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1.
Cell Oncol (Dordr) ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33534128

RESUMO

PURPOSE: Non-medullary thyroid cancer (NMTC) treatment is based on the ability of thyroid follicular cells to accumulate radioactive iodide (RAI). However, in a subset of NMTC patients tumor dedifferentiation occurs, leading to RAI resistance. Digoxin has been demonstrated to restore iodide uptake capacity in vitro in poorly differentiated and anaplastic NMTC cells, termed redifferentiation. The aim of the present study was to investigate the in vivo effects of digoxin in TPO-Cre/LSL-BrafV600E mice and digoxin-treated NMTC patients. METHODS: Mice with thyroid cancer were subjected to 3D ultrasound for monitoring tumor growth and 124I PET/CT for measurement of intratumoral iodide uptake. Post-mortem analyses on tumor tissues comprised gene expression profiling and measurement of intratumoral autophagy activity. Through PALGA (Dutch Pathology Registry), archived tumor material was obtained from 11 non-anaplastic NMTC patients who were using digoxin. Clinical characteristics and tumor material of these patients were compared to 11 matched control NMTC patients never treated with digoxin. RESULTS: We found that in mice, tumor growth was inhibited and 124I accumulation was sustainably increased after short-course digoxin treatment. Post-mortem analyses revealed that digoxin treatment increased autophagy activity and enhanced expression of thyroid-specific genes in mouse tumors compared to vehicle-treated mice. Digoxin-treated NMTC patients exhibited significantly higher autophagy activity and a higher differentiation status as compared to matched control NMTC patients, and were associated with favourable clinical outcome. CONCLUSIONS: These in vivo data support the hypothesis that digoxin may represent a repositioned adjunctive treatment modality that suppresses tumor growth and improves RAI sensitivity in patients with RAI-refractory NMTC.

2.
Immunology ; 2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33454989

RESUMO

The endocrine and the immune systems interact by sharing receptors for hormones and cytokines, cross-control and feedback mechanisms. To date, no comprehensive study has assessed the impact of thyroid hormones on immune homeostasis. By studying immune phenotype (cell populations, antibody concentrations, circulating cytokines, adipokines and acute-phase proteins, monocyte-platelet interactions and cytokine production capacity) in two large independent cohorts of healthy volunteers of Western European descent from the Human Functional Genomics Project (500FG and 300BCG cohorts), we identified a crucial role of the thyroid hormone thyroxin (T4) and thyroid-stimulating hormone (TSH) on the homeostasis of lymphocyte populations. TSH concentrations were strongly associated with multiple populations of both effector and regulatory T cells, whereas B-cell populations were significantly associated with free T4 (fT4). In contrast, fT4 and TSH had little impact on myeloid cell populations and cytokine production capacity. Mendelian randomization further supported the role of fT4 for lymphocyte homeostasis. Subsequently, using a genomics approach, we identified genetic variants that influence both fT4 and TSH concentrations and immune responses, and gene set enrichment pathway analysis showed enrichment of fT4-affected gene expression in B-cell function pathways, including the CD40 pathway, further supporting the importance of fT4 in the regulation of B-cell function. In conclusion, we show that thyroid function controls the homeostasis of the lymphoid cell compartment. These findings improve our understanding of the immune responses and open the door for exploring and understanding the role of thyroid hormones in the lymphocyte function during disease.

3.
Ann Transl Med ; 8(16): 1028, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32953828

RESUMO

Tumor associated macrophages (TAMs) are important components of the tumor microenvironment (TME). They are characterized by a remarkable functional plasticity, thereby mostly promoting cancer progression. Changes in immune cell metabolism are paramount for this functional adaptation. Here, we review the functional consequences of the metabolic programming of TAMs and the influence of local and systemic targeted therapies on the metabolic characteristics of the TME that shape the functional phenotype of the TAMs. Understanding these metabolic changes within the context of the cross-talk between the different components of the TME including the TAMs and the tumor cells is an essential step that can pave the way towards identifications of ways to improve responses to different treatments, to overcome resistance to treatments, tumor progression and reduce treatment-specific toxicity.

