Δευτέρα, 29 Ιουλίου 2019

Endocrine

LncRNA MCM3AP-AS1 promotes proliferation and invasion through regulating miR-211-5p/SPARC axis in papillary thyroid cancer

Abstract

Background

Long non-coding RNAs (lncRNAs) are an emerging class of regulators in cancer. A lncRNA, MCM3AP-AS1, has been demonstrated as a versatile mediator in many cancers, except papillary thyroid cancer. The aim of this study is to investigate the role and mechanism of MCM3AP-AS1 in papillary thyroid cancer.

Methods

Quantitative real-time PCR was used to assess the level of MCM3AP-AS1 and miR-211-5p in papillary thyroid cancer tissues and cells. Western blot was used to detect E-cadherin and secreted protein acidic and cysteine rich (SPARC) protein levels. CCK-8, scratch wound assay, and transwell assay were used to evaluate papillary thyroid cancer cell proliferation, migration, and invasion, respectively. BLAST alignment and luciferase assay were used to explore the interaction among MCM3AP-AS1, mi/r-211, and SPARC.

Results

In papillary thyroid cancer, MCM3AP-AS1 was upregulated, while miR-211 was downregulated. MCM3AP-AS1 overexpression promoted papillary thyroid cancer proliferation, migration, and invasion. Further, MCM3AP-AS1 was shown to be negatively correlated with miR-211-5p. We next validated that miR-211-5p overexpression could reverse the promoting role of MCM3AP-AS1 in papillary thyroid cancer, whereby SPARC plays an important regulating role. In vivo, we confirmed the anti-tumor role of MCM3AP-AS1 silencing and the close relation among MCM3AP-AS1, miR-211-5p, and SPARC.

Conclusions

MCM3AP-AS1 promotes papillary thyroid cancer by regulating the MCM3AP-AS1/miR-211-5p/SPARC axis, which could potentially be a therapeutic target in papillary thyroid cancer.



Extended cycle streptozotocin/5-FU chemotherapy for maintenance therapy in pancreatic neuroendocrine tumors

Abstract

Purpose

The standard of care treatment for patients with advanced pancreatic neuroendocrine tumors (pNET) is a combination of streptozotocin and 5-FU. Although widely used, little is known about the best long-term strategy with these substances.

Methods

We here report our experience of 28 patients treated with streptozotocin/5-FU for advanced pNET with special consideration for long-term management using an extended cycle protocol.

Results

Standard 6-weekly Moertel protocol resulted in a median progression-free survival of 21 months (range 3–128) and a median overall survival of 69 months (range 3–157+) in the whole cohort. Thirteen of the 28 patients were switched to an extended 3-month cycle protocol for maintenance therapy. Of these 13 patients, 2 achieved complete remission, 1 partial remission, and 8 stable disease as best response while 2 showed progressive disease following switch to the extended protocol, resulting in an additional median progression-free survival of 23 months. Median overall survival after the start of chemotherapy in this patient group was 69 months (21–157+). Patients benefitted from extended periods free of chemotherapy-associated side effects after switching to the extended cycle protocol.

Conclusions

Switching to an extended cycle protocol of 3 months for maintenance therapy following initial standard cycles may achieve long-term disease stabilization in selected patients with advanced pNET with good patient acceptance.



Impact of adrenomedullin blockage on lipid metabolism in female mice exposed to high-fat diet

Abstract

Purpose

Adrenomedullin (ADM) levels are elevated in gestational and type 2 diabetic patients. ADM also stimulates lipolysis in vitro. Disturbed lipid metabolism has been implicated in the pathogenesis of diabetes. Here, we explore whether blockade of ADM is beneficial for metabolic homeostasis in a diabetic mouse model.

Methods

C57BL/6J female mice were placed on either a control or a high fat high sucrose (HFHS) diet for 8 weeks. At week 4, osmotic mini-pumps were implanted for constant infusion of either saline or ADM antagonist, ADM22–52. Glucose tolerance tests were performed prior to infusion and 4 weeks after infusion began. Animals were then sacrificed and visceral adipose tissue collected for further analysis.

