Current histopathological diagnosis methods cannot distinguish the two types of thyroid carcinoma: clinically significant carcinomas with a potential risk of recurrence, metastasis, and cancer death, and clinically insignificant carcinomas with a slow growth rate. Both thyroid tumors are diagnosed as “carcinoma” in current pathology practice. The clinician usually recommends surgery to the patient and the patient often accepts it because of cancer terminology. The treatment for these clinically insignificant carcinomas does not benefit the patient and negatively impacts society. The author proposed risk stratification of thyroid tumors using the growth rate (Ki-67 labeling index), which accurately differentiates four prognostically relevant risk groups based on the Ki-67 labeling index, ≥30%, ≥10 and <30%, >5 and <10%, and ≤5%. Indolent thyroid tumors with an excellent prognosis have the following four features: young age, early-stage (T1-2 M0), curatively treated, and low proliferation index (Ki-67 labeling index of ≤5%), and are unlikely to recur, metastasize, or cause cancer death. Accurate identification of these indolent tumors helps clinicians select more conservative treatments to avoid unnecessary aggressive (total thyroidectomy followed by radio-active iodine) treatments. Clinicians can alleviate the fears of patients by confirming these four features, including the low proliferation rate, in a pathology report immediately after surgery when patients are most concerned.

Widely invasive follicular thyroid carcinoma (wi-FTC) is regarded as having an aggressive character and a dire prognosis, but it has not been known whether all wi-FTCs have a dire prognosis. Herein we retrospectively analyzed the cases of 133 patients with wi-FTCs to determine the prognostic significance of vascular invasion and cell-proliferation activity based on the Ki-67 labeling index (LI). Of the 119 patients without distant metastasis (M0), 11 (9.2%) showed recurrence during the postoperative follow-up. In a univariate analysis, the recurrence-free survival (RFS) rates of the M0 patients with vascular invasion and those with a Ki-67 LI ≥5% were significantly poorer (p = 0.0013 and p = 0.0268, respectively) than those of the patients without vascular invasion or with a Ki-67 LI <5%. Other clinicopathological factors such as patient age, gender, tumor size, and oxyphilic tumor were not significantly related to the patients’ RFS. In a multivariate analysis, positive vascular invasion independently affected the RFS (p = 0.0133), but Ki-67 >5% did not (p = 0.1348). To date, only five patients have died of their thyroid carcinoma; four cases were M1. In conclusion, although M0 wi-FTC generally has a favorable prognosis, cases with positive vascular invasion or a high Ki-67 LI are likely to recur, and careful postoperative follow-up is necessary.

This study aimed to investigate the relationships between genetic polymorphisms of leptin/receptor genes and clinical/biochemical characteristics in children with growth hormone deficiency (GHD). Ninety-three GHD children and 69 age-matched normal controls were enrolled. Anthropometric measurements, bone age, and laboratory test results were obtained. Polymorphisms in the LEP gene promoter locus (LEP-2548, rs7799039) and LEPR genes (K109R, rs1137100 and Q223R, rs1137101) were analyzed using PCR-RFLP. The serum leptin levels were measured using an ELISA kit. The median height and BMI z-scores of all GHD subjects were –2.20 and –0.26, respectively, and those of normal controls were –0.30 and –0.13, respectively. The serum leptin levels were similar between GHD subjects and normal controls (p = 0.537), but those were different between the complete GHD (6.97 ng/mL) and partial GHD (4.22 ng/mL) groups (p = 0.047). There were no differences in the genotypic distributions of LEP-2548, LEPR K109R, and Q223R between GHD subjects and normal controls. However, GHD subjects with the G allele at LEP-2548 showed higher IGF-1 (p = 0.047) and IGFBP-3 SDSs (p = 0.027) than GHD subjects with the A allele. GHD subjects with the G allele at LEPR Q223R showed lower stimulated GH levels (p = 0.023) and greater height gain after 1 year of GH treatment (p = 0.034) than GHD subjects with the A allele. In conclusion, leptin/leptin receptor genes are suggested to have the role of growth-related factors, which can affect various growth responses in children who share the same disease entity.

