The relationship between stathmin-2 level and metabolic parameters in newly diagnosed type 2 diabetes mellitus patients.

BACKGROUND: Stathmin is a phosphoprotein that plays a role in intercellular and intracellular signaling, inflammation, and differentiation. Our aim was to evaluate the stathmin-2 level and its relationship with the metabolic parameters of newly diagnosed type 2 diabetes mellitus (nT2DM) patients. MATERIAL AND METHOD: This case-control study included 76 patients with nT2DM and 76 healthy individuals with a normal oral glucose tolerance test who were matched for body mass index (BMI), age, and gender. In addition to laboratory and anthropometric measurements related to type 2 diabetes mellitus (T2DM), stathmin-2 levels were determined using an enzyme-linked immunosorbent assay. RESULTS: We observed significantly higher circulating stathmin-2 levels in subjects with T2DM compared to the control group (6.39±1.60 ng/mL and 4.66±0.80 ng/mL, p<0.0001). In patients with metabolic syndrome, circulating stathmin-2 levels were significantly elevated compared to those without metabolic syndrome in both the T2DM and control groups (T2DM: 7.16±1.24 vs 5.06±1.24 ng/mL, p<0.001; Control: 3.84±1.40 vs 3.82±1.40 ng/mL). In both groups, we observed a positive correlation between stathmin-2 levels and BMI and circumference. Moreover, stathmin-2 showed a positive correlation with high-sensitivity C-reactive protein (hs-CRP), homeostatic model assessment of insulin resistance, insulin, fasting blood glucose, hemoglobin A1c, BMI, low-density lipoprotein cholesterol, and total cholesterol. A negative correlation was observed with stathmin-2 and high-density lipoprotein cholesterol. Stathmin-2 did not show any correlation with age, triglyceride, and lactate dehydrogenase. CONCLUSIONS: Stathmin-2 levels were found to be elevated in patients with nT2DM and exhibited positive correlations with hyperinsulinaemia, hyperglycaemia, HOMO-IR and hs-CRP levels. These results indicate that stathmin-2 may play a role in T2DM pathogenesis.

Expression of Stathmin and vascular endothelial growth factor C in esophageal cancer and their combined diagnostic value.

PURPOSE: To investigate the expression of Stathmin and vascular endothelial growth factor C (VEGF-C) in the serum of patients with esophageal cancer (EC) and the diagnostic value of the combined two factors. METHODS: 88 EC patients (the EC Group) treated in Shaanxi Provincial People's Hospital and 50 healthy people (the Control Group) were selected as subjects of this study. After detecting the levels of Stathmin mRNA and VEGF-C mRNA using real-time quantitative PCR (qRT-PCR) and the expression levels of Stathmin protein and VEGF-C protein using enzyme-linked immunosorbent assay (ELISA), analysis of the relationship between the expression levels of Stathmin mRNA and VEGF-C mRNA in the serum and the clinicopathological features of EC were analyzed. RESULTS: The levels of Stathmin mRNA and VEGF-C mRNA, Stathmin protein and VEGF-C protein in the serum of the Control Group were lower than those in the EC group (p<0.001). The mRNA and protein expressions of Stathmin and VEGF-C in the serum of EC group were related to lymph node metastasis, clinical stage, grade of differentiation and degree of infiltration (p<0.05). Compared with the combined detection of mRNA, the sensitivity of separate detection of Stathmin mRNA and VEGF-C mRNA was lower, but the specificity of the separate detection of Stathmin mRNA was higher (p<0.05). Compared with the sensitivity of the combined detection of protein, the sensitivity of the separate test of Stathmin protein and VEGF-C protein was lower (p<0.05). CONCLUSION: Stathmin and VEGF-C could be used as markers for early diagnosis of EC, and the combined detection of the two factors could improve the sensitivity of diagnosis since the expression levels of mRNAs and proteins of Stathmin and VEGFC in the serum of EC patients were proved to be higher than those of healthy volunteers.

A novel rapid quantitative method reveals stathmin-1 as a promising marker for esophageal squamous cell carcinoma.

