Thyroid cancer is the most prevalent endocrine cancer worldwide. Angiogenesis, the formation of new blood vessels, plays a pivotal role in the development and progression of tumors. Over the past years, cancer research has focused on the ability of tumors to induce newly formed blood vessel, because tumor growth and the process of cancer metastasis mainly depends on angiogenesis. Tumor neovascularization occurs following the imbalance between pro-angiogenic and anti-angiogenic factors until the tumor switches to an angiogenic phenotype. A number of signaling factors and receptors that are implicated in the regulation of angiogenesis have been identified and characterized; most notably, the vascular endothelial growth factors (VEGFs) family and their receptors, which are the main pro-angiogenic molecules during early development and in pathological conditions such as cancer. Although thyroid is a highly vascularized organ, angiogenic switch in tumors of this organ leads to the formation of a vast network of blood vessels that favors the dissemination of tumor cells to distant organs and results in deterioration of patient conditions. Accordingly, the identification of key angiogenic biomarkers for thyroid cancer can facilitate diagnosis, prognosis and clinical decision-making and also may help to discover targeting factors for effective cancer therapy as well as monitoring response to therapy. Hence, the main purposes of this review are to summarize the types and mechanisms of angiogenesis emphasizing the prominent factors implicated in thyroid cancer angiogenesis.
Therapeutic blocking antibodies against programmed death 1 (PD1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) are applied for advanced cancer therapy, but induce a wide range of immune-related adverse events. In our recent case of a 52-year-old female doctor suffering from breast cancer having metastasized to the lung and liver, it was decided to use nivolumab to prevent the disease progressing after excisional surgeries and multiple chemotherapies. One month after completing the nivolumab course, fatigue, hypoglycemia and hypotension developed and isolated ACTH deficiency (IAD) was diagnosed. A further month later, under steroid supplementation, hyperglycemia emerged alongside thirst and polydipsia, prompting a diagnosis of fulminant type 1 diabetes (FT1D). Her susceptibility to type 1 diabetes was examined by HLA haplotype and CTLA4 gene polymorphism analyses. Polymorphisms CT60G>A and +49G>A in CTLA4 both generated a GG genotype. Our patient manifested one of the rarest combinations of autoimmune disease induced by nivolumab. Whereas the HLA haplotype was unsusceptible to autoimmune type 1 diabetes, polymorphisms of CTLA4, the antibody of which frequently causes hypophysitis, were susceptible to FT1D. Peripheral modulation of activated T cells, mainly by PD-1 antibodies, induced FT1D associated with IAD in patients with CTLA4 polymorphism. This case reveals hints of the T-cell etiology in T1D and evidence of CTLA4 involvement in IAD.
Nodular thyroid disease is a very common disorder in patients with acromegaly. Insulin-like growth factor-1 (IGF-1) is a thyroid growth factor, and there is a correlation between IGF-1 levels and thyroid volume (TV) in patients with acromegaly. There is no study investigating the impact of somatostatin analog (SSA) treatment on thyroid nodule volume in patients with acromegaly. We aimed to assess thyroid nodule volume change with SSA treatment in patients with persistent acromegaly. We retrospectively analyzed data from 108 consecutive patients with acromegaly who were followed up by our clinic after undergoing surgery between 2002 and 2014. Patients who were cured after surgery were excluded. We only selected 43 patients (21 males, 22 females, mean age 52.8 ± 11.9 years) who did not meet the criteria of remission postoperatively, who were treated with SSA for at least six months and had normal thyroid function. Patients were divided into three groups (well-controlled, controlled, and active) according to their IGF-1 and growth hormone (GH) levels. All patients underwent an evaluation of TV and total thyroid nodule volume (TTNV) by ultrasound. TTNV decreased significantly in patients with well-controlled acromegaly (0.44 [0.75] to 0.23 [0.73], p < 0.001). TTNV did not change in controlled patients (0.18 [1.28] to 0.13 [1.54], p = 0.959); however TTNV increased in patients with active acromegaly (0.77 [1.46] to 1.03 [1.88], p = 0.028). Successful medical treatment of patients with active acromegaly decreases thyroid nodule volume. Sustained exposure to IGF-1 may cause an increase in thyroid nodule volume in patients with acromegaly.