Results

Mice fed HFHS displayed glucose intolerance, increased mRNA expressions in VAT for Adm and its receptor components, Crlr. HFHS fed mice also had increased basal and isoprenaline-induced glycerol release by VAT explants. ADM22–52 did not significantly affect glucose intolerance. ADM22–52 did suppress basal and isoprenaline-induced glycerol release by VAT explants. This alteration was associated with enhanced mRNA expression of insulin signaling factors Insr and Glut4, and adipogenic factor Pck1.

Conclusions

HFHS diet induces glucose intolerance and enhances ADM and its receptor expressions in VAT in female mice. ADM22–52 treatment did not affect glucose intolerance in HFHS mice, but reduced both basal and isoprenaline-induced lipolysis, which is associated with enhanced expression of genes involved in adipogenesis. These results warrant further research on the effects of ADM blockade in improving lipid homeostasis in diabetic patients.



Relationship between metabolic syndrome and thyroid nodules and thyroid volume in an adult population

Abstract

Purpose

The effects of metabolic syndrome (MetS) on thyroid nodules (TN) and thyroid volume (TV), especially the related gender and age disparities, are controversial. In this study, we aimed to assess the relationships between MetS and TN and TV in an adult population.

Methods

This cross-sectional study was performed in an adult population in Tianjin. A total of 2606 subjects were enrolled. TV and TN were measured by thyroid ultrasonography. Blood samples were collected to measure biochemical and metabolic parameters.

Results

The prevalence of TN was significantly higher in the MetS (+) group than in the MetS (−) group (P < 0.0001). MetS was independently associated with increased TN risk (OR: 1.24, 95% CI: 1.01–1.51). When stratified by gender, MetS was associated with higher prevalence of TN in males (OR: 1.38, 95% CI: 1.05–1.81) compared with females (OR: 1.02, 95% CI: 0.75–1.39). However, the interaction effect of gender and MetS on TN was not statistically significant (Pfor interaction = 0.94). MetS was associated with the greater risks of TN in both the <60-year-old group (OR: 1.32, 95% CI: 1.05–1.68) and the ≥60-year-old group (OR: 1.84, 95% CI: 1.24–2.73), while the OR value was significantly higher in the elderly group (P for interaction = 0.03). Additionally, TV was significantly higher in subjects with TN (β = 1.94, P < 0.0001) and MetS (β = 0.94, P = 0.0037).

Conclusions

This study suggested positive relationships between MetS and an increased risk of TN and enlarged TV. Elderly people (≥60 years old) with MetS were associated with a higher risk of TN than younger people (<60 years old). The effect of MetS on TN was not significantly affected by gender.



SDHx -related pheochromocytoma/paraganglioma – genetic, clinical, and treatment outcomes in a series of 30 patients from a single center

Abstract

Purpose

Germline mutations in the four genes that encode the succinate dehydrogenase complex (SDHx) are a risk factor for developing pheochromocytomas and/or paragangliomas. The precise genotype–phenotype correlations are still uncertain and the most common SDHx genetic defects in the Portuguese population are poorly described. The objectives of our study were to characterize the genetic alterations, clinical features, and treatment outcomes of a cohort of SDHx-related pheochromocytomas and/or paragangliomas patients.

Methods

Single center, retrospective analysis based on the presence of a SDHx mutation in cases diagnosed from 1986 until October 2016.

Results

Thirty cases were included. The mean age at diagnosis was 36.8 years (±15.4 years) and 53.3% were females. Remission was observed in 33.3% and stable disease (including partial responses) in 53.0%. SDHC and SDHD patients were prone to develop single and multiple head and neck paragangliomas, respectively. SDHB patients carried an increased risk of malignancy. Deletions in SDHB exon-1 and in SDHD exon-4 were the most common genetic findings. SDHB patients and head and neck paragangliomas had the worse prognosis, the former related to malignancy, and the latter to cranial nerve deficits, unresectable disease, and multimodality interventions. Peptide receptor radionuclide therapy and radioactive iodine MIBG therapy proved to be ineffective. Radiotherapy represented a good alternative in unresectable head and neck paragangliomas and in bone metastases.