4.
J Immunother Cancer ; 8(2)2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32943450

RESUMO

BACKGROUND: Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME) in non-medullary thyroid carcinoma (TC) and neuroblastoma (NB), being associated with a poor prognosis for patients. However, little is known about how tumors steer the specific metabolic phenotype and function of TAMs. METHODS: In a human coculture model, transcriptome, metabolome and lipidome analysis were performed on TC-induced and NB-induced macrophages. The metabolic shift was correlated to functional readouts, such as cytokine production and reactive oxygen species (ROS) production, including pharmacological inhibition of metabolic pathways. RESULTS: Based on transcriptome and metabolome analysis, we observed a strong upregulation of lipid biosynthesis pathways in TAMs. Subsequently, lipidome analysis revealed that tumor-induced macrophages have an increased total lipid content and enriched levels of intracellular lipids, especially phosphoglycerides and sphingomyelins. Strikingly, this metabolic shift in lipid synthesis contributes to their protumoral functional characteristics: blocking key enzymes of lipid biosynthesis in the tumor-induced macrophages reversed the increased inflammatory cytokines and the capacity to produce ROS, two well-known protumoral factors in the TME. CONCLUSIONS: Taken together, our data show that tumor cells can stimulate lipid biosynthesis in macrophages to induce protumoral cytokine and ROS responses and advocate lipid biosynthesis as a potential therapeutic target to reprogram the TME.

5.
Nat Commun ; 11(1): 3981, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769997

RESUMO

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.


Assuntos
Pleiotropia Genética , Estudo de Associação Genômica Ampla , Neoplasias da Glândula Tireoide/genética , Tireotropina/genética , Loci Gênicos , Predisposição Genética para Doença , Bócio/genética , Humanos , Análise da Randomização Mendeliana , Herança Multifatorial/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Mapeamento Físico do Cromossomo , Prevalência , Fatores de Risco , Tireoglobulina/genética , Neoplasias da Glândula Tireoide/epidemiologia
6.
Rev Endocr Metab Disord ; 21(4): 547-568, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32458292

RESUMO

Acromegaly is characterized by Growth Hormone (GH) and Insulin-like Growth Factor 1 (IGF-1) excess. Uncontrolled acromegaly is associated with a strongly increased risk of cardiovascular disease (CVD), and numerous cardiovascular risk factors remain present after remission. GH and IGF-1 have numerous effects on the immune and cardiovascular system. Since endothelial damage and systemic inflammation are strongly linked to the development of CVD, and have been suggested to be present in both controlled as uncontrolled acromegaly, they may explain the presence of both micro- and macrovascular dysfunction in these patients. In addition, these changes seem to be only partially reversible after remission, as illustrated by the often reported presence of endothelial dysfunction and microvascular damage in controlled acromegaly. Previous studies suggest that insulin resistance, oxidative stress, and endothelial dysfunction are involved in the development of CVD in acromegaly. Not surprisingly, these processes are associated with systemic inflammation and respond to GH/IGF-1 normalizing treatment.

7.
Proc Natl Acad Sci U S A ; 117(11): 5997-6002, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32132206

RESUMO

Genome-wide association studies (GWASs) have identified at least 10 single-nucleotide polymorphisms (SNPs) associated with papillary thyroid cancer (PTC) risk. Most of these SNPs are common variants with small to moderate effect sizes. Here we assessed the combined genetic effects of these variants on PTC risk by using summarized GWAS results to build polygenic risk score (PRS) models in three PTC study groups from Ohio (1,544 patients and 1,593 controls), Iceland (723 patients and 129,556 controls), and the United Kingdom (534 patients and 407,945 controls). A PRS based on the 10 established PTC SNPs showed a stronger predictive power compared with the clinical factors model, with a minimum increase of area under the receiver-operating curve of 5.4 percentage points (P ≤ 1.0 × 10-9). Adding an extended PRS based on 592,475 common variants did not significantly improve the prediction power compared with the 10-SNP model, suggesting that most of the remaining undiscovered genetic risk in thyroid cancer is due to rare, moderate- to high-penetrance variants rather than to common low-penetrance variants. Based on the 10-SNP PRS, individuals in the top decile group of PRSs have a close to sevenfold greater risk (95% CI, 5.4-8.8) compared with the bottom decile group. In conclusion, PRSs based on a small number of common germline variants emphasize the importance of heritable low-penetrance markers in PTC.


Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Herança Multifatorial , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Estudo de Associação Genômica Ampla , Humanos , Islândia/epidemiologia , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Penetrância , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Curva ROC , Medição de Risco/métodos , Fatores de Risco , Câncer Papilífero da Tireoide/epidemiologia , Câncer Papilífero da Tireoide/patologia , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/patologia , Reino Unido/epidemiologia , Estados Unidos/epidemiologia
8.
J Voice ; 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32005626

RESUMO

BACKGROUND: Active acromegaly is characterized by Growth Hormone and Insulin-like Growth Factor (IGF)-1 excess. Voice complaints are common in active acromegaly and are suggested to be caused by effects of Growth Hormone or IGF-1 on vocal cords and the surrounding soft tissues. Prospective studies on the course of voice characteristics in acromegaly patients are scarce and results are conflicting. This study investigates objective changes in voice parameters, self-reported perception of voice and laryngostroboscopic features during the first 2.5 years of acromegaly treatment. MATERIAL AND METHOD: In this prospective study, acoustic voice analysis (and videolaryngostroboscopic examination were performed in 27 consecutive treatment-naive acromegaly patients at diagnosis (T0), after 1 year (T1) and after 2.5 years (T2) of treatment. The voice handicap index (VHI-30) questionnaire was taken. RESULTS: During acromegaly treatment, VHI scores decreased, and mucosal edema & hypertrophy diminished. No significant changes in objective voice parameters were detected. The within-subject change in serum IGF-1 levels (97.3 (40.6-208) to 22.4 (10.2-34.1) nmol/L (P < 0.001)) during follow-up correlated positively with the changes in VHI questionnaire scores (R 0.32-0.45; P = 0.002-0.03). CONCLUSIONS: At diagnosis and during acromegaly treatment, mean VHI scores were in the normal range, although they decreased during follow-up. Mucosal edema and hypertrophy largely resolved during treatment. No significant changes in objective voice parameters were observed. Voice characteristics are in the normal range in patients with acromegaly, but may change during treatment. However, voice complaints are important to discuss, since they may influence quality of life.

9.
Thyroid ; 30(8): 1169-1176, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32079487

RESUMO

Background: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to evaluate fertility in female survivors of childhood DTC by assessing various reproductive characteristics combined with anti-Müllerian hormone (AMH) levels (a marker of ovarian reserve). Methods: Female survivors of childhood DTC, diagnosed at ≤18 years of age between 1970 and 2013, were included. Survivors were excluded when follow-up time was less than five years or if they developed other malignancies before or after diagnosis of DTC. Survivors filled out a questionnaire regarding reproductive characteristics (e.g., age at menarche and menopause, pregnancies, pregnancy outcomes, need for assisted reproductive therapy). Survivors aged <18 years during evaluation received an altered questionnaire without questions regarding pregnancy and pregnancy outcomes. These data were combined with information from medical records. AMH levels were measured in serum samples and were compared with AMH levels from 420 women not treated for cancer. Results: Fifty-six survivors with a median age of 31.0 (interquartile range, IQR, 25.1-39.6) years were evaluated after a median follow-up of 15.4 (IQR 8.3-24.7) years. The median cumulative dose of 131I administered was 7.4 (IQR 3.7-13.0) GBq/200.0 (IQR 100.0-350.0) mCi. Twenty-five of the 55 survivors aged 18 years or older during evaluation reported 64 pregnancies, 45 of which resulted in live birth. Of these 55, 10.9% visited a fertility clinic. None of the survivors reported premature menopause. Age at AMH evaluation did not differ between DTC survivors and the comparison group (p = 0.268). Median AMH levels did not differ between DTC survivors and the comparison group [2.0 (IQR 1.0-3.7) µg/L vs. 1.6 (IQR 0.6-3.1) µg/L, respectively, p = 0.244]. The cumulative dose of 131I was not associated with AMH levels in DTC survivors (rs = 0.210, p = 0.130). Conclusions: Female survivors of DTC who received 131I treatment during childhood do not appear to have major abnormalities in reproductive characteristics nor in predictors of ovarian failure.