The taller-than-wide sign indicates that the anteroposterior dimension-to-transverse dimension ratio (AP/T ratio) is higher than 1. The aim of the present study was to reconfirm the accuracy of the taller-than-wide sign for diagnosing malignant thyroid nodules by ultrasonography in multicenter collaborative research, and investigate differences according to tumor sizes, histological types, and the influence of the tilt and orientation of the probe. At 6 registered institutes, 2,032 thyroid nodules were successively operated on and diagnosed pathologically. The accuracy of the taller-than-wide sign for diagnosing malignant tumors by ultrasonography was retrospectively analyzed across all nodules as well as in analyses separately stratified by tumor size and histology. The influence of the tilt and orientation of the probe was also assessed. The taller-than-wide sign showed high specificity for diagnosing malignancy in all nodules tested. It also showed high specificity regardless of the tumor size. When tumors were analyzed by histological types, the AP/T ratio of papillary carcinoma was significantly higher than that of benign nodules, whereas no significant difference was observed between follicular carcinoma and benign nodules. The specificity of longitudinal sections was significantly higher, while the AUC of longitudinal sections was significantly larger than those of transverse sections. The AP/T ratio obtained when the probe was tilted was not significantly different from that when it was straight. The present results support the usefulness of the taller-than-wide sign for diagnosing malignant tumors regardless of size, but not follicular carcinoma. The influence of the tilt and orientation of the probe was negligible.

The STELLA-LONG TERM prospective post-marketing surveillance study assessed ipragliflozin in Japanese patients with type 2 diabetes mellitus (T2DM). This subgroup analysis of patients with liver impairment used the final 3-year results. Data on patients, adverse drug reactions (ADRs), and changes in glycemic parameters and liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [γ-GTP] and alkaline phosphatase [ALP]) were collected, and the fatty liver index (FLI) was calculated. In the effectiveness analysis (n = 8,763), baseline liver function was normal in 2,605 patients (ALT <31/<21 U/L [men/women]) and abnormal in 3,277 (ALT ≥31/≥21 U/L). The abnormal liver function group had higher mean body weight and BMI than the normal liver function group (p < 0.001). In the safety analysis (n = 11,051), urinary tract infections, genital infections and hepatic disorders were more common in the abnormal than normal liver function group (2.25% vs. 1.07%; 1.78% vs. 1.14% and 1.85% vs. 1.01%). In the abnormal liver function group, there were significant (p < 0.001) decreases from baseline at 36 months in AST and ALT (from 38.8 and 53.7 U/L to 29.3 and 37.7 U/L, respectively), γ-GTP (from 75.4 to 51.7 U/L) and ALP (from 254.8 to 234.5 U/L), which were greater than in the normal liver function group. FLI reductions at 36 months were significant (p < 0.001) in subgroups with baseline FLI of ≥30 or ≥60. In conclusion, ipragliflozin improved liver function over 3 years in patients with impaired liver function, although ADRs occurred more frequently than in the normal liver function group.

Gestational diabetes mellitus (GDM) is known to be a significant risk factor for the future development of type 2 diabetes. Here, we investigated whether a precise evaluation of β- and α-cell functions helps to identify women at high risk of developing glucose intolerance after GDM. Fifty-six women with GDM underwent a 75-g oral glucose tolerance test (OGTT) at early (6–12 weeks) postpartum. We measured their concentrations of glucose, insulin, proinsulin and glucagon at fasting and 30, 60 and 120 min. At 1-year post-delivery, we classified the women into a normal glucose tolerance (NGT) group or an impaired glucose tolerance (IGT)/diabetes mellitus (DM) group. Forty-three of the 56 women completed the study. At 1-year post-delivery, 17 women had developed IGT/DM and 26 women showed NGT. In the early-postpartum OGTTs, the IGT/DM group showed a lower insulinogenic index, a less glucagon suppression evaluated by the change from fasting to 30 min (ΔGlucagon 30 min), and a higher glucagon-to-insulin ratio at 30 min compared to the NGT group. There were no significant between-group differences in proinsulin levels or proinsulin-to-insulin ratios. Insulinogenic index <0.6 and ΔGlucagon 30 min >0 pg/mL were identified as predictors for the development of IGT/DM after GDM, independent of age, body mass index, and lactation intensity. These results suggest that the bihormonal disorder of insulin and glucagon causes the postpartum development of glucose intolerance. The measurement of plasma insulin and glucagon during the initial OGTT at early postpartum period can help to make optimal decisions regarding the postpartum management of women with GDM.

