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Open access

Jintao Hu, Qingbo Chen, Xiao Ding, Xin Zheng, Xuefeng Tang, Song Li and Hui Yang

Objective

Many cancer cells cannot survive without exogenous glutamine (Gln); however, cancer cells expressing glutamine synthetase (GS) do not have this restriction. Previous metabolomics studies have indicated that glutamine metabolism is altered during pituitary tumorigenesis. However, the main role of Gln in pituitary adenoma (PA) pathophysiology remains unknown. The aim of this study was to evaluate the expression of GS and the main role of Gln in human PAs.

Methods

We used cell proliferation assay and flow cytometry to assess the effect of Gln depletion on three different pituitary cell lines and human primary PA cells. We then investigated the expression level of Gln synthetase (GS) in 24 human PA samples. At last, we used LC-MS/MS to identify the differences in metabolites of PA cells after the blockage of both endogenous and exogenous Gln.

Results

PA cell lines showed different sensitivities to Gln starvation, and the sensitivity is correlated with GS expression level. GS expressed in 21 out of the 24 human PA samples. Furthermore, a positive p53 and ki-67 index was correlated with a higher GS expression level (P < 0.05). Removal of both endogenous and exogenous Gln from GS-expressing PA cells resulted in blockage of nucleotide metabolism and cell cycle arrest.

Conclusions

Our data indicate that GS is needed for PA cells to undergo proliferation during Gln deprivation, and most human PA cells express GS and might have a negative response to exogenous Gln depletion. Moreover, Gln is mainly responsible for nucleotide metabolism in the proliferation of GS-expressing pituitary tumor cells.

Open access

M L M Barreto-Chaves, N Senger, M R Fevereiro, A C Parletta and A P C Takano

The cardiac growth process (hypertrophy) is a crucial phenomenon conserved across a wide array of species and is critically involved in the maintenance of cardiac homeostasis. This process enables an organism to adapt to changes in systemic demand and occurs due to a plethora of responses, depending on the type of signal or stimuli received. The growth of cardiac muscle cells in response to environmental conditions depends on the type, strength and duration of stimuli, and results in adaptive physiological responses or non-adaptive pathological responses. Thyroid hormones (TH) have a direct effect on the heart and induce a cardiac hypertrophy phenotype, which may evolve to heart failure. In this review, we summarize the literature on TH function in the heart by presenting results from experimental studies. We discuss the mechanistic aspects of TH associated with cardiac myocyte hypertrophy, increased cardiac myocyte contractility and electrical remodeling, as well as the associated signaling pathways. In addition to classical crosstalk with the sympathetic nervous system (SNS), emerging work pointing to the new endocrine interaction between TH and the renin-angiotensin system (RAS) is also explored. Given the inflammatory potential of the angiotensin II peptide, this new interaction may open the door for new therapeutic approaches which target the key mechanisms responsible for TH-induced cardiac hypertrophy.

Open access

C Sui, Q He, R Du, D Zhang, F Li, G Dionigi, N Liang and H Sun

Purpose

This study examined the clinicopathological characteristics of 6279 N1 differentiated thyroid cancer (DTC) patients who underwent operations in our center.

Methods

This was a retrospective longitudinal analysis. We categorized the DTC patients on the basis of various lymph node (LN) characteristics. Logistic regression models and multiple linear regression models were used for the correlation analysis.

Results

A total of 3693 (58.8%) N1a patients and 2586 (41.2%) N1b patients were included. Patients with N1b disease had larger metastatic foci (0.5 vs 0.15 cm), a greater number of metastatic LNs (5 vs 2), a greater number of dissected LNs (25 vs 7), and a smaller lymph node ratio (NR, number of positive LNs/number of sampled LNs) (23.1% vs 28.6%) than patients in stage N1a. Comparing the clinicopathological features, we found that male, increased tumor size, multifocality, and thyroiditis increased the risk of stage N1b disease (P < 0.05). Sex, multifocality, capsular infiltration, and tumor size were associated with the size of the metastatic LNs (P < 0.05). Sex, capsular infiltration, and nodular goiter were associated with the NR (P < 0.05). Female sex, tumor located in inferior lobe, maximal tumor diameter (MTD) < 1 cm, and nodular goiter were independent predictors for skip metastases (P < 0.05). MTD > 1 cm, central neck metastasis and age were independent predictors for bilateral lateral neck metastasis (BLNM) (P < 0.05).