10.
Psychol Health ; 35(2): 128-143, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31130004

RESUMO

Objective: To examine self-reported medication adherence and its association with illness perceptions, beliefs about medication and personality among thyroid cancer survivors. Methods: Individuals diagnosed with thyroid cancer between 1990 and 2008, as registered in the Eindhoven Cancer Registry, received our survey; 86% (n = 306) responded.Results: Many patients reported that they never forgot taking their medicines (n = 168; 56%), never altered the dose (n = 258; 88%), never stopped taking them (n = 291; 99%), never decided to miss a dose (n = 284; 97%) and never took less than instructed (n = 286; 97%). Fifty-two percent were classified as nonadherent; of which 14% intentional nonadherent only, 70% were nonintentional nonadherent only and 16% were both intentional and nonintentional nonadherent. Nonadherers were younger, more highly educated, more often employed, had a lower stage at diagnosis, and less often reported ≥2 comorbid conditions than adherers. Furthermore, their illness affected them more emotionally and they more often reported that their life would be impossible without their medicine. Logistic regression models showed that higher age, lower education and lower perceived necessity of medication was associated with better adherence while beliefs about medication, illness perceptions, and personality were not associated with adherence.Conclusions: Despite lifelong dependence on supplement therapy, 52% of thyroid cancer survivors were nonadherent.


Assuntos
Antineoplásicos/uso terapêutico , Sobreviventes de Câncer/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Adesão à Medicação/psicologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/psicologia , Personalidade Tipo D , Adulto , Idoso , Sobreviventes de Câncer/estatística & dados numéricos , Feminino , Humanos , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Sistema de Registros , Autorrelato
11.
J Clin Endocrinol Metab ; 105(1)2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31612224

RESUMO

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is common in active acromegaly and negatively influences quality of life, morbidity, and mortality. This prospective study with 3 predetermined timepoints and a standardized treatment protocol investigates changes in sleep parameters during the first 2.5 years of acromegaly treatment. METHODS: Before initiation of acromegaly treatment (medical pretreatment followed by surgery), polysomnography (PSG) was performed in 27 consecutive patients with treatment-naive acromegaly. PSG was repeated after 1 year (N = 24) and 2.5 years (N = 23), and anthropometric and biochemical parameters were obtained. RESULTS: At baseline, 74.1% of the patients was diagnosed with OSAS. The respiratory disturbance index (RDI; P = 0.001), oxygen desaturation index (ODI; P = 0.001), lowest oxygen saturation (LSaO2; P = 0.007) and the Epworth Sleepiness Scale (ESS; P < 0.001) improved significantly during treatment, with the greatest improvement in the first year. After 2.5 years of treatment, all patients had controlled acromegaly. Of the 16 patients with repeated PSG and OSAS at baseline, 11 (68.8%) were cured of OSAS. Changes in RDI, ODI, LSaO2, and ESS correlated with insulin-like growth factor 1 levels. CONCLUSION: OSAS has a high prevalence in active acromegaly. There is a substantial decrease in prevalence and severity of OSAS following acromegaly treatment, with the largest improvement during the first year. Most patients recover from OSAS following surgical or biochemical control of the acromegaly. Therefore, a PSG is advised after diagnosis of acromegaly. When OSAS is present, it should be treated and PSG should be repeated during acromegaly treatment.


Assuntos
Acromegalia/complicações , Acromegalia/epidemiologia , Acromegalia/terapia , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/patologia , Acromegalia/diagnóstico , Adenoma/complicações , Adenoma/epidemiologia , Adenoma/terapia , Adulto , Idoso , Estudos de Casos e Controles , Progressão da Doença , Agonistas de Dopamina/uso terapêutico , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/epidemiologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/terapia , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Polissonografia , Prevalência , Prognóstico , Apneia Obstrutiva do Sono/diagnóstico , Sonolência , Resultado do Tratamento
12.
J Clin Endocrinol Metab ; 105(3)2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31641763