The brain mechanism responsible for the pulsatile secretion of gonadotropin-releasing hormone (GnRH) is important for maintaining reproductive function in mammals. Accumulating evidence suggests that kisspeptin/neurokinin B/dynorphin A (KNDy) neurons in the hypothalamic arcuate nucleus (ARC) play a critical role in the regulation of pulsatile GnRH and subsequent gonadotropin secretion. Dynorphin A (Dyn) and its receptor, kappa-opioid receptor (KOR, encoded by Oprk1), have been shown to be involved in the suppression of pulsatile GnRH/luteinizing hormone (LH) release. On the other hand, it is still unclear whether the inhibitory Dyn signaling affects KNDy neurons or KOR-expressing non-KNDy cells in the ARC or other brain regions. We therefore aimed to clarify the role of ARC-specific Dyn-KOR signaling in the regulation of pulsatile GnRH/LH release by the ARC specific cell deletion of KOR-expressing cells using Dyn-conjugated-saporin (Dyn-SAP). Estrogen-primed ovariectomized female rats were administered Dyn-SAP to the ARC. In situ hybridization of Oprk1 showed that ARC Dyn-SAP administration significantly decreased the number of Oprk1-expressing cells in the ARC, but not in the ventromedial hypothalamic nucleus and paraventricular nucleus. The frequency of LH pulses significantly increased in animals bearing the ARC Dyn-SAP administration. The number of Kiss1-expressing cells in the ARC was not affected by ARC Dyn-SAP treatment. Dyn-KOR signaling within the ARC seems to mediate the suppression of the frequency of pulsatile GnRH/LH release, and ARC non-KNDy KOR neurons may be involved in the mechanism modulating GnRH/LH pulse generation.

Although Rathke’s cleft cysts (RCCs) are common sellar/parasellar lesions, studies examining pituitary function in patients with nonsurgical RCC are limited. This study aimed to clarify the importance of RCCs, including small nonsurgical ones, as a cause of hypopituitarism by determining the prevalence of pituitary hormone secretion impairment and its relationship to cyst/tumor size in patients with RCC and in those with nonfunctioning pituitary adenoma (NFA). We retrospectively investigated the basal levels of each anterior pituitary hormone, its responses in the stimulation test(s), and cyst/tumor size in patients with RCC (n = 67) and NFA (n = 111) who were consecutively admitted to our hospital for endocrinological evaluation. RCCs were much smaller than NFAs (median height, 12 vs. 26 mm). The prevalence of gonadotropin, PRL, and GH secretion impairment in RCC was lower in comparison to NFA (19% vs. 44%, 34% vs. 61%, and 24% vs. 46%, respectively), whereas the prevalence of TSH and ACTH secretion impairment was comparable (21–27% and 17–24%, respectively). A significant positive relationship between cyst/tumor size and number of impaired hormones was observed in both groups, but smaller cysts could cause hormone secretion impairment in RCC. Stimulation tests suggested that most hormone secretion impairment was attributable to the interrupted hypothalamic-pituitary axis in both groups. Therefore, RCC, even small ones, can cause pituitary dysfunction. Different mechanisms may underlie hypothalamic–pituitary interruption in RCC and NFA.