Conclusion

This single center study is the most complete Portuguese cohort in the literature and helps to understand the behavior of tumors based on their genotype and anatomical location.



Genetic analysis of adult Slovenian patients with combined pituitary hormone deficiency

Abstract

Purpose

Among genetic causes of combined pituitary hormone deficiency (CPHD), mutations of genes coding for transcription factors involved in pituitary development have been implicated. Congenital CPHD is a rare disease; therefore, it is important to expand the knowledge about incidence and regional distribution of specific mutations. The aim of this paper is to report results of genetic analyses of adult Slovenian patients with CPHD.

Methods

Twenty-three adult Slovenian patients with early childhood onset CPHD were included in the study. Blood samples were collected through the GENHYPOPIT network to assess possible mutations of six genes (PROP1/HESX1/LHX4/LHX3/POU1F1) involved in the pituitary development following an established algorithm.

Results

In seven out of 23 patients (30%) a specific mutation in genes encoding pituitary transcription factors was discovered. In five patients, two different mutations of the PROP1 gene (c.150delA and c.301-302delAG) were identified. One patient was heterozygous for a missense variant in the LHX4 gene. Additionally, one patient was positive for a mutation in the gene coding for prokineticin receptor-2.

Conclusions

Our study confirms that the two most common mutations of the PROP1 gene globally are also the most frequent mutations in the cohort of adult Slovenian patients with CHPD. Other mutations of pituitary transcription factor genes are extremely rare.



Copeptin relates to a fatty liver and measures of obesity in a South African population with mixed ethnicities

Abstract

Purpose

Elevated copeptin, a vasopressin marker, is linked to metabolic disease, and obese rats with low-vasopressin concentration had a decreased risk of liver steatosis. We here investigated the association between copeptin and nonalcoholic fatty liver disease (NAFLD) and possible differences in copeptin concentration between ethnicities.

Methods

In this cross-sectional study of 361 South Africans (n = 172 African black, 189 = Caucasian) with a mean age of 45 years and 45% men, plasma copeptin was measured and associated with NAFLD according to a validated fatty liver index accounting for measures of BMI, waist, triglycerides, and gamma-glutamyltransferase.

Results

There was no significant difference in copeptin concentrations between ethnicities after age and gender adjustment (p = 0.24). Increasing copeptin tertile levels were significantly associated with obesity, overweight, and abdominal obesity, respectively, after multivariate adjustment for age, gender, ethnicity, and high HOMA-IR (p = 0.02 for all). Individuals in the second and third copeptin tertile had an increased odds (95% CI) of NAFLD of 1.77 (1.04–3.02) and 2.97 (1.74–5.06), respectively, compared to the bottom tertile (p < 0.001). The association between increasing copeptin tertile and NAFLD remained significant after adjustment for age, gender, ethnicity, high HOMA-IR, self-reported current alcohol intake, and statin treatment (p = 0.01).

Conclusions

Elevated plasma copeptin is independently associated with NAFLD in a population with mixed ethnicities, pointing at the pharmacologically modifiable vasopressin system as a new mechanism behind NAFLD.



True MEN1 or phenocopy? Evidence for geno-phenotypic correlations in MEN1 syndrome

Abstract

Purpose

Multiple endocrine neoplasia type 1 is a rare tumor syndrome caused by germline mutations of MEN1 gene. Phenotype varies widely, and no definitive correlation with the genotype has been observed. Mutation-negative patients with MEN1-associated tumors represent phenocopies. By comparing mutation-positive and mutation-negative patients, we aimed to identify phenotype features predictive for a positive genetic test and to evaluate the role of MEN1mutations in phenotype modulation.

Methods

Mutation screeening of MEN1 gene by Sanger sequencing and assessment of clinical data of 189 consecutively enrolled probands and relatives were performed at our national and European Reference Center. Multiple ligation probe amplification analysis of MEN1 gene and Sanger sequencing of CDKN1B were carried out in clinically suspicious but MEN1-negative cases.

