Sharmatorp6660

Knockdown of lncRNA MSTRG.292666.16 decreased osimertinib resistance of H1975R cells. Our results suggest that exosomal lncRNA MSTRG.292666.16 might be associated with osimertinib resistance in NSCLC.INTRODUCTION Inactivating mutations in CYP24A1, encoding vitamin D-24-hydroxylase, can lead to an accumulation of active vitamin D metabolites and consequent hypercalcaemia. Patient (infantile and adult) presentation is varied and includes mild-severe hypercalcaemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. This study aimed to characterize the clinical and biochemical phenotypes of a family with two CYP24A1 missense variants. METHODS The proband and seven family members underwent detailed clinical and biochemical evaluation. Laboratory measurements included serum calcium, intact parathyroid hormone (iPTH), vitamin D metabolites and urine calcium and creatinine. RESULTS The proband presented during the second trimester of a planned pregnancy with flu-like symptoms. Laboratory tests showed elevated adjusted calcium of 3.27 (upper reference limit (URL2.30) mmol/L), suppressed iPTH (50) and may be associated with a variable phenotype or incomplete penetrance.AIMS Heterozygous inactivating mutations in the GCK gene cause the familial, mild fasting hyperglycaemia named MODY2. Many patients with MODY2 in Asia have delayed timely treatment because they did not receive the correct diagnosis. This study aims to analyze the clinical characteristics and GCK mutations in Asian MODY2. METHODS We have collected 110 Asian patients with MODY2 from the Pubmed, Embase, Medline, Web of Science, CNKI, and Wanfang with the following search terms "Maturity-Onset Diabetes of the Young" OR "MODY" OR "Maturity-Onset Diabetes of the Young type 2" OR "MODY2" OR "GCK-DM" OR "GCK-MODY". Both mutations of GCK and clinical characteristics of MODY2 were analyzed. RESULTS There were 96 different mutations occurred in coding regions and non-coding regions. Exon 5 and 7 were the most common location in coding regions, and missense was the primarily mutation type. The proportion of probands younger than 25 was 81.8%, and 81.4% of the probands had family history of hyperglycaemia. Ninety percent and 93% of Asian MODY2 probands exhibited the mild elevating in FPG (5.4-8.3 mmol/L) and HbA1c (5.6-7.6%), respectively. CONCLUSIONS Most Asian MODY2 patients were due to GCK mutation in coding region, and exon 5 and 7 were the most common locations. FPG, HbA1c, and familial diabetes were important reference indicators for diagnosing MODY2. Altogether, the study indicates that for the young onset of diabetes with mild elevated blood glucose and HbA1c, and family history of hyperglycaemia, molecular genetic testing is suggested in order to differ MODY2 from other types of diabetes earlier.INTRODUCTION Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, obesity, and insulin resistance, that leads to subfertility. Sam68 is an RNA-binding protein with signaling functions that is ubiquitously expressed, including gonads. Ruboxistaurin molecular weight Sam68 is recruited to leptin signaling, mediating different leptin actions. OBJECTIVE We aimed to investigate the role of Sam68 in leptin signaling mediating the effect on aromatase expression in granulosa cells, and the posible implication of Sam68 in the leptin resistance in PCOS. MATERIALS AND METHODS Granulosa cells were from healthy donor (n=25) and women with PCOS (n=25), within age range 20-40 years old, from Valencian Infertility Institute (IVI), Seville, Spain. Sam68 expression was inhibited by siRNA method and overexpressed by expression vector. Expression level was analysed by qPCR and immunoblot. Statistical significance was assessed by ANOVA followed by different post hoc tests. A P value less then 0.05 was considered statistically significant. RESULTS We have found that leptin stimulation increases phosphorylation, and expression level of Sam68, and aromatase in granulosa cells. Downregulation of Sam68 expression resulted in a lower activation of MAPK and PI3K pathways in response to leptin, whereas overexpression of Sam68 increased leptin stimulation of signaling, enhancing aromatase expression. Granulosa cells from women with PCOS presented lower expression of Sam68 and were resistant to the leptin effect on aromatase expression. CONCLUSIONS These results suggest the participation of Sam68 in leptin receptor signaling, mediating the leptin effect on aromatase expression in granulosa cells, and points to a new target in leptin resistance in PCOS.OBJECTIVE Multiple endocrine neoplasia type 2A (MEN 2A) is a rare syndrome caused by RET germline mutations, and have been associated with primary hyperparathyroidism (PHPT) in up to 30% of cases. Recommendations on RET screening in patients with apparently sporadic PHPT are unclear. We aimed to estimate the prevalence of cases presenting with PHPT as first manifestation among MEN 2A index cases and to characterize the former cases. DESIGN AND METHODS An international retrospective multicenter study of 1085 MEN 2A index cases. Experts from MEN 2 centres all over the world were invited to participate. A total of 19 centers in 17 different countries provided registry data of index cases followed from 1974 to 2017. RESULTS Ten cases presented with PHPT as their first manifestation of MEN 2A, yielding a prevalence of 0.9% (95% CI 0.4-1.6). 9/10 cases were diagnosed with medullary thyroid carcinoma (MTC) in relation to parathyroid surgery and 1/10 was diagnosed 15 years after parathyroid surgery. 7/9 cases with full TNM data were node-positive at MTC diagnosis. CONCLUSIONS Our data suggest that the prevalence of MEN 2A index cases that present with PHPT as their first manifestation is very low. The majority of index cases presenting with PHPT as first manifestation, have synchronous MTC, often node-positive. Thus, our observations suggest that not performing RET mutation analysis in patients with apparently sporadic PHPT would result in an extremely low false negative rate, if no other MEN 2A component, specifically MTC, are found during work up or resection of PHPT.