Serum exosomal miR-7977 as a novel biomarker for lung adenocarcinoma

Exosomal microRNAs (miRNAs) have great potentials as a novel biomarker to predict lung cancer. We applied a miRNA microarray to identify aberrantly expressed serum exosomal miRNAs as candidate biomarkers for patients with lung adenocarcinoma (LUAD). Compared with the normal control, 31 exosomal miRNAs were found to be upregulated and 29 exosomal miRNAs were downregulated in the serum of LUAD respectively. Then, 10 dysregulated exosomal miRNAs expression levels in serum were further validated via qRT-polymerase chain reaction. Notably, exosomal miR-7977 was highest expressed and miR-98-3p was lowest expressed in the patients with LUAD, and exosomal miR-7977 showed significant correlation with the N stage and TNM stage with patients with LUAD (P < .05). Receiver operating characteristic curve showed that the abundant level of exosomal miR-7977 may predict LUAD with an area of under the curve (AUC) of 0.787. In comparison with exosomal miR-7977, exosomal miR-98-3p had a smaller area (0.719). The combination of exosomal miR-7977 and miR-98-3p improved the AUC to 0.816. Furthermore, in vitro experiments revealed that inhibition of miR-7977 enhanced the proliferation, invasion, and inhibited apoptosis in A549 cells, the opposite results were performed by miR-7977 mimics. In conclusion, exosomal miR-7977 was identified as a novel biomarker for patients with LUAD and may play as a tumor suppressor in lung cancer.     

Serum lactate as a novel potential biomarker in multiple sclerosis

Multiple sclerosis (MS) is a primary inflammatory demyelinating disease associated with a probably secondary progressive neurodegenerative component. Impaired mitochondrial functioning has been hypothesized to drive neurodegeneration and to cause increased anaerobic metabolism in MS. The aim of our multicentre study was to determine whether MS patients had values of circulating lactate different from those of controls. Patients (n = 613) were recruited, assessed for disability and clinically classified (relapsing–remitting, secondary progressive, primary progressive) at the Catholic University of Rome, Italy (n = 281), at the MS Centre Amsterdam, The Netherlands (n = 158) and at the S. Camillo Forlanini Hospital, Rome, Italy (n = 174). Serum lactate levels were quantified spectrophotometrically with the analyst being blinded to all clinical information. In patients with MS serum lactate was three times higher (3.04 ± 1.26 mmol/l) than that of healthy controls (1.09 ± 0.25 mmol/l, p < 0.0001) and increased across clinical groups, with higher levels in cases with a progressive than with a relapsing–remitting disease course. In addition, there was a linear correlation between serum lactate levels and the expanded disability scale (EDSS) (R² = 0.419; p < 0.001). These data support the hypothesis that mitochondrial dysfunction is an important feature in MS and of particular relevance to the neurodegenerative phase of the disease. Measurement of serum lactate in MS might be a relative inexpensive test for longitudinal monitoring of “virtual hypoxia” in MS and also a secondary outcome for treatment trials aimed to improve mitochondrial function in patients with MS.     

A novel thyroid hormone receptor-beta mutation,not anticipated to occur in resistance to thyroid hormone,causes variable phenotypes

Resistance to thyroid hormones (RTH) is a syndrome characterized by a variable tissue hyposensitivity to thyroid hormones and is linked to mutations in the thyroid hormone receptor-beta (TRbeta) gene. We report here for the first time in vivo the mutation R429W (CCG-->TCG) located in the exon 10. The artificial mutant obtained in vitro displayed a normal T(3)-binding affinity and transactivation function. Therefore, it was thought to produce little, if any, clinical effect and to escape to clinical detection. The present report is at least in part discordant with this prediction since the propositus and his grandmother had an authentic hyperthyroidism with high FT(4) plasma level in the presence of inappropriate TSH. On the other hand, spontaneous variations of clinical features and - interestingly - of plasma FT(4) concentrations with time in the propositus, and the phenotype observed in his mother who never complained with thyrotoxic symptoms, confirmed the in vitro binding and functional predictions. The most intriguing is the clinical course of the grandmother as she first presented with predominant pituitary RTH and a diffuse goiter and finally with a toxic multinodular goiter with normal T(3) and T(4) plasma concentrations and suppressed TSH. In conclusion, we report a novel mutation in the gene encoding the thyroid hormone receptor responsible for predominant pituitary RTH already described in vitro but not in vivo. The fluctuant phenotype of the propositus suggests that other factors modulate the degree of tissue resistance that is under genetic control. Toxic multinodular goiter, possibly due to chronic TSH stimulation during RTH, in addition to the phenotype variability, increases the difficulty to diagnose this thyroid disorder.     