Results

Twenty-seven probands and twenty family members carried MEN1 mutations. Five mutations have not been described earlier. Pronouncedly high number of phenocopies (>70%) was observed. Clinical suspicion of MEN1 syndrome emerged at significantly earlier age in MEN1-positive compared to MEN1-negative probands. Gastroenteropancreatic neuroendocrine tumors developed significantly earlier and more frequently in carriers compared to non-carriers. Probands with high-impact (frameshift, nonsense, large deletions) mutations, predicted to affect menin function significantly, developed GEP-NETs more frequently compared to low-impact (inframe and missense) mutation carriers.

Conclusions

MEN1 phenocopy is common and represents a significant confounder for the genetic testing. GEP-NET under 30 years best predicted a MEN1 mutation. The present study thus confirmed a previous proposal and suggested that GEP-NET under 30 years should be considered as a part of the indication criteria for MEN1 mutational analysis.



High-intensity focused ultrasound (HIFU) for benign thyroid nodules: 2-year follow-up results

Abstract

Background

High-intensity focused ultrasound (HIFU) is the last introduced thermal treatment of thyroid nodules. Here we evaluated the results at 24 months after HIFU.

Methods

Since 2016, HIFU was considered as a therapeutic option at our institute in patients with benign thyroid nodules presenting local symptoms. We searched in our database all patients who had undergone thyroid HIFU and selected for the study only cases followed-up for at least 24 months after the treatment. Volume reduction rate (VRR) was evaluated. A reduction above 50% defined the success of HIFU.

Results

Thirty-one nodules of 31 patients (24 females and 7 males, median age 67 years) with median major diameter from 17 to 34 mm and estimated nodule volume of 5.48 mL were included. HIFU was performed with median power of 42 W/site (interquartile range 25–45) and median energy of 263 J/site (interquartile range 225–273). Median duration of the procedure was 6 min (interquartile range 5–7). At 2 years after HIFU, nodule volume was significantly (p < 0.0001) lower (i.e., 3.40 mL) with VRR of 43.3%, and 26 (83.9%) lesions were reduced. A reduction by at least 50% was observed at 6, 12, and 24 months in 2 (6.4%), 5 (16.1%), and 7 (22.5%) nodules, respectively. Visual analog score showed a significant improvement (p < 0.0001). No complications were recorded.

Conclusions

A reduction of benign thyroid nodule by more than 40% could be reached within 1 year by HIFU. Given the non-significant size increase of some lesions later, a larger study with a longer follow-up is necessary.



Abnormal expression of Pappa2 gene may indirectly affect mouse hip development through the IGF signaling pathway

Abstract

Introduction

Developmental dysplasia of the hip (DDH) is a major cause of disability in children, and the genetic mechanism of this disease remains unclear. In our previous study, we found that pregnancy-associated plasma protein-A2 (PAPP-A2) was associated with DDH significantly.

Objectives

The aim of this study was to investigate the insulin-like growth factor (IGF) expression and collagen synthesis as well as cartilage proliferation-related proteins in the case of abnormal expression of Pappa2 in mice to research the relationship between PAPP-A2 and the pathological changes of DDH.

Methods

In vivo animal experiments, the mice were directly injected with 50 µl of Cas9/PAPP-A2 sgRNA lentiviruses around the hip to downregulate the Pappa2 gene expression and injected with control lentiviruses on the other side, then to observe the expression and localization of related proteins. And in an in vitro experiment, mice fibroblasts and primary chondrocytes were cultured with insulin-like growth factor binding protein-5 (IGFBP-5) protein, PAPP-A2 protein and Cas9/PAPP-A2 sgRNA lentiviruses to detect of related proteins and mRNA expression.

Results

Cartilage proliferation-related proteins demonstrated a significant decrease in the PAPP-A2 knockdown hips acetabulum and femoral head cartilage, meanwhile the IGF expression was also downregulated in the soft tissue around the acetabulum compared with the control hips. Furthermore, the role PAPP-A2 played in chondrocytes and fibroblasts was the same as in the in vivo experiments, downregulation of PAPP-A2 expression or upregulation of IGFBP-5 expression can reduce collagen synthesis and cartilage proliferation.

Conclusions

PAPP-A2 may be involved in the development of the mouse hip joint by interfering the fibrous and cartilaginous metabolism via IGF pathway-associated proteins pathway.



Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

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