Male patients with acromegaly frequently have hypogonadism. However, whether excess GH affects gonadal function remains unclear. We retrospectively compared clinical features affecting total testosterone (TT) and free testosterone (FT) levels between 112 male patients with acromegaly and 100 male patients with non-functioning pituitary adenoma (NFPA) without hyperprolactinemia. Median maximum tumor diameter (14.4 vs. 26.5 mm) and suprasellar extension rate (33 vs. 100%) were lower in acromegaly, but LH, FSH, TT, and FT were not significantly different. In acromegaly, TT was less than 300 ng/dL in 57%, and FT was below the age-specific reference range in 77%. TT and FT were negatively correlated with GH, IGF-1, and the tumor size, and positively correlated with LH. In NFPA, they were positively correlated with IGF-1, LH, FSH, ACTH, cortisol, and free T4, reflecting hypopituitarism. Multiple regression analysis showed that TT and FT had the strongest correlation with GH in acromegaly, and with LH in NFPA. Surgical remission was achieved in 87.5% of 56 follow-up patients with acromegaly. TT and FT increased in 80.4 and 87.5%, respectively, with a significant increase in LH. In acromegaly, the degree of postoperative increase in TT(FT) correlated with the fold increase of TT(FT)/LH ratio, a potential parameter of LH responsiveness, but not with fold increase of LH, whereas in NFPA it correlated with both. These results suggest that excessive GH is the most relevant factor for hypogonadism in male acromegaly, and may cause impaired LH responsiveness as well as the suppression of LH secretion.

Various researches have reported that the application of topical insulin improves wound healing. Considering the lack of a quantitative comprehensive research on this matter, we conducted a meta-analysis of clinical research and experimental animal studies. Prospective and randomized controlled trials of PubMed, Embase, and Cochrane Library were conducted using appropriate search strategies to compare the effectiveness of topical application of saline and insulin on wounds. The standardized mean difference was calculated as follows: wound healing time, wound healing rate, wound area, and the percentage of wound contraction. Each study used the Cochrane risk-of-bias tool and RevMan 5.3 software to create aggregated assessments and forest plots. The quality of evidence was evaluated in accordance with the methods of the Grading of Recommendations, Assessment, Development and Evaluation working group. Four clinical and nine animal studies eligible for inclusion were included in the meta-analysis. The assessments for clinical studies were as follows: wound healing time, –2.48 [–3.44, –1.51] and wound healing rate, 22.23 [18.17, 26.28]. Meanwhile, for animal studies, the following assessments were noted: wound healing time, –1.27 [–1.75, –0.79]; wound contraction rate, 15.91 [13.88, 17.95]; and wound area, –19.3 [–21.16, –17.44]. For the measurement of the following results, only one animal study was performed, pericyte recruitment of microvessels. Based on the analysis, it can be preliminarily judged that application of topical insulin can aid wound healing.

Honokiol plays an important role in anti-oxidation, but its role in diabetic vascular complications is unclear. In this study, the effects of honokiol in high glucose/high fat (HG/HF)-induced human umbilical vein endothelial cells (HUVECs) were explored. After pre-treatment with honokiol, the cells were transferred to an HG/HF medium, and cell viability and apoptosis were respectively measured by methyl tetrazolium and flow cytometry. Moreover, the contents of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured. The expressions of C/EBP homologous protein (CHOP), glucose-regulated protein 78 (GRP78), phosphorylated-protein kinase RNA-like endoplasmic reticulum kinase (p-PERK), phosphorylated-inositol requiring enzyme-1α (p-IRE1α), cleaved caspase-3 and SIRT1 were determined by Western blot or quantitative reverse transcription PCR, respectively. Finally, the viability, apoptosis, and the contents of ROS, MDA, and SOD, as well as the expressions of CHOP, GRP78, p-PERK, p-IRE1α, cleaved caspase-3, Akt, p-Akt, and SIRT1 in the cells transfected with small interfering RNA SIRT1 (siSIRT1) were detected by the previously mentioned methods. Honokiol reversed the effect of HG/HF on promoting cell apoptosis, ROS and MDA contents, and the expressions of CHOP, GRP78, p-PERK, p-IRE1α and cleaved caspase-3, and also reversed the inhibitory effect of HG/HF on cell viability, SOD content and SIRT1 expression. However, siSIRT1 reversed the above effects caused by honokiol. Honokiol activated SIRT1 promoter. SIRT1 interacted with Akt, consequently promoting the activity of Akt. Therefore, honokiol activates the Akt pathway by regulating SIRT1 expression to regulate endoplasmic reticulum stress, promotes cell viability and inhibits the apoptosis of HG/HF-induced HUVECs.