RESUMO

BACKGROUND: Metastatic disease is the main cause of cancer-related mortality in thyroid carcinoma (TC) patients. Clinical studies have suggested differences in metastatic patterns between the different subtypes of TC. This study systematically evaluates the metastatic patterns of different subtypes in TC patients. METHODS: A nationwide review of pathological records of all 650 patients diagnosed with a primary malignancy in the thyroid who underwent an autopsy between 1991 and 2010 was performed. Patients were selected from the Dutch pathology registry (PALGA). RESULTS: Metastatic disease was present in 228 (35.1%) patients and was found in 38.7%, 17.3%, 75.4%, and 47.8% of patients with follicular, papillary, anaplastic, and medullary types of TC, respectively (P < .0001). The majority of patients had more than 1 metastasis. The most common site of metastatic disease was the lung for papillary (79.7%), follicular (72.9%), and anaplastic (92.1%) carcinoma but not for medullary carcinoma (56.3%), P < .0001. Medullary carcinoma patients most frequently had metastases to the liver (81.3%). The combination of metastases also differed between subtypes. CONCLUSION: There are major differences in metastatic patterns between different subtypes of TC. The patterns and frequencies identified in this autopsy study may reflect the underlying biology of metastatic thyroid cancer and have potential to influence future monitoring and treatment strategies depending on clinical correlations.


Assuntos
Adenocarcinoma Folicular/secundário , Carcinoma Medular/secundário , Carcinoma Papilar/secundário , Sistema de Registros/estatística & dados numéricos , Neoplasias da Glândula Tireoide/patologia , Adenocarcinoma Folicular/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Medular/cirurgia , Carcinoma Papilar/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Prognóstico , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/cirurgia
13.
J Clin Endocrinol Metab ; 105(4)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31858120

RESUMO

BACKGROUND: Although major improvements are achieved after cure of Cushing syndrome (CS), fatigue and decreased quality of life persist. This is the first study to measure aerobic exercise capacity in patients in remission of CS for more than 4 years in comparison with matched controls, and to investigate whether the reduction in exercise capacity is related to alterations in muscle tissue. METHODS: Seventeen patients were included. A control individual, matched for sex, estrogen status, age, body mass index, smoking, ethnicity, and physical activity level was recruited for each patient. Maximal aerobic capacity (VO2peak) was assessed during incremental bicycle exercise to exhaustion. In 8 individually matched patients and controls, a percutaneous muscle biopsy was obtained and measures were made of cross-sectional areas, capillarization, and oxphos complex IV (COXIV) protein content as an indicator of mitochondrial content. Furthermore, protein content of endothelial nitric oxide synthase (eNOS) and eNOS phosphorylated on serine1177 and of the NAD(P)H-oxidase subunits NOX2, p47phox, and p67phox were measured in the microvascular endothelial layer. FINDINGS: Patients showed a lower mean VO2peak (SD) (28.0 [7.0] vs 34.8 [7.9] ml O2/kg bw/min, P < .01), maximal workload (SD) (176 [49] vs 212 [67] watt, P = .01), and oxygen pulse (SD) (12.0 [3.7] vs 14.8 [4.2] ml/beat, P < .01) at VO2peak. No differences were seen in muscle fiber type-specific cross-sectional area, capillarization measures, mitochondrial content, and protein content of eNOS, eNOS-P-ser1177, NOX2, p47phox, and p67phox. INTERPRETATION: Because differences in muscle fiber and microvascular outcome measures are not statistically significant, we hypothesize that cardiac dysfunction, seen in active CS, persists during remission and limits blood supply to muscles.

