatosa do Colo , Neoplasias da Glândula Tireoide , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Feminino , Patrimônio Genético , Humanos , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/patologiaRESUMO
SUMMARY Thyroid cancer is the most common endocrine malignancy, and papillary thyroid carcinoma (PTC) is the main subtype. The cribriform morular variant is a histological phenotype of PTC characterized by its relationship with familial adenomatous polyposis (FAP). Description of the case: We report the genetic assessment of a 20-year-old female patient diagnosed with a cribriform-morular variant of PTC and FAP. We aimed to assess the genetic background of the reported patient, looking for variants that would help us explain the predisposition to tumorigenesis. Genomic DNA was extracted from peripheral blood lymphocytes, and whole exome sequencing was performed. We applied an overrepresentation and gene-set enrichment analysis to look for an accumulation of effects of variants in multiple genes at the genome. We found an overrepresentation of single nucleotide variants (SNVs) in extracellular matrix interactions and cell adhesion genes. Underrepresentation of SNVs in genes related to the regulation of autophagy and cell cycle control was also observed. We hypothesize that the package of alterations of our patient may help to explain why she presented colonic manifestations and thyroid cancer. Our findings suggest that multiple variants with minor impact, when considered together, may be helpful to characterize one particular clinical condition.
Assuntos
Humanos , Feminino , Neoplasias da Glândula Tireoide/patologia , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Patrimônio Genético , Câncer Papilífero da Tireoide/genéticaRESUMO
BACKGROUND: An accurate prediction of progression is critical to define the management of bladder cancer (BC). The ectonucleotidases CD39 and CD73 play strategic roles in calibrating purinergic signals via an extracellular balance between ATP and adenosine. The altered expression of these enzymes plays a potential role in tumor invasion and metastasis, therefore, has been proposed to be used for prognosis of solid tumor. In BC this is not yet clear. OBJECTIVE: This study aimed to evaluate CD39 and CD73 expression in a cohort of patients with non-muscle-invasive (NMI) and muscle-invasive (MI) BC regard to its association with clinicopathological features. MATERIALS AND METHODS: Retrospective clinical follow-up data and primary urothelial BC specimens of 162 patients were used (87 from patients who underwent transurethral resection and 75 from cystectomized patients). Tissue microarrays were constructed, and immunohistochemistry for CD39 and CD73 was performed to make associations with clinicopathological data. RESULTS: Overall, 96 were NMI (59.3%) and 66 MI (40.7%). CD39 immunoreactivity in BC cells was found in 72% of the cases, while CD73 was found in 97%. High CD39 expression alone was more frequent in NMI BC (p < 0.001), while CD73 expression was not powerful to predict the stage of BC. The association of both markers confirmed that only CD39 has potential in BC prognosis. CONCLUSIONS: The altered expression of CD39 presented herein supports the idea that this ectonucleotidase may be involved in bladder tumorigenesis. High expression of CD39 in tumor cells is correlated with the early stage of BC.
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Medullary thyroid carcinoma (MTC) is a malignant tumor originating from thyroid C-cells that can occur either in sporadic (70-80%) or hereditary (20-30%) form. In this study we aimed to identify recurrent copy number alterations (CNA) that might be related to the pathogenesis or progression of MTC. We used Affymetrix SNP array 6.0 on MTC and paired-blood samples to identify CNA using PennCNV and Genotyping Console software. The algorithms identified recurrent copy number gains in chromosomes 15q, 10q, 14q and 22q in MTC, whereas 4q cumulated losses. Coding genes were identified within CNA regions. The quantitative PCR analysis performed in an independent series of MTCs (n = 51) confirmed focal recurrent copy number gains encompassing the DLK1 (14q32.2) and AIFM3 (22q11.21) genes. Immunohistochemistry confirmed AIFM3 and DLK1 expression in MTC cases, while no expression was found in normal thyroid tissues and few MTC samples were found with normal copy numbers. The functional relevance of CNA was also assessed by in silico analysis. CNA status correlated with protein expression (DLK1, p = 0.01), tumor size (DLK1, p = 0.04) and AJCC staging (AIFM3p = 0.01 and DLK1p = 0.05). These data provide a novel insight into MTC biology, and suggest a common CNA landscape, regardless of if it is sporadic or hereditary MTC.
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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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Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Receptores de Hidrocarboneto Arílico/genética , Triptofano/análogos & derivados , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/sangue , Linhagem Celular Tumoral , Citocromo P-450 CYP1A1/sangue , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/sangue , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1B1/sangue , Citocromo P-450 CYP1B1/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/sangue , Cinurenina/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/sangue , Transdução de Sinais/efeitos dos fármacos , Triptofano/farmacologia , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
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.
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Ácidos Nucleicos Livres/metabolismo , Hipotireoidismo/complicações , Pré-Eclâmpsia/diagnóstico , Tireotropina/sangue , Adulto , Ácidos Nucleicos Livres/sangue , Biologia Computacional , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/diagnóstico , Hipotireoidismo/genética , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/genética , Gravidez , Terceiro Trimestre da Gravidez/sangue , Terceiro Trimestre da Gravidez/genética , Valores de Referência , Tireotropina/normas , Transcriptoma , Adulto JovemRESUMO
BACKGROUND: Indoleamine 2,3-dioxygenase (IDO1) is an enzyme that acts as an immunomodulatory molecule. It is found in several types of cancer where it seems to be associated with tumor escape due to its immunosuppressive mechanisms. However, the role of IDO1 expression in prostate cancer (PC) is unclear. The aim of our study was to evaluate the expression of IDO1 in localized PC and to correlate with the classic prognostic factor and recurrence after surgical treatment. METHODS: 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 follow-up was 123 months. IDO1 expression was evaluated by immunohistochemistry in 72 cases of which 42 (58%) had biochemical recurrence. RESULTS: Lower IDO1 expression was associated with higher Gleason score (p = 0.022) and PSA levels (p = 0.042). The multivariate analyses revealed that the loss of IDO1 and higher PSA were independently associated with biochemical recurrence. The chance of recurrence was increased by 85% in patients with lower IDO1 [OR = 0.15; p = 0.009 CI 95% (0.038-0.633)] and increased by 5.5 times in patients with higher PSA [OR = 5.51; p = 0.012 CI 95% (1.435-21.21)]. The recurrence-free survival curve also demonstrates that lower IDO1 was associated with lower time to biochemical recurrence (p = 0.0004). CONCLUSION: The loss of IDO1 expression was associated with increased chance of biochemical recurrence, higher PSA, and a Gleason score in localized PC.
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Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese , Neoplasias da Próstata/enzimologia , Adulto , Idoso , Correlação de Dados , Intervalo Livre de Doença , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/enzimologia , Prognóstico , Prostatectomia , Neoplasias da Próstata/cirurgia , Estudos RetrospectivosRESUMO
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.