Serum Phosphate and 1-Year Outcome in Patients With Acute Ischemic Stroke and Transient Ischemic Attack.

Objective: To determine the association between serum phosphate level and 1-year clinical outcomes in patients with acute ischemic stroke and transient ischemic attack. Methods: We included 7,353 patients with acute ischemic stroke and transient ischemic attack from the China National Stroke Registry III for analysis. Participants were divided into 4 groups according to serum phosphate quartiles. Composite end point included recurrent stroke, myocardial infarction, other ischemic vascular events, and all-cause mortality. Poor functional outcome is defined as modified Rankin Scale score of 3 to 6. Multivariable Cox regression or logistic regression was used to evaluate the independent association of serum phosphate with 1-year all-cause mortality, recurrent stroke, composite end point and poor functional outcome. Results: The mean age of the included 7,353 patients was 62.5 years, and 68.6% of them were men. Plotting hazard ratios over phosphate levels suggested a U-shaped association especially for recurrent stroke and composite end point, and therefore the third quartile group was set as reference group. Compared with the third quartile of phosphate (1.06-1.20 mmol/L), the adjusted hazard ratios/odds ratios (95% CI) of the lowest quartile (<0.94 mmol/L) were 0.98 (0.67-1.42) for all-cause mortality, 1.31 (1.05-1.64) for stroke recurrence, 1.26 (1.02-1.57) for composite end point, and 1.27 (1.01-1.61) for poor functional outcome, and the adjusted odds ratio of the highest quartile (≥1.2 mmol/L) was 1.40 (1.11-1.77) for poor functional outcome. Conclusions: Serum phosphate may be an independent predictor of stroke recurrence, composite end point and poor functional outcome after ischemic stroke.

Discovery of 4,6-Disubstituted Pyrimidine Derivatives as Novel Dual VEGFR2/FGFR1 Inhibitors.

Abnormalities in the FGFRs signaling pathway and VEGFR2 amplification often occur in a variety of tumors, and they synergistically promote tumor angiogenesis. Studies have shown that the up-regulation of FGF-2 is closely related to the resistance of VEGFR2 inhibitors. Activation of the FGFRs signal is a signal of compensatory angiogenesis after VEGFR2 resistance. Dual VEGFR2/FGFR1 inhibitors contribute to overcoming the resistance of VEGFR2 inhibitors and inhibit tumor growth significantly. Based on this, we designed and synthesized a series of 4,6-disubstituted pyrimidine derivatives as dual VEGFR2/FGFR1 inhibitors by the molecular hybridization strategy. 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)amino]pyrimidin-4-yl}-1-methylurea (8b) had the best inhibitory activities against VEGFR2 and FGFR1 at 10 µM (82.2 % and 101.0 %, respectively), it showed moderate antiproliferative activities against A549 and KG-1 cell lines as well. Besides, molecular docking was also carried out to study the binding mode of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)-amino]-pyrimidin-4-yl}-1-methylurea (8b) with VEGFR2 and FGFR1. These studies reveal that this series of compounds deserve further optimization.

Serum calcium and long-term outcome after ischemic stroke: Results from the China National stroke registry III.

BACKGROUND AND AIMS: Serum calcium abnormality is associated with adverse cardiovascular outcomes, but the effects of serum calcium level on stroke outcomes remain unknown. We aimed to assess the relationship between serum calcium level and 1-year outcomes in patients with acute ischemic stroke and transient ischemic attack. METHODS: We included 9375 stroke patients from the China National Stroke Registry III for analysis. Participants were divided into 4 groups according to albumin corrected-calcium quartiles. Composite end point comprised recurrent stroke, myocardial infarction, other ischemic vascular events, and all-cause mortality. Multivariable Cox or logistic regression was used to evaluate the independent association of albumin corrected-calcium with all-cause mortality, recurrent stroke, composite end point, and poor functional outcome (modified Rankin Scale score ≥3). RESULTS: Compared with the lowest calcium quartile (<2.16 mmol/L), the adjusted hazard ratio (95% CI) of the top quartile (≥2.31 mmol/L) was 1.56 (1.11-2.18) for all-cause mortality, 1.06 (0.87-1.28) for recurrent stroke and 1.08 (0.90-1.01) for composite end point, and the adjusted odds ratio for poor functional outcome was 1.18 (0.96-1.44). The addition of serum calcium to conventional risk factors improved risk prediction of all-cause mortality, leading to a small but significant increase in C-statistics and reclassification with non-significant integrated discrimination improvement (C-statistics, p = 0.02; net reclassification index 11.8%, p = 0.038; integrated discrimination improvement 0.08%, p = 0.42). CONCLUSIONS: High serum calcium levels at baseline were associated with all-cause mortality at 1-year after ischemic stroke, suggesting that serum calcium may be a potential prognostic biomarker and therapeutic target for ischemic stroke.

Design and Synthesis of Novel Thiazolo[5,4-d]pyrimidine Derivatives as Potential Angiogenesis Inhibitors.