Stathmin-1 is a microtubule depolymerization protein that regulates cell division, growth, migration, and invasion. Overexpression of stathmin-1 has been observed to be associated with metastasis, poor prognosis, and chemoresistance in various human cancers. Our previous studies found that serum stathmin-1 was significantly elevated in patients with esophageal squamous cell carcinoma (ESCC) by ELISAs. Here, we constructed high-affinity monoclonal antibodies and then developed a competitive AlphaLISA for rapid, accurate quantitation of stathmin-1 in serum. Compared to ELISA, our homogeneous AlphaLISA showed better sensitivity and accuracy, a lower limit of detection, and a wider linear range. The measurements of nearly 1000 clinical samples showed that serum stathmin-1 level increased dramatically in patients with squamous cell carcinoma (SCC), especially in ESCC, with a sensitivity and a specificity of 81% and 94%, respectively. Even for early stage ESCC, stathmin-1 achieved an area under the receiver operating characteristic curve (AUC) of 0.88. Meanwhile, raised concentrations of stathmin-1 were associated with lymph node metastasis and advanced cancer stage. Notably, various types of SCC showed significantly higher AUCs in serum stathmin-1 detection compared to adenocarcinoma. Furthermore, we confirmed that stathmin-1 was enriched in the oncogenic exosomes, which can explain the reason why it enters into the blood to serve as a tumor surrogate. In conclusion, this large-scale and systematic study of serum stathmin-1 measured by our newly established AlphaLISA showed that stathmin-1 is a very promising diagnostic and predictive marker for SCC in the clinic, especially for ESCC.

Increased stathmin in serum as a potential tumor marker for lung adenocarcinoma.

BACKGROUND: Stathmin has been found to be involved in malignant tumors; the aim of this study was to investigate the relationship between serum stathmin and clinico-pathological features of lung cancer. METHODS: In three lung cancer cell lines, stathmin expression and its secretion level in the supernatant were examined by Western blot and enzyme-linked immunosorbent assay (ELISA). Expression of stathmin was examined by immunohistochemistry in 48 lung cancer tissues, and serum stathmin expression level was examined by ELISA in 96 patients with lung cancer and 82 normal individuals. Sensitivity and specificity of serum stathmin were determined by receiver operator characteristic curve (ROC). RESULTS: In the three cell lines and their supernatant, stathmin levels were higher than those in 16 HBE cell line. Lung cancer tissues expressed higher level stathmin more frequently than normal lung tissue (P < 0.05). Serum stathmin level was significantly higher in the patients with lung cancer than in normal individuals (P < 0.001). Increased stathmin level in cancer tissue and serum were significantly associated with adenocarcinoma histology, lymph node metastasis and advanced stage. The threshold level of serum stathmin for distinguishing lung cancer from normal individuals was 1.86 ng/ml. The sensitivity and specificity were 93.7% and 91.5%, respectively. CONCLUSIONS: Measurement of serum stathmin level could be a potential biomarker for lung cancer, especically those of adenocarcinoma, with lymph node metastasis and at advanced clinical stages.

Erythropoietin preconditioning improves clinical and histologic outcome in an acute spinal cord ischemia and reperfusion rabbit model.