Conclusion

The LN characteristics of stage N1a and N1b disease were associated with significantly different features, such as sex, tumor size, multifocality, capsular infiltration, and nodular goiter.

Open access

Klaudia Zajkowska, Janusz Kopczyński, Stanisław Góźdź and Aldona Kowalska

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a borderline thyroid tumour formerly known as noninvasive encapsulated follicular variant of papillary thyroid carcinoma. The prevalence of NIFTP is estimated at 4.4–9.1% of all papillary thyroid carcinomas worldwide; however, the rate of occurrence of NIFTP is eight times lower in Asian countries than in Western Europe and America. At the molecular level, NIFTP is characterised by the lack of BRAF V600E and BRAF V600E-like mutations or other high-risk mutations (TERT, TP53) and a high rate of RAS mutations, which is similar to other follicular-pattern thyroid tumours. The diagnosis of NIFTP can only be made after histological examination of the entire tumour removed during surgery and is based on strictly defined inclusion and exclusion criteria. Although the diagnosis is postoperative, the combination of certain findings of preoperative tests including ultrasonography, cytology, and molecular testing may raise suspicion of NIFTP. These tumours can be effectively treated by lobectomy, although total thyroidectomy remains an option for some patients. Radioactive iodine and thyroid stimulating hormone suppression therapy are not required. NIFTP has an extremely good prognosis, even when treated conservatively with lobectomy alone. Nevertheless, it cannot be considered as a benign lesion. The risk of adverse outcomes, including lymph node and distant metastases, is low but not negligible.

Open access

A Rouland, J-C Chauvet-Gelinier, A-L Sberna, E Crevisy, P Buffier, T Mouillot, J-M Petit and B Vergès

Objective

The Type A personality, characterized by impatience, strong career ambition and competitiveness, is associated with greater sensitivity to external stress. Type 1 diabetes (T1D) is an auto-immune disease, which is potentially influenced by stress, unlike type 2 diabetes (T2D). The aim of this study was to assess whether individuals with T1D and T2D exhibited significant differences on the Type A personality scale. We also assessed personality in patients with thyroid auto-immune diseases to validate potential links between auto-immune disease and Type A personality.

Design and methods

The Bortner questionnaire was used to assess Type A personality in 188 patients with T1D, 430 patients with T2D and 85 patients with auto-immune thyroid disease (Graves’ disease or Hashimoto’s thyroiditis).

Results

Type A Bortner scores were significantly higher in T1D patients than in T2D patients (188 ± 34 vs 177 ± 36, P < 0.0001). Patients with auto-immune thyroid diseases and T1D patients had similar Type A Bortner scores (189 ± 33 vs 188 ± 34, P = 0.860).

Conclusion

Patients with auto-immune T1D have higher Type A scores than T2D patients. Furthermore, patients with auto-immune thyroid disease also have elevated Type A scores similar to those observed in type 1 diabetes, suggesting that an elevated Type A score in T1D is potentially related to its auto-immune origin. This suggests a possible link between Type A personality and auto-immune diseases via stress-triggering psychobiological pathways. The different personality score between T1D and T2D is an important factor, which could influence self-care coping strategies in diabetes and long-term prognosis.