Serum thyroglobulin as a biomarker of iodine excess and thyroid disease occurrence in adults

BackgroundThyroglobulin (Tg) is considered a sensitive indicator of iodine deficiency. However, the usefulness of Tg as a biomarker of excess iodine is uncertain. The present study aimed to determine the influence of different iodine intake on serum Tg levels, evaluate the influence of thyroid diseases on the distribution of Tg, and identify the factors that may affect Tg levels.MethodsA cross-sectional survey with a total of 1208 adults was conducted in different water iodine areas in China. Urinary iodine concentration (UIC), water iodine concentration (WIC), serum Tg, thyroid-stimulating hormone (TSH), and thyroid antibodies were measured. The thyroid volumes and nodules were measured by B-scan ultrasound.ResultsBased on the WIC data, subjects were divided into three groups. Based on the median urinary iodine concentration (MUIC) data, the iodine levels were adequate, more than adequate, and excess for the WIC < 10 μg/L group, 10 μg/L ≤ WIC ≤ 100 μg/L g, and WIC > 100 μg/L groups, respectively. The median Tg was significantly higher in the excess iodine group than in the adequate iodine group and the more than adequate iodine group (14.6 μg/L vs.12.7 μg/L, P = 0.042; 14.6 μg/L vs.12.5 μg/L, P = 0.004). Multiple linear regression analysis showed that excess iodine intake, goitre, thyroid nodules, and hypothyroidism were significantly related to higher serum Tg levels.ConclusionSerum Tg level can be a promising biomarker of excessive iodine intake, but other factors, especially the presence of thyroid disease, should be considered when using this parameter.     

Serum sulfatides as a novel biomarker for cardiovascular disease in patients with end-stage renal failure

Sulfatides, normal components of serum lipoproteins, may play an important role in cardiovascular disease due to their various modulatory functions in haemostasis. The incidence of cardiovascular disease in patients with end-stage renal failure undergoing maintenance hemodialysis has been reported to be approximately 10 to 30 times higher than that in the general population. To elucidate the possible roles of serum sulfatides in this high incidence, we measured the level of sulfatides in 59 such patients, by converting them to lysosulfatides according to a recently developed quantitative, qualitative, high-throughput technique using matrix-assisted laser desorption ionization-time of flight mass spectrometry. The mean level of sulfatides in patients 3.58 ± 1.18 nmol/ml was significantly lower than that in age-matched normal subjects (8.21 ± 1.50 nmol/ml; P < 0.001). Patients receiving maintenance hemodialysis over a longer period had lower levels of sulfatides. When the mean levels of sulfatides were compared between patients with cardiovascular disease (N = 22) and those without the disease (N = 37), the level in the former group 2.85 ± 0.67 nmol/ml was found to be significantly lower than that in the latter group 4.01 ± 1.22 nmol/ml (P < 0.001). These findings reveal a close correlation between low levels of serum sulfatides and a high risk of cardiovascular disease in these patients. Determination of the level of serum sulfatides can contribute to predictions of the incidence of cardiovascular disease in patients with end-stage renal failure undergoing maintenance hemodialysis.     

Urinary oxytocin as a non-invasive biomarker for neurohypophyseal hormone secretion