Type 2 diabetic patients are becoming younger and having a tendency to family aggregation, they are easily suspected as maturity-onset diabetes of young (MODY) in the outpatient clinic and send to genetic testing. 9 diabetic families were compared in our outpatient clinic who met the primary diagnosis criteria of MODY. Detailed clinical features and laboratory data including gene sequence were collected and analyzed. The patients met the primary clinical diagnostic criteria of MODY for genetic testing at the first look. However, members of families A1 to A3 had normal Body mass index (BMI) and a lower C-peptide level which indicated impaired pancreatic islet function. In contrast, the members with diabetes of families B1 to B6 had normal or increased C-peptide level which indicated insulin resistance and were overweight with BMI. Genetic testing showed that the mutations in HNF1A, INS, KCNJ11 and so on in families A were consistent with the diagnosis of MODY. No pathogenic mutation was found in the members of families B which were diagnosed with familial T2D. Before the clinical laboratory testing and the further gene test, BMI and the concentration of C-peptide are important for the promptly differential diagnosis of MODY from familial type 2 diabetes and medication instruction in the outpatient clinic which could help to alleviate the burden of genetic testing for them.
Hyperparathyrodism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder. Loss of function of the cell division cycle protein 73 homolog (CDC73) gene is responsible for the syndrome. This gene encodes an ubiquitously expressed 531 amino acid protein, parafibromin, that acts as a tumor suppressor. Loss of heterozygosity (LOH) of the CDC73 locus in many HPT-JT associated parathyroid tumors from patients with germline mutation is in accordance with Knudson’s “two-hit” model for hereditary cancer. A 41-year-old man with mandible ossifying fibroma suffered from severe hypercalcemia due to parathyroid carcinoma (PC). Genetic analysis was performed to evaluate germinal and somatic CDC73 gene mutation as well as real-time qRT-PCR to quantify CDC73 mRNA, miR-155 and miR-664 expression levels. Immunohistochemistry and Western blotting (WB) assay were carried out to evaluate parafibromin protein expression. A novel heterozygous nonsense mutation, c.191-192 delT, was identified in the CDC73 gene. No CDC73 LOH was found in PC tissue, nor any differences in expression levels for CDC73 gene, miR-155 and miR-664 between PC and parathyroid adenoma control tissues. On the contrary, both immunohistochemistry and WB assay showed an approximate 90% reduction of parafibromin protein expression in PC. In conclusion, this study describes a novel germinal mutation, c.191-192 delT, in the CDC73 gene. Despite normal CDC73 gene expression, we found a significant decrease in parafibromin. We hypothesize that a gene silencing mechanism, possibly induced by microRNA, could play a role in determining somatic post-transcriptional inactivation of the wild type CDC73 allele.
This research aimed to examine the relationship between anti-glutamic acid decarboxylase antibody (GADA) titers and clinical parameters at onset and to clarify the association between clinical severity and GADA titers in GADA-positive fulminant type 1 diabetes. This cross-sectional observational study included 20 cases with GADA-positive fulminant type 1 diabetes (4 cases from our hospital and 16 from cases reported in the literature). The association between GADA titers and clinical parameters [age, sex, body weight, body mass index, period from appearance of any prodromal symptoms to diagnosis, period from development of hyperglycemic symptoms to diagnosis, GADA titer, HbA1c level, blood pH and HCO3– level, serum levels of ketone bodies and pancreatic exocrine enzymes] were analyzed. Spearman’s rank correlation coefficient (rs) was used for the correlation analysis. The results showed that there was a significant inverse correlation between GADA titers and the “period from appearance of any prodromal symptoms to diagnosis” (rs = –0.559, p < 0.05). Moreover, GADA titers were inversely correlated with blood pH and HCO3– level (rs = –0.576, p < 0.05, rs = –0.578, p < 0.05, respectively), and positively correlated with serum levels of total ketone bodies, acetoacetate, and 3-hydroxybutyrate (rs = 0.661, p < 0.05; rs = 0.700, p < 0.05; and rs = 0.782, p < 0.01, respectively). These findings suggest that higher GADA titers may be linked to more severe clinical severity of GADA-positive fulminant type 1 diabetes at onset. This association may be attributed to possible pre-existence of autoimmunity-related β-cell damage before the onset of fulminant type 1 diabetes.