We did a systematic review and meta-analysis, aiming to examine the association of available polymorphisms in the receptor for advanced glycation end products (AGER) gene with the risk of type 2 diabetes. Literature search, eligibility assessment, and data extraction were independently performed by two authors. Risk was expressed as by odds ratio (OR) and 95% confidence interval (CI) under the random-effects model. A total of 26 publications, involving 29 independent studies (8,318 patients with type 2 diabetes and 5,589 healthy or orthoglycemic controls) were included in this meta-analysis. Six polymorphisms in AGER gene, rs2070600, rs1800624, rs1800625, rs184003, rs3134940, and rs55640627, were eligible for inclusion. Overall analyses indicated that the mutations of rs1800624 (–374A) and rs55640627 (2245A) were associated with a significantly increased risk of type 2 diabetes (OR = 1.17 and 1.55, 95% CI: 1.00 to 1.38 and 1.21 to 1.98, respectively). Subsidiary analyses revealed that the mutation of rs2070600 was associated with 2.13-folded increased risk of type 2 diabetes in Caucasians (95% CI: 1.28 to 3.55), and the mutation of rs1800624 was associated with 1.57-folded increased risk in South Asians (95% CI: 1.09 to 2.25), with no evidence of heterogeneity (I²: 42.5% and 44.5%). There were low probabilities of publication bias for all studied polymorphisms. Taken together, our findings indicate an ethnicity-dependent contribution of AGER gene in the pathogenesis of type 2 diabetes, that is, rs2070600 was a susceptibility locus in Caucasians, yet rs1800624 in South Asians.

Circular RNAs (circRNAs) are correlated with the occurrence and progression of differentiated thyroid cancer (THCA). However, the regulatory mechanism of circRNAs in differentiated THCA is unclear. In the present study, we analyzed the circRNA microarray dataset (GSE93522) of thyroid tumors and discovered that circRNA HACE1 (circHACE1) was downregulated in differentiated THCA. We detected circHACE1 expression by quantitative real-time polymerase chain reaction (qRT-PCR). Gain-of-function experiments were performed to analyze the biological function of circHACE1 in differentiated THCA cells in vitro. The regulatory mechanism of circHACE1 in differentiated THCA was explored through bioinformatics analysis, dual-luciferase reporter, RIP (RNA immunoprecipitation), and/or RNA pull-down assays. The biological function of circHACE1 in THCA was confirmed by xenograft assay. We verified that circHACE1 was downregulated in differentiated THCA. Also, differentiated THCA patients with low circHACE1 expression were associated with TNM grade, lymphoid node metastasis, tumor size, and poor prognosis. CircHACE1 overexpression decreased xenograft tumor growth in vivo and induced cell cycle arrest, apoptosis, impeded proliferation, migration, and invasion in differentiated THCA cells in vitro. CircHACE1 could function as a microRNA (miR)-346 sponge and regulated Tfcp2L1 (transcription factor CP2 like 1) expression. MiR-346 overexpression offset circHACE1 elevation-mediated effects on malignant behaviors of differentiated THCA cells. Furthermore, Tfcp2L1 silencing counteracted the suppressive impact of miR-346 inhibitor on the malignancy of differentiated THCA cells. In conclusion, circHACE1 adsorbed miR-346 and elevated Tfcp2L1 expression, thus curbing cell malignancy in differentiated THCA, manifesting that circHACE1 might be a target for differentiated THCA treatment.