14.
Sci Rep ; 9(1): 14812, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31616008

RESUMO

Here, we assessed whether 41 SNPs within steroid hormone genes associated with erosive disease. The most relevant finding was the rheumatoid factor (RF)-specific effect of the CYP1B1, CYP2C9, ESR2, FcγR3A, and SHBG SNPs to modulate the risk of bone erosions (P = 0.004, 0.0007, 0.0002, 0.013 and 0.015) that was confirmed through meta-analysis of our data with those from the DREAM registry (P = 0.000081, 0.0022, 0.00074, 0.0067 and 0.0087, respectively). Mechanistically, we also found a gender-specific correlation of the CYP2C9rs1799853T/T genotype with serum vitamin D3 levels (P = 0.00085) and a modest effect on IL1ß levels after stimulation of PBMCs or blood with LPS and PHA (P = 0.0057 and P = 0.0058). An overall haplotype analysis also showed an association of 3 ESR1 haplotypes with a reduced risk of erosive arthritis (P = 0.009, P = 0.002, and P = 0.002). Furthermore, we observed that the ESR2, ESR1 and FcγR3A SNPs influenced the immune response after stimulation of PBMCs or macrophages with LPS or Pam3Cys (P = 0.002, 0.0008, 0.0011 and 1.97•10-7). Finally, we found that a model built with steroid hormone-related SNPs significantly improved the prediction of erosive disease in seropositive patients (PRF+ = 2.46•10-8) whereas no prediction was detected in seronegative patients (PRF- = 0.36). Although the predictive ability of the model was substantially lower in the replication population (PRF+ = 0.014), we could confirm that CYP1B1 and CYP2C9 SNPs help to predict erosive disease in seropositive patients. These results are the first to suggest a RF-specific association of steroid hormone-related polymorphisms with erosive disease.


Assuntos
Artrite Reumatoide/complicações , Doenças Ósseas/diagnóstico , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP2C9/genética , Hormônios Esteroides Gonadais/metabolismo , Adulto , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Doenças Ósseas/genética , Doenças Ósseas/imunologia , Citocromo P-450 CYP1B1/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Progressão da Doença , Feminino , Hormônios Esteroides Gonadais/imunologia , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Fator Reumatoide/sangue , Fator Reumatoide/imunologia
15.
Cell Oncol (Dordr) ; 42(5): 691-703, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31201646

RESUMO

PURPOSE: Interleukin 32 (IL-32) is a pro-inflammatory cytokine of which different isoforms have been identified. Recently, IL-32 has been shown to act as a potent inducer of cell migration in several types of cancer. Although previous research showed that IL-32 is expressed in differentiated thyroid cancer (TC) cells, the role of IL-32 in TC cell migration has not been investigated. Furthermore, tumour-associated macrophages (TAMs) may play a facilitating role in cancer cell migration. The aim of this study was to explore whether the interaction between TC cells and TAMs results in increased expression of IL-32 in TC cells and to investigate whether this affects TC cell migration. METHODS: TPC-1 cells were co-culture with TC-induced or naive macrophages. Next, transcriptome analysis on TPC-1 cells was performed and supernatants were used for stimulation of TPC-1 cells. IL-32ß and IL-32γ were exogenously overexpressed in TPC-1 cells using transient transfection, after which an in vitro gap closure assay was performed to assess cell migration, and the expression of migratory factors was assessed using RT-qPCR. RESULTS: We found that TC-induced macrophages induced IL-32 expression in TC cells and that TAM-derived TNFα was the main inducer of IL-32ß expression in TC cells. Overexpression of IL-32ß and IL-32γ did not affect TC cell migration, but increased cell death. Finally, we found that IL-32ß overexpression led to increased mRNA expression of the pro-survival cytokine IL-8, while the expression of other migratory factors was not affected. CONCLUSIONS: From our data, we conclude that TAM-derived TNFα induces IL-32ß in TC cells. Although IL-32ß does not affect TC cell migration, alternative splicing of IL-32 towards the IL-32ß isoform may be beneficial for TC cell survival through induction of the pro-survival cytokine IL-8.