The objective was to characterize the urinary oxytocin (OT) system with the goal of using it as a biomarker for neurohypophyseal peptide secretion. We studied urinary OT secretion in mice under three conditions: (1) in OT gene deletion mice (OT -/-) which lack the ability to produce the peptide; (2) after arterial vascular infusion of OT and (3) after physiological stimulation with consumption of 2% sodium chloride. OT was measured by radioimmunoassay (RIA) and Surface-Enhanced Laser Desorption Ionization Time of Flight Mass Spectroscopy (SELDI TOF MS). In OT -/- mice (n=25), urinary OT levels were not detectable, while in OT +/+ mice (n=23) levels were 250.2+/-35.3 pg/ml. To evaluate blood/urine transfer, mice with chronic carotid arterial catheters were infused with saline or OT (5 or 20 pmol/min). Peak urine OT levels were 89+/-11.5 and 844+/-181 ng/ml in the low and high OT groups, respectively. Proteomic evaluation showed MS peaks, corresponding to OT ( approximately 1009 Da) and a related peptide ( approximately 1030 Da) with highest levels in mice infused with OT. Salt loading (5 days of 2% NaCl as drinking water) increased plasma osmolality (3.3%), increased plasma and urinary vasopressin (AVP), but caused no changes in OT. Thus, using non-invasive urine samples, we document that urinary OT and AVP can be used to monitor changes in peptide secretion. Urinary OT and AVP, as well as other urinary peptides, may provide a viable biomarker for peptide secretion and may be useful in clinical studies.     

循环血中microRNAs作为疾病标志物的研究进展

新近研究发现成熟的microRNA能够游离于细胞之外,稳定存在于循环血中,具备疾病分子生物标志物的某些优点,已在多种肿瘤和非肿瘤疾病的早期诊断和预后中显示了独特的价值,同时循环血中microRNA的功能研究也已开始。该文针对近两年循环血中microRNA标志物及功能研究的成果,对microRNA研究中的这一热点问题进行综述。     

Serum thyroid hormone levels in male buffalo calves as related to age and sexual development

A total of 155 male buffalo calves were classified into 17 groups according to chronological age. The body weight was recorded on a balance or computed. Sera samples were analysed for thyroxine (T(4)) and triiodothyronine (T(3)) by radioimmunoassay. Highest concentration of thyroid hormones (T(4), 87.6+/-17.6; T(3), 3.1+/-0.07 ng/ml) were seen during the first week after birth followed by a gradual decline until two months of age. Later, the mean T(4) and T(3) levels fluctuated between 30 and 40 ng/ml and at around 1.0 ng/ml, respectively, except for a mild peak at 12 to 15 months of age. T4:T3 ratio did not vary significantly among various age groups. Both T4 and T3 were negatively correlated with age.     

Serum microRNA expression profile as a biomarker for the diagnosis of pertussis

Pertussis is a highly contagious, respiratory disease associated with substantial morbidity and mortality. A rapid and reliable diagnostic method is essential for appropriate treatment and prevention. Expression profiles of circulating microRNAs (miRNAs) have been proven as new non-invasive biomarkers for infectious diseases. We aimed to investigated the serum miRNA profile in pertussis patients and explored its potential as a novel diagnostic biomarker for pertussis. Among 664 different miRNAs analyzed using a miRNA array, 50 were overexpressed and 81 were underexpressed in the serum of pertussis patients. Expression levels of seven candidate miRNAs were further evaluated by real-time qRT-PCR. A panel of five miRNAs (miR-202, miR-342-5p, miR-206, miR-487b, miR-576-5p) was confirmed overexpressed in pertussis patients (p < 0.05). Risk score and receiver-operating characteristic (ROC) analysis showed that the area under the curve of the five-member miRNA profile was 0.980. At an optimal cutoff value (0.707), this panel of miRNAs yielded a sensitivity of 97.4 % and a specificity of 94.3 %. These data suggest that the five-member serum miRNA profile may serve as a new biomarker for pertussis diagnosis with high specificity and sensitivity.     

The thyroid hormone receptors: molecular basis of thyroid hormone resistance.

Major progress has been achieved in the mechanism of action of thyroid hormones thanks to the identification of the T3 receptor as the product of the proto-oncogene c-erbA. Recognition of subsets of receptors with and without T3-binding properties and of the interaction of different receptors with each other leads to new insights in cell regulation and development. In thyroid hormone resistance, distinct mutations in the T3-binding domain of thyroid hormone receptor (TR)beta have been identified in unrelated families. No correlation between the type of mutation and tissue resistance has been established. Mutant TRs bind to thyroid hormone response elements (TREs) on both negative or positive T3-controlled genes. Subjects with heterozygous TR beta gene deletion are not affected, supporting the hypothesis that mutant TRs act through a dominant negative effect. In generalized thyroid hormone resistance, mutated TR beta may interfere through competition for TREs and/or formation of inactive dimers. Finally, deficiency in T3 receptor auxiliary protein or other accessory proteins or competition between mutant and normal TRs for these factors is not excluded.     