OBJECTIVE: This study examined effects and functional outcome of recombinant human erythropoietin (rhEPO) and carbamylated erythropoietin fusion protein (cEPO-FC) preconditioning in a rabbit model for spinal cord ischemia and resulting paraplegia. This model was chosen because only a small surgical effect is needed to cause paraplegia in rabbits, which facilitates postoperative observation of animals. METHODS: Anesthetized but spontaneously breathing New Zealand White rabbits randomly received cEPO-FC (50 µg/kg; n = 8), rhEPO (5000 IU/kg; n = 10), or vehicle (control; n = 10) 30 minutes before and after infrarenal aortic clamping. Ideal clamping time of 22 minutes was identified from preceding clamping tests (15-25 minutes). Postoperative observation time was 96 hours. Spinal cord function was assessed by neurologic evaluation of hind limb motor function every 12 hours using a modified Tarlov score. Spinal cord tissue damage was evaluated after 96 hours using hematoxylin and eosin, elastica van Gieson, Nissl, Masson-Goldner, and hemosiderin staining. Plasma levels of cell senescence markers stathmin, chitinase 1/3, elongation factor 1-α were determined. RESULTS: Rabbits that received rhEPO showed significant improvement of spontaneous lower limb movements until 36 hours of reperfusion and improved histologic scores upon examination of the lumbar spinal cord compared with the control group. In contrast, cEPO-FC treatment showed comparable outcome to the control group concerning movements of the lower limbs and histology. Senescence markers were elevated in the control group, but not in the treatment groups, except for chitinase 3 in the rhEPO group. Only stathmin showed no significant effect. Markers for senescence might increase after acute ischemic injury. Attenuation of senescence markers might not come alone from improvement of the spinal cord. CONCLUSIONS: Preconditioning with rhEPO attenuates ischemia/reperfusion injury of the spinal cord, whereas the carbamylated derivative (cEPO-FC) showed no positive effect on spinal cord function.

[Expression and significance of stathmin1 in acute leukemia].

This study was aimed to investigate the expression of stathmin1 mRNA and stathmin1 protein in de novo patients with acute leukemia (AL), relapsed patients with AL and complete remission patients with AL, and its clinical significance. The expression of stathmin1 mRNA and stathmin1 protein in peripheral blood samples from 76 cases of AL and 25 healthy persons were examined by fluorescent quantitative PCR (FQ-PCR) and Western blot, respectively. The results showed that the stathmin1 protein expression could not be detected in healthy persons, only the low level of its mRNA could be observed in them. The stathmin1 mRNA expression level in de novo AL patients was higher than that in healthy persons (P < 0.05), the stathmin1 mRNA expression level in relapsed patients with AL was higher than that in de novo patients (P < 0.05), and there was no significant difference of stathmin1 mRNA expression between patients with AML and patients with ALL. The positive rate of stathmin1 protein expression in de novo patients with AL was 89%, while it obviously decreased or did not express in complete remission patients with AL. The stathmin1 protein expression in relapsed patients with AL did not display significant difference as compared with that in de novo patients (P > 0.05). There was no significant difference in stathmin1 protein expression between patients with AML and patients with ALL (P > 0.05). It is concluded that stathmin1 protein and mRNA are overexpressed in de novo patients and relapsed patients, and lowly expressed in complete remission patients. Therefore, the stathmin1 may be a new biological marker for evaluation of minimal residual disease.

Expression of CD147, BIGH3 and Stathmin and their potential role as diagnostic marker in patients with urothelial carcinoma of the bladder.

BACKGROUND: Urothelial carcinoma of the bladder is characterised by very high recurrence rate, followed up by cystoscopy which being invasive technique makes the need for non-invasive markers important for Transitional Cell Carcinoma (TCC) detection. CD147 is a transmembrane protein highly expressed in tumour cells which aids in tumour invasion and growth. BIGH3, an Extracellular matrix protein (ECM) which interacts with various ECM component in different tissue system and Stathmin(STMN1) is cytosolic microtubule destabilising protein also called as Oncoprotein18 due to its role in tumour promotion. So far the expression of BIGH3 and STMN1 remains undetermined in cancer subjects including TCC. We therefore studied the levels and molecular expression of these molecules in TCC patients, to evaluate their usefulness as diagnostic markers. METHODS: Thirty consecutive TCC patients and two sets of control- 15 Benign prostatic hyperplasia (BPH) patient and 15 healthy were taken. Serum and urine levels of these molecules were estimated by ELISA and relative mRNA expression by Q-PCR from tumour and normal urothelium. Post-Hoc analysis and ROC curve were determined to evaluate the significance and sensitivity and specificity. RESULTS: The mean concentrations of these molecules were found to be significantly increased (p<0.001) in the serum and urine of TCC patients, with varying significance in each grade for different molecules. The urinary levels of CD147 (67 pg/ml) and serum STMN1 concentration (1.38 ng/ml) showed a specific increase as compared to the controls, while BIGH3 was elevated in both serum and urine samples. Molecular (mRNA) expression was elevated in the high grade (Muscle Invasive) stage of the disease for all the molecules, with a significant 3-fold increase that correlated with disease severity being observed for STMN1. ROC analysis gave optimal combination of sensitivity and specificity for diagnosis of the disease in urine and serum sample for STMN1. CONCLUSION: Of CD147, BIGH3 and STMN1, significant results were obtained for STMN1 and it could serve as the best possible diagnostic marker for TCC detection in future.