Assuntos
Movimento Celular/imunologia , Interleucinas/metabolismo , Macrófagos/imunologia , Neoplasias da Glândula Tireoide/imunologia , Fator de Necrose Tumoral alfa/farmacologia , Processamento Alternativo/genética , Morte Celular/efeitos dos fármacos , Morte Celular/imunologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Interleucina-8/metabolismo , Interleucinas/genética , Antígeno Ki-67/imunologia , Monócitos/metabolismo , Isoformas de Proteínas/genética , Neoplasias da Glândula Tireoide/genética , Transcriptoma/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
16.
Sci Rep ; 9(1): 5396, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30932012

RESUMO

Sufficient thyroid iodine uptake is needed to ensure effective radioactive iodine (RAI) treatment, which is mediated by the sodium-iodide symporter (NIS). Activation of AMP-activated-protein-kinase (AMPK), leads to decreased NIS expression and thyroid iodine uptake in in vitro and animal models. Clinically relevant conditions that lead to AMPK activation include metformin use and hypocaloric conditions. Here, we aim to assess the effects of metformin and hypocaloric diet on thyroid iodine uptake in healthy volunteers. Healthy male volunteers were included and randomized. Group 1 (n = 8) received metformin, group 2 (n = 7) followed a hypocaloric diet (1500 kcal/day), superposed on a moderate iodine restriction diet; Baseline measurements included thyroid iodine-123 (I-123) uptake and TSH, fT4, T3 and rT3 levels. After two weeks, thyroid function and I-123 uptake measurements were repeated. Baseline characteristics were similar between groups. Levels of TSH and fT4 were similar after each intervention. T3 decreased after hypocaloric diet and metformin (-0.2 ± 0.19 nmol/L, p = 0.0327; respectively -0.13 ± 0.13 nmol/L, p = 0.0282), resulting in decreased T3/rT3 ratios. There was no significant difference in thyroid I-123 uptake after each intervention. In conclusion, metformin treatment and hypocaloric diet resulted in a significant decrease in T3 levels and T3/rT3 ratios in healthy volunteers, without significant effects on thyroid iodine uptake. We found no indications that metformin or hypocaloric diet will have clinically relevant effects on RAI uptake.


Assuntos
Dieta Redutora/métodos , Metabolismo Energético/efeitos dos fármacos , Voluntários Saudáveis/estatística & dados numéricos , Metformina/farmacologia , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Adulto , Transporte Biológico/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Radioisótopos do Iodo/farmacocinética , Radioisótopos do Iodo/urina , Masculino , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue , Adulto Jovem
17.
Oncologist ; 24(3): e106-e110, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30606882

RESUMO

BACKGROUND: Aggressive forms of thyroid carcinoma (TC) show an abundant infiltration of immune cells, and this correlates with prognosis. However, little is known about circulating immune cell levels in advanced TC. OBJECTIVE: Investigate T-cell and myeloid-derived suppressor cell (MDSC) levels in peripheral blood of patients with advanced TC and correlate them with survival. METHODS: T cells and MDSCs were quantified by flow cytometry in peripheral blood from nine patients with advanced TC and nine healthy volunteers. RESULTS: No significant differences in MDSC or regulatory T-cell levels were detected between patients with TC and healthy controls. CD3, CD4, and CD8 T-cell levels were significantly lower in patients with TC. CD3 and CD4 T-cell levels further decreased in patients with survival of less than 1 month. CONCLUSION: These data suggest that T-cell lymphopenia in patients with TC indicates an aggressive tumor behavior and might influence therapeutic choices in the future. Restoring T-cell levels may become a potential therapeutic option within the multitarget approaches.


Assuntos
Linfopenia/complicações , Neoplasias da Glândula Tireoide/complicações , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Glândula Tireoide/fisiopatologia
18.
Oncogene ; 38(19): 3743-3755, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30670777

RESUMO

PTEN hamartoma tumor syndrome (PHTS) is caused by inactivating germline PTEN mutations with subsequent activation of Akt-mTOR signaling, leading to an increased risk of developing thyroid carcinoma (TC). Activation of Akt-mTOR signaling is essential for innate immune cell activation and reprogramming of TC-induced macrophages. Here, we aim to assess the effect of PTEN mutations on innate immune cell function in PHTS patients, especially in the context of TC, using a unique ex vivo model. Monocyte-derived cytokine responses were assessed in 29 PHTS patients and 29 controls. To assess the functional profile of TC-induced-macrophages, a co-culture model with two TC cell lines was performed. Rapamycin, a lactate transport blocker and metformin were used as modulators of the Akt-mTOR pathway and cell metabolism. Monocytes from PHTS patients showed increased production of IL-6, TNF-α, IL-8 and MCP-1, and higher lactate production. After co-culture with TC cell lines, TC-induced macrophages showed significantly increased production of cytokines in both patients and controls, especially after co-culture with a PTEN-deficient TC cell line; these effects were abolished after use of rapamycin or a lactate transport blocker. Metformin blocked the production of anti-inflammatory cytokines. In conclusion, innate immune cells from PHTS patients have increased lactate production and a more proinflammatory phenotype, especially after co-culture with PTEN-deficient TC. Metformin promotes a proinflammatory phenotype by blocking anti-inflammatory cytokine response, whereas rapamycin reduces production of proinflammatory cytokines. This indicates that PHTS patients may benefit from treatment with mTOR blocking agents to limit the inflammatory response in the tumor microenvironment.