Obesity is linked to a low-grade systemic inflammation and lipopolysaccharide (LPS) is a key factor. Sleeve gastrectomy (SG) can significantly cause weight loss, but few reports have looked into the changes of LPS and inflammatory cytokines after surgery. To explore the potential short-term impact of SG on LPS and inflammatory cytokines and their relationship to early metabolic changes in obesity. 30 Chinese adults with obesity (BMI 39.37 ± 8.22 kg/m2, 25 female) receiving SG were included in this study. Fasting blood samples were collected at baseline and 30 days after SG. Serum LPS markedly reduced from 336.50 (73.54, 500) pg/mL to 5.00 (5.00, 5.24) pg/mL at 1 month after SG (p < 0.05). There was a significant decrease in plasma IL-6, IL-8, and serum CRP after SG (all p < 0.05). Insulin resistance improved remarkably after surgery as displayed by reductions in fasting insulin level (FINS, p < 0.001), and HOMA-IR (p < 0.001). In addition, visceral fat area (VFA) decreased from 209.70 ± 39.96 cm2 to 193.28 ± 43.68 cm2 after SG (p < 0.001). LPS was positively correlated with FINS (r = 0.391, p = 0.033) and HOMA-IR (r = 0.38, p = 0.038) before SG. Meanwhile, VFA was positively associated with CRP (r = 0.388, p = 0.034) before surgery. When assessing 30-days postoperative changes, a positive correlation was found between the variations of LPS, IL-8 and the reduction of VFA. After multivariate analyses, only the reduced IL-8 level was independently associated with the reduction of VFA (p = 0.015). In conclusion, SG can significantly relieve the inflammation in obesity in the short term and LPS might be an earlier predictor of inflammatory changes after surgery.
Methimazole (MMI) and propylthiouracil (PTU) are commonly used for the treatment of Graves’ disease. They share similar inhibitory effects on thyroid hormone biosynthesis by interfering with thyroid peroxidase (TPO)-mediated oxidation and organification of iodine. However, their potential effects on other thyroid functional molecules have not been explored in depth. To identify novel effects of MMI and PTU, DNA microarray analysis, real-time PCR, Western blotting, immunofluorescence staining and confocal laser scanning microscopy were performed using FRTL-5 rat thyroid cells. DNA microarray analysis indicated that both MMI and PTU suppress iodotyrosine deiodinase 1 (Iyd, Dehal1) mRNA levels. Further studies revealed that Dehal1 mRNA levels was stimulated by TSH, insulin and serum, while it was suppressed by iodine and a follicular concentration of thyroglobulin. MMI and PTU significantly suppressed Dehal1 expression induced by TSH, insulin and serum. On the other hand, although MMI suppressed Dehal1 expression in the absence of TSH, PTU only weakly suppressed Dehal1 without TSH. These results suggest that PTU and MMI may use different mechanisms to regulate Dehal1 expression, and TSH may play essential and differential roles in mediating PTU and MMI signals in thyrocytes. The drugs also inhibited re-distribution of Dehal1 protein into newly formed lysosomes following thyroglobulin endocytosis. These findings imply complex and multifaceted regulation of Dehal1 in the thyroid and suggest that MMI and PTU modulate Dehal1 expression and distribution of the protein in thyrocytes to exert their effect.
The Japan Endocrine Society (JES) has the largest ratio of female membership among societies associated with Internal Medicine in Japan; half of female members are in their 20s or 30s at present. In 2009, JES organized the “JES-We-Can” committee to promote women’s career development. To evaluate the effectiveness of JES-We-Can, we investigated the gender balance of various activities at JES in fiscal 2009 and 2017. Significant gender-differences were not observed in the acquisition rate of board-certified endocrinologists (BCEs) aged <40 y in 2009 and 2017. However, the acquisition rate of BCEs among women aged ≥40 y was significantly lower than men in 2009. In 2017, the gender-difference among BCEs in this group (currently aged ≥50 y) has considerably improved, but is not resolved. The acquisition rate of certificated endocrine educators (CEEs) among women was still significantly lower than men at all ages in 2017. Since the ratio of women oral speakers or poster presenters at annual academic meetings have grown to equal or surpass the membership ratio, female members make efficient contributions to JES. The numbers of women chairpersons, symposiasts, lecturers and invited speakers have increased, but remain limited. JES-We-Can was found to be effective in reducing the gender gap in academic activities at JES, but JES-We-Can should support women more intensely to raise the rate of CEEs among all ages and BCEs currently over 50 y, and to promote more women into higher positions in JES in the future. These actions are expected to introduce new and diverse perspectives into academia.