Open access

Neil R Chappell, Beth Zhou, Amy K Schutt, William E Gibbons and Chellakkan S Blesson

Polycystic ovary syndrome (PCOS) is the most common ovulatory defect in women. Although most PCOS patients are obese, a subset of PCOS women are lean but show similar risks for adverse fertility outcomes. A lean PCOS mouse model was created using prenatal androgen administration. This developmentally programmed mouse model was used for this study. Our objective was to investigate if mitochondrial structure and functions were compromised in oocytes obtained from lean PCOS mouse. The lean PCOS mouse model was validated by performing glucose tolerance test, HbA1c levels, body weight and estrous cycle analyses. Oocytes were isolated and were used to investigate inner mitochondrial membrane potential, oxidative stress, lipid peroxidation, ATP production, mtDNA copy number, transcript abundance and electron microscopy. Our results demonstrate that lean PCOS mice have similar weight to that of the controls but exhibit glucose intolerance and hyperinsulinemia along with dysregulated estrus cycle. Analysis of their oocytes show impaired inner mitochondrial membrane function, elevated reactive oxygen species (ROS) and increased RNA transcript abundance. Electron microscopy of the oocytes showed impaired mitochondrial ultrastructure. In conclusion, the lean PCOS mouse model shows a decreased oocyte quality related to impaired mitochondrial ultrastructure and function.

Open access

Solène Castellnou, Alexandre Vasiljevic, Véronique Lapras, Véronique Raverot, Eudeline Alix, Françoise Borson-Chazot, Emmanuel Jouanneau, Gérald Raverot and Hélène Lasolle

Objective

Somatostatin receptor type 5 (SST5) is inconsistently expressed by corticotroph tumors, with higher expression found in corticotropinomas having ubiquitin-specific protease 8 (USP8) mutations. Aims were to study the correlation between characteristics of corticotropinomas and SST5 expression/USP8 mutation status and to describe the response to pasireotide in five patients.

Design

Retrospective cohort study.

Methods

Clinico-biochemical, radiological and pathological data of 62 patients, operated for a functioning or silent corticotropinoma between 2013 and 2017, were collected. SST5 expression was measured by immunohistochemistry (clone UMB-4, Abcam, IRS > 1 being considered positive), and Sanger sequencing was performed on 50 tumors to screen for USP8 mutations.

Results

SST5 expression was positive in 26/62 pituitary tumors. A moderate or strong IRS was found in 15/58 corticotropinomas and in 13/35 functioning corticotropinomas. Among functioning tumors, those expressing SST5 were more frequent in women (22/24 vs 9/15, P = 0.04) and had a lower grade (P = 0.04) compared to others. USP8 mutations were identified in 13/50 pituitary tumors and were more frequent in functioning compared to silent tumors (11/30 vs 2/20, P = 0.05). SST5 expression was more frequent in USP8mut vs USP8wt tumors (10/11 vs 7/19, P = 0.007). Among treated patients, normal urinary free cortisol levels were obtained in three patients (IRS 0, 2 and 6), while a four-fold decrease was observed in one patient (IRS 4).

Conclusion

SST5 expression appears to be associated with functioning, USP8mut and lower grade corticotropinomas. A correlation between SST5 expression or USP8mut and response to pasireotide remains to be confirmed.

Open access

Li Li, Qifa Song and Xi Yang

Insufficient insulin release plays a crucial role in the development of unhealthy status in patients with obesity; the present study aimed to classify these patients by the indices for insulin resistance and insulin release. After the indices from OGTT were assessed to achieve high differentiability and low redundancy in classifying patients, HOMA-IR and IGI30min were chosen to classify the patients using K-means clustering method. A total of 249 non-diabetic patients with obesity were classified into four groups. In Group 1, 19 patients were characteristic of high insulin resistance and high insulin release, as well as well-controlled glucose levels, the highest BMI, the youngest age, and the highest early phase release of insulin. In Group 2, 38 patients were unhealthiest in terms of high insulin resistance, reduced insulin release and IGT status. Group 3 consisted of 63 patients that were healthiest with low insulin resistance and high insulin release. In Group 4, 46 IGT patients and 14 IFG patients were identified among 129 patients that showed low insulin resistance, low insulin release, moderate obesity and older age. These concurrent impotent insulin release, older age, and moderate obesity indicated decreasing obesity with increasing age and reduced insulin release. The classification of patients with obesity using K-means clustering method by HOMA-IR and IGI30min provides more information about the development of obesity and unhealthy status. The patients with distinct insulin resistance and insulin release should be followed up, especially for those with reduced or even absent insulin response to glucose stimulation.