Assuntos
Mutação em Linhagem Germinativa , Síndrome do Hamartoma Múltiplo/imunologia , Imunidade Inata/genética , PTEN Fosfo-Hidrolase/genética , Adulto , Estudos de Casos e Controles , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/metabolismo , Síndrome do Hamartoma Múltiplo/genética , Humanos , Metformina/farmacologia , Pessoa de Meia-Idade , Monócitos/imunologia , PTEN Fosfo-Hidrolase/imunologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Glândula Tireoide/patologia , beta-Glucanas/farmacologia
19.
Eur J Endocrinol ; 180(1): 1-9, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30400068

RESUMO

Objective To assess the effect of somatostatin analogs (SSAs) on mortality in relation to disease control of acromegaly after pituitary surgery. Design A retrospective study in two large tertiary referral centers in The Netherlands. Methods Overall, 319 patients with acromegaly in whom pituitary surgery was performed as primary therapy between January 1980 and July 2017 were included. Postoperative treatment with SSA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Disease control at last visit was assessed by IGF1 standard deviation score (SDS). Adequate disease control was defined as IGF1 SDS ≤2. Univariate determinants of mortality and standardized mortality ratios (SMRs) were calculated for groups with and without SSA at any moment postoperatively and at last visit. Results In total, 27 deaths were observed. In univariate analysis, determinants of mortality were inadequate disease control (relative risk (RR): 3.41, P = 0.005), surgery by craniotomy (RR: 3.53, P = 0.013) and glucocorticoid substitution (RR: 2.11, P = 0.047). There was a strong trend toward increased mortality for patients who used SSA (RR: 2.01, P = 0.067) and/or dopamine agonists (RR: 2.54, P = 0.052) at last visit. The SMR of patients with adequate disease control who used SSA at any moment postoperatively (1.07, P = 0.785) and at last visit (1.19; P = 0.600) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.92, P = 0.006). Conclusions Postoperative use of SSA is not associated with increased mortality in patients with acromegaly who attain adequate disease control. In contrast, inadequate disease control, primary surgery by craniotomy and glucocorticoid substitution are associated with increased mortality.


Assuntos
Acromegalia/cirurgia , Adenoma/cirurgia , Hipófise/cirurgia , Neoplasias Hipofisárias/cirurgia , Somatostatina/análogos & derivados , Acromegalia/tratamento farmacológico , Acromegalia/mortalidade , Adenoma/tratamento farmacológico , Adenoma/mortalidade , Adulto , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/mortalidade , Período Pós-Operatório , Estudos Retrospectivos , Taxa de Sobrevida
20.
Clin Nucl Med ; 43(7): 524-525, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29847321

RESUMO

A 56-year-old man who was recently diagnosed with a carcinoid tumor of the os petrosum was referred for a Ga-DOTA-TOC PET/CT scan. Besides the moderately increased Ga-DOTA-TOC accumulation in the carcinoid tumor, the scan showed strongly increased and focal Ga-DOTA-TOC uptake in an additional lesion in the right parotid gland. The markedly different Ga-DOTA-TOC avidity suggested a different etiology, and histological examination demonstrated a pleomorphic adenoma.


Assuntos
Adenoma Pleomorfo/diagnóstico por imagem , Octreotida/análogos & derivados , Compostos Organometálicos , Neoplasias Parotídeas/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Adenoma Pleomorfo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Parotídeas/patologia
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