Association between heart failure and sarcopenia has been reported, however, the association between sarcopenia and brain natriuretic peptide (BNP) is unclear. Thus, we investigated the association between sarcopenia and BNP in type 2 diabetic patients without heart failure. In this cross-sectional study, skeletal muscle mass index (SMI, kg/m2) was calculated as appendicular muscle mass, measured by bioimpedance analyzer, by the square of the height. Sarcopenia was defined as having both handgrip strength of <26 kg for men and <18 kg for women, and SMI of <7.0 kg/m2 for men and <5.7 kg/m2 for women. To investigate the impact of BNP levels on the presence of sarcopenia, propensity-score matching analysis was used to remove the bias of confounding variables, including age, sex, duration of diabetes, body mass index, exercise, systolic blood pressure, smoking status, hemoglobin A1c, creatinine, energy and protein intake. The area under the curve (AUC) of BNP levels for the presence of sarcopenia was calculated by the receiver operating characteristic curve (ROC). Among 433 patients (236 men and 65.4 (11.1) years), 32 patients (7.4%) were diagnosed as sarcopenia. In the propensity-matched 58 patients, BNP levels (Δ10 pg/mL incremental) were associated with the presence of sarcopenia by logistic regression analysis, (odds ratio: 1.56, 95% confidence interval: 1.14–2.13, p = 0.002). The optimal cut-off point of BNP levels for sarcopenia is 27.3 pg/mL (AUC 0.777, 95%CI, 0.691–0.863, sensitivity = 0.813, specificity = 0.736, p < 0.001). In conclusion, BNP levels were associated with sarcopenia in type 2 diabetic patients without heart failure.
Parathyroid adenoma with prominent lymphocytic infiltrate is a rare disease. Until now, 11 patients have been reported. Herein, we report a 57-year-old man who had a neck mass that was incidentally found. Aspiration cytology and subsequent needle biopsy of the tumor were performed and suggested papillary thyroid carcinoma. From the resected specimen, however, the patient was finally diagnosed with parathyroid adenoma with prominent lymphocytic infiltrate, characterized by hyperplastic parathyroid cells with nuclear atypia within fibrotic stroma along with numerous lymphocytes forming germinal centers. Some eosinophils and plasma cells were also observed with some histological features highly suggestive of IgG4-related disease (IgG4-RD), including increased IgG4-positive plasma cells and IgG4/IgG-positive plasma cell ratio, storiform-type fibrosis, and obliterative phlebitis. It turned out that microfollicular or trabecular architecture and cellular atypia with high expression of HBME-1 observed in the aspiration cytology and needle biopsy had been misinterpreted as a thyroid malignancy. This is the first report describing microscopic features of aspiration cytology and needle biopsy of parathyroid adenoma with prominent lymphocytic infiltrate, warning that it can mimic papillary thyroid carcinoma in biopsy specimens. Furthermore, the IgG4-RD-like features of the present case and previous reports imply that parathyroid adenoma with prominent lymphocytic infiltrate may be a type of IgG4-RD.
Endogenous and exogenous androgens induce masculinization of external genitalia through binding to the androgen receptor (AR). The target genes of androgens in external genitalia remain to be determined, although previous studies have shown that the apolipoprotein D gene (APOD) was significantly upregulated by dihydrotestosterone (DHT), the most potent androgen in humans. In the present study, we performed microarray analysis for genital skin fibroblasts obtained from four boys with buried penis (the control individuals) and a patient with partial androgen insensitivity syndrome (PAIS) due to a hypomorphic mutation in AR (the PAIS patient). We identified 24 transcripts that were upregulated or downregulated by DHT in all samples of control individuals and, to a lesser extent, in the sample of the PAIS patient. Differences between DHT-treated and -untreated samples were small; the results of 24 transcripts did not reach statistical significance. The 24 transcripts included CYP1B1, a gene possibly involved in the development of genital tubercle in mice, and APOD, as well as several genes that have been reported as androgen targets in prostate or other tissues. The results of this study indicate that androgen-mediated masculinization of external genitalia is unlikely to depend on massive transcriptional changes in specific AR target genes. Rather, minor transcriptional changes of several genes, and/or a complex molecular network may play a major role in penile development. Importantly, our data suggest the possible involvement of CYP1B1 in human genital development and confirm the clinical importance of APOD as a biomarker for AR function.