Telomere dysfunction-related serological markers are associated with type 2 diabetes.

OBJECTIVE: Recent studies have identified a set of serological markers for telomere dysfunction and DNA damage. The relevance of these serological markers in type 2 diabetes remains elusive. We investigated the association of serological markers (elongation factor 1α [EF-1α], stathmin, and N-acetyl-glucosaminidase) with leukocyte telomere length, a functional variant of uncoupling protein-2 (UCP2), and susceptibility of type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 930 patients and 867 control subjects were recruited to examine the association between leukocyte telomere length, UCP2 variant (-886G>A), recently identified serological markers, and type 2 diabetes. Telomere length was determined by a quantitative real-time PCR-based assay. EF-1α, stathmin, and C-reactive proteins were measured by enzyme-linked immunosorbent assays. N-acetyl-glucosaminidase was measured by an enzyme activity assay. The UCP2 variant was determined by PCR and restriction enzyme digestion. RESULTS: The average telomere length of type 2 diabetic patients was significantly shorter than that of control subjects. Serological N-acetyl-glucosaminidase correlates with both age and telomere length and was significantly higher in patients than in control subjects. Neither EF-1α nor stathmin showed significant difference between patients and control subjects. The UCP2-886G>A variant correlated with type 2 diabetes status but did not correlate with telomere length or the serological markers. Multivariate analysis showed that higher serological N-acetyl-glucosaminidase, shorter telomeres, and the UCP2-886G>A variant are independent risk factors for type 2 diabetes. CONCLUSIONS: Serological N-acetyl-glucosaminidase, telomere length, and the UCP2-886G>A variant are independent risk factors for type 2 diabetes. Serological N-acetyl-glucosaminidase correlates with telomere length but not with the UCP2-886G>A variant.

Changes in breast cancer biomarkers in the IGF1R/PI3K pathway in recurrent breast cancer after tamoxifen treatment.

Development of resistance to the antioestrogen tamoxifen occurs in a large proportion of patients with oestrogen receptor-positive (ER+) breast cancer and is an important clinical challenge. While loss of ER occurs in c.20% of tamoxifen-resistant tumours, this cannot be the sole explanation for tamoxifen treatment failure. PI3K pathway activation, including by insulin-like growth factor receptor 1 (IGF1R), has been implicated in some resistance models. The primary aim was to determine whether evidence exists in clinical breast cancer for a role of IGF1R and/or the PI3K pathway, in acquisition of resistance to tamoxifen. Invasive primary and recurrent tamoxifen-resistant tumours from the same patient (n=77) were assessed for changes in ER, progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), IGF1R, stathmin, PTEN expression and PIK3CA mutations where possible. ER and PgR levels were significantly reduced at recurrence with 22 and 45%, respectively, showing negative status at this time. Acquisition of HER2 overexpression occurred in 6% of cases. IGF1R expression was significantly reduced in both ER+ and ER- recurrences and stathmin levels increased. A positive association between stathmin and IGF1R emerged in recurrent samples, despite their opposing relationships with ER, suggesting some coalescence of their activities may be acquired. The data confirm loss of ER and PgR and gain of HER2 in some tamoxifen-resistant tumours. There is no evidence for IGF1R gain in tamoxifen resistance; increases in stathmin levels suggest that activation of the PI3K pathway may have contributed, but PTEN loss and PIK3CA hotspot mutations were relatively rare.