BackgroundThe STAT3 transcription factor is a major intracellular signaling protein and is frequently dysregulated in the most common and lethal brain malignancy in adults, glioblastoma multiforme (GBM). Activation of STAT3 in GBM correlates with malignancy and poor prognosis. The phosphorylating signal transducer JAK2 activates STAT3 in response to cytokines and growth factors. Currently there are no JAK-STAT pathway inhibitors in clinical trials for GBM, so we sought to examine the anti-GBM activity of SAR317461 (Sanofi-Aventis), a newer generation, highly potent JAK2 inhibitor that exhibits low toxicity and good pharmacokinetics. SAR317461 was initially approved for patient testing in the treatment of primary myelofibrosis (PMF), and has shown activity in preclinical models of melanoma and pulmonary cancer, but has not been tested in GBM.MethodsWe hypothesized that a potent small molecule JAK2 inhibitor could overcome the heterogeneous nature of GBM, and suppress a range of patient derived GBM tumorsphere lines and immortalized GBM cell lines. We treated with SAR317461 to determine IC50 values, and using Western blot analysis we asked whether the response was linked to STAT3 expression. Western blot analysis, FACS, and cell viability studies were used to identify the mechanism of SAR317461 induced cell death.ResultsWe report for the first time that the JAK2 inhibitor SAR317461 clearly inhibited STAT3 phosphorylation and had substantial activity against cells (IC50 1–10 µM) from 6 of 7 different patient GSC derived GBM tumorsphere lines and three immortalized GBM lines. One patient GSC derived line did not constitutively express STAT3 and was more resistant to SAR317461 (IC50 ≈25 µM). In terms of mechanism we found cleaved PARP and clear apoptosis following SAR317461. SAR317461 also induced autophagy and the addition of an autophagy inhibitor markedly enhanced cell killing by SAR317461.ConclusionsWe conclude that SAR317461 potently inhibits STAT3 phosphorylation and that it has significant activity against those GBM cells which express activated STAT3. Further studies are warranted in terms of the potential of SAR317461 as single and combined therapy for selectively treating human patients afflicted with GBMs expressing activation of the JAK2-STAT3 signaling axis.
Background/AimsThe application of glycated hemoglobin (HbA1c) for the diagnosis of diabetes is currently under extensive discussion. In this study, we explored the validity of using HbA1c as a screening and diagnostic test in Chinese subjects recruited in Nanjing, China.MethodsIn total, 497 subjects (361 men and 136 women) with fasting plasma glucose (PG) ≥ 5.6 mmol/L were recruited to undergo the oral glucose tolerance test (OGTT) and HbA1c test. Plasma lipid, uric acid, and blood pressure were also measured.ResultsUsing a receiver operating characteristic curve, the optimal cutoff point of HbA1c related to diabetes diagnosed by the OGTT was 6.3%, with a sensitivity and specificity of 79.6% and 82.2%, respectively, and the area under the curve was 0.87 (95% confidence interval, 0.83 to 0.92). A HbA1c level of 6.5% had a sensitivity and specificity of 62.7% and 93.5%, respectively. When comparing the HbA1c ≥ 6.5% or OGTT methods for diagnosing diabetes, the former group had significantly higher HbA1c levels and lower levels of fasting and 2-hour PG than the latter group. No significant difference was observed in the other metabolism indexes between the two groups.ConclusionsOur results suggest that HbA1c ≥ 6.5% has reasonably good specificity for diagnosing diabetes in Chinese subjects, which is in concordance with the American Diabetes Association recommendations.
BackgroundTo determine the frequency of chronic kidney disease (CKD) and its associated risk factors in Chinese type 2 diabetic patients, we conducted a cross-sectional study in Nanjing, China, in the period between January 2008 and December 2009.MethodsPatients with type 2 diabetes under the care by Jiangsu Province Official Hospital, Nanjing, China were invited for assessment. CKD was defined as the presence of albuminuria or estimated glomerular filtration rate <60 mL/min/1.73 m2. Albuminuria was defined as urinary albumin-to-creatinine ratio ≥30 mg/g.ResultsWe recruited 1,521 urban Chinese patients with type 2 diabetes (mean age, 63.9±12.0 years). The frequency of CKD and albuminuria was 31.0% and 28.9%, respectively. After adjusted by age and sex, hypertension, anemia and duration of diabetes were significantly associated with CKD with odds ratio (95% confidence interval) being 1.93 (1.28 to 2.93), 1.70 (1.09 to 2.64), and 1.03 (1.00 to 1.06), respectively.ConclusionIn conclusion, CKD was common in the urban Nanjing Chinese with type 2 diabetes. Strategies to prevent or delay progression of kidney disease in diabetes should be carried out at the early disease course of type 2 diabetes.
This study aimed to evaluate the glycemic levels in Chinese patients with type 2 diabetes mellitus (T2DM) and to explore the factors related to the results of glycemic control. A total of 2454 T2DM patients from 11 communities were examined for glycosylated hemoglobin levels and glycemic control options. Potential factors related to the results of glycemic control were analyzed using logistic regression. Of all the patients, 55.3 % achieved the glycemic control target of HbA1c < 7 %. Multivariate analysis showed that male sex (OR 1.345, 95 % CI 1.022-1.769; P = 0.034), higher levels of fasting blood glucose (OR 1.954, 95 % CI 1.778-2.147; P < 0.001), and low-density lipoprotein cholesterol (OR 1.181, 95 % CI 1.020-1.367; P = 0.026) were significantly associated with poor glycemic control. The complexity of antidiabetics was also associated with poor glycemic control (P < 0.05). Compared to diet and exercise, insulin injection was most strongly associated with poor glycemic control (OR 6.210, 95 % CI 4.054-9.514; P < 0.001). Male patients with higher levels of total cholesterol, lower levels of high-density lipoprotein cholesterol, or longer diabetic durations showed poor glycemic control, which was not found in female patients. Glycemic control was not satisfactory in T2DM patients of Nanjing communities. Various factors are associated with poor results of glycemic control.
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