Open access

Monika Karczewska-Kupczewska, Agnieszka Nikołajuk, Radosław Majewski, Remigiusz Filarski, Magdalena Stefanowicz, Natalia Matulewicz and Marek Strączkowski

Objective

Insulin resistance is a major pathophysiological link between obesity and its metabolic complications. Weight loss (WL) is an effective tool to prevent obesity-related diseases; however, the mechanisms of an improvement in insulin sensitivity (IS) after weight-reducing interventions are not completely understood. The aim of the present study was to analyze the relationships between IS and adipose tissue (AT) expression of the genes involved in the regulation of lipolysis in obese subjects after WL.

Methods

Fifty-two obese subjects underwent weight-reducing dietary intervention program. The control group comprised 20 normal-weight subjects, examined at baseline only. Hyperinsulinemic-euglycemic clamp and s.c. AT biopsy with subsequent gene expression analysis were performed before and after the program.

Results

AT expression of genes encoding lipases (PNPLA2, LIPE and MGLL) and lipid-droplet proteins enhancing (ABHD5) and inhibiting lipolysis (PLIN1 and CIDEA) were decreased in obese individuals in comparison with normal-weight individuals. The group of 38 obese participants completed dietary intervention program and clamp studies, which resulted in a significant WL and an improvement in mean IS. However, in nine subjects from this group IS did not improve in response to WL. AT expression of PNPLA2, LIPE and PLIN1 increased only in the group without IS improvement.

Conclusions

Excessive lipolysis may prevent an improvement in IS during WL. The change in AT PNPLA2 and LIPE expression was a negative predictor of the change in IS after WL.

Open access

Sebastião Freitas de Medeiros, Márcia Marly Winck Yamamoto, Matheus Antônio Souto de Medeiros, Bruna Barcelo Barbosa, José Maria Soares Junior and Edmund Chada Baracat

Objective

To verify whether aging can modify the clinical and biochemical characteristics of women with polycystic ovary syndrome (PCOS).

Material and methods

This observational cross-sectional study was conducted at the reproductive endocrinology clinics of Julio Muller University Hospital and Tropical Institute of Reproductive Medicine in Cuiabá, MT, Brazil, between 2003 and 2017. Both, 796 PCOS and 444 non-PCOS normal cycling women underwent the same examination. PCOS was diagnosed using the Rotterdam criteria as recommended for adolescent and adult subjects. Anthropometric, metabolic, and endocrinological modifications with aging were initially examined in the two groups: control and PCOS. Further analyses were performed after a 5-year age stratification of data throughout the reproductive period. All participants signed a consent form approved by the local ethical committee.

Results

Biomarkers of adiposity were more remarkable in African descendant PCOS women. Body weight, waist/hip ratio, fat mass, and BMI were higher in PCOS women and tended to increase at all 5 age-strata, between ≤19 and 35 years of age. Serum androgen levels decreased with aging, markedly in PCOS subjects (P < 0.01 for all age-strata comparisons), but remained elevated when compared with the levels found in controls. Carbohydrate markers, triglycerides, and total cholesterol tended to increase over time in PCOS (P < 0.01 for all age-strata comparisons). Total cholesterol also tended to increase with age in non-PCOS women (P = 0.041).

Conclusion

The present study has shown that the advancing age influences many features of PCOS women. Biochemical hyperandrogenism, the core criterion recommended in the current systems to define the syndrome, showed statistically significant tendencies to decrease with aging progression but did not normalize. The use of age-adjusted features for the diagnosis of PCOS are recommended.