A lysosomal pepstatin-insensitive proteinase as a novel biomarker for breast carcinoma

Lysosomal proteinases play an important role in the turnover of intracellular proteins, and acidic proteinases such as cathepsin D are known to be increased in breast carcinoma. In the present study the activity of a newly discovered acidic lysosomal pepstatin-insensitive proteinase (CLN2p) was measured in breast tissues by the most sensitive and highly specific assay that we had developed for the diagnosis of late-infantile neuronal ceroid lipofuscinosis (LINCL) (2). Samples from eight normal subjects undergoing reductive mammoplasty and 200 patients with primary breast carcinoma were analyzed. The results suggest a two- to seventeen-fold higher CLN2p activity in tumors, which was significantly and positively correlated with already known breast cancer biomarkers such as levels of cathepsin D, estrogen receptor and progesterone receptor. These results suggest a diagnostic and prognostic potential for this novel acid proteinase in breast cancer.     

Circulating omentin as a novel biomarker of endothelial dysfunction

Omentin is a novel soluble lectin expressed mainly in the stromal‐vascular cells from visceral adipose tissue with vasodilator effect in isolated blood vessels. To gain insight in the relationship between obesity and cardiovascular risk factors, we aimed to explore the interaction among circulating omentin, metabolic parameters, and endothelial function. Circulating omentin (enzyme‐linked immunosorbent assay) was studied in 248 white men (148 with normal glucose tolerance (NGT) and 100 with impaired glucose tolerance (IGT)). Insulin sensitivity was measured using the frequently sampled intravenous glucose tolerance test. Vascular reactivity was measured by high‐resolution ultrasound of the brachial artery. Circulating omentin concentration was significantly increased in lean compared with overweight and obese subjects (53.7 ± 16.9 vs. 45.2 ± 16.8 and vs. 40.1 ± 15.5 ng/ml, P < 0.0001). Circulating omentin concentration correlated with age, BMI, waist‐to‐hip ratio (WHR), percentage of fat mass, systolic and diastolic blood pressure, endothelium‐dependent and independent vasodilation (EDV and EIV), C‐reactive protein, and interleukin‐6 (IL‐6). In IGT subjects, circulating omentin concentration also correlated with insulin sensitivity, although this association did not remain significant after controlling for BMI. In a multiple linear regression analysis, circulating omentin concentration (P = 0.01), systolic blood pressure (P = 0.04), and BMI (P = 0.04) contributed independently to EDV after controlling for age and C‐reactive protein in IGT subjects. In NGT subjects, only circulating omentin concentration (P = 0.01) was significantly associated with EDV. In conclusion, circulating omentin concentration could be a useful marker of endothelial function.     

Circulating microRNA-1 as a potential novel biomarker for acute myocardial infarction

Recent studies have revealed the role of microRNAs (miRNAs) in a variety of basic biological and pathological processes and the association of miRNA signatures with human diseases. Circulating miRNAs have been proposed as sensitive and informative biomarkers for multiple cancers diagnosis. We have previously documented aberrant up-regulation of miR-1 expression in ischemic myocardium and the consequent slowing of cardiac conduction. However, whether miR-1 could be a biomarker for predicting acute myocardial infarction (AMI) is unclear. In the present study, we recruited 159 patients with or without AMI for quantification of miR-1 level in plasma using real-time RT-PCR method. We performed Wilcoxon rank sum and signed rank tests for comparison. Univariable linear regression and logistics regression analyses were performed to assess the potential correlation between miR-1 and known AMI markers. We also conducted receiver-operator characteristic curve (ROC) analysis to evaluate the diagnostic ability of miR-1. We found that: miR-1 level was significantly higher in plasma from AMI patients compared with non-AMI subjects and the level was dropped to normal on discharge following medication. Increased circulating miR-1 was not associated with age, gender, blood pressure, diabetes mellitus or the established biomarkers for AMI. However, miR-1 level was well correlated with QRS by both univariable linear and logistics regression analyses. The area under ROC curve (AUC) was 0.7740 for separation between non-AMI and AMI patients and 0.8522 for separation AMI patients under hospitalization and discharge. Collectively, our results revealed that circulating miR-1 may be a novel, independent biomarker for diagnosis of AMI.