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays an important role in both vasculogenesis and angiogenesis. Inhibition of VEGFR-2 has been demonstrated as a key method against tumor-associated angiogenesis. Thiazolopyrimidine is an important analog of the purine ring, and we choose the thiazolopyrimidine scaffold as the mother nucleus. Two series of thiazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activity. In HUVEC inhibition assay, compounds 3l (=1-(5-{[2-(4-chlorophenyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}pyridin-2-yl)-3-(3,4-dimethylphenyl)urea) and 3m (=1-(5-{[2-(4-chlorophenyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}pyridin-2-yl)-3-(4-methoxyphenyl)urea) exhibited the most potent inhibitory effect (IC50 =1.65 and 3.52 µm, respectively). Compound 3l also showed the best potency against VEGFR-2 at 50 µm (98.5 %). These results suggest that further investigation of compound 3l might provide potential angiogenesis inhibitors.

Phenyl and Diaryl Ureas with Thiazolo[5,4-d]pyrimidine Scaffold as Angiogenesis Inhibitors: Design, Synthesis and Biological Evaluation.

Angiogenesis is crucial for tumor growth and inhibition of angiogenesis has been regarded as a promising approach for cancer therapy. Vascular endothelial growth factor receptor-2 (VEGFR-2) is an important factor in angiogenesis. In this work, a novel series of thiazolo[5,4-d]pyrimidine derivatives inhibiting angiogenesis were rationally designed and synthesized. Their inhibitory activities against human umbilical vein endothelial cells (HUVEC) were investigated in vitro. 1-(4-Fluorophenyl)-3-{4-[(5-methyl-2-phenyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl)amino]phenyl}urea (19b) and 1-(3-Fluorophenyl)-3-{4-[(5-methyl-2-phenyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl)amino]phenyl}urea (19g) exhibited the most potent inhibitory effect on HUVEC proliferation (IC50 =12.8 and 5.3 µm, respectively). Compound 19g could inhibit the migration of human umbilical vein endothelial cells. These results support the further investigation of these compounds as potent anticancer agents.

Recent developments and advances of FGFR as a potential target in cancer.

FGFs and their receptors (FGFRs) are critical for many biologic processes, including angiogenesis, wound healing and tissue regeneration. Aberrations in FGFR signaling are common in cancer, making FGFRs a promising target in antitumor studies. To date, many FGFR inhibitors are being detected in clinical studies, and resistance to some inhibitors has emerged. Understanding the mechanisms of resistance is a fundamental step for further implementation of targeted therapies. In this review, we will describe the basic knowledge regarding FGF/FGFR signaling and categorize the clinical FGFR inhibitors. The mechanisms of resistance to FGFR inhibitors and corresponding strategies of overcoming drug resistance will also be discussed.

[Expression of mast cell tryptase in scar].

OBJECTIVE: To investigate the expression and distribution of mast cell tryptase (MCT) in scar, and to discuss the different MCT gene expression in keloid, hypertrophic scar and normal skin. METHODS: 20 samples of keloid, 20 samples of hypertrophic scar and 20 samples of normal skin were collected. The distribution of MCT was investigated by immunofluorescence histochemistry, and the MCT mRNA expression was detected by Relative Quantification real-time fluorescent PCR. RESULTS: MCT gene was mainly located in the collagen fiber bundles of the scar, especially in the superficial layer of scar. MCT mRNA expression was significantly higher in keloid than that in hypertrophic scar and normal skin (P < 0.01). Averagely, the MCT gene expression in keloid was 2.5 times and 5.4 times of that in hypertrophic scar and normal skin. CONCLUSIONS: MCT gene may play a role in the pathogenesis of scar.

[Expression of tumor necrosis factor related apoptosis inducing ligand and its receptor in thymus during early post-burn stage in rat with severe burns].

OBJECTIVE: To investigate the effect of tumor necrosis factor related apoptosis inducing ligand (TRAIL) and its receptor on apoptosis in thymus during early post-burn stage in rat with severe burns. METHODS: Fifty Wistar rats were randomly divided into sham scald group (SS, n = 10) and burn group (n = 40). The apoptosis in thymus in rats was detected with annexin V/FITC-PI double staining at 4, 12, 24, 48 post-burn hours (PBH). The expression of TRAIL death receptor DR5, DR4 and its decoy receptor DcR1, DcR2 in thymus were detected by RT-PCR and Western blot at above time-points. RESULTS: Compared with that in SS group (6.7 +/- 0.8)%, the apoptosis in the thymus in burn group started to increase at 4 PBH [(17.1 +/- 0.4)%], peaked at 12 PBH [(25.2 +/- 1.1)%], and it was still evidently higher than that in SS group at 48 PBH (P < 0.05). There was no obvious difference in the apoptosis rate in rats in burn group among all the time-points. The expression of DR5 in burn group at each time-points was significantly higher than those in SS group, while that of DcR2 shown an opposite tendency (P < 0.05). The expression of DR4, DcR1 was similar in both groups. CONCLUSION: The marked increase in apoptosis rate in rat thymus at early post-burn stage, and the significant change in the expression of DR5 and DcR2 show that TRAIL pathway may participate in apoptosis.

[Expression and significance of TRAIL receptors in fibroblasts of hypertrophic scar].

OBJECTIVE: To detect the expression of TRAIL receptors in fibroblasts of hypertrophic scar in the proliferative stage and explore its significance. METHODS: 30 samples of hypertrophic scar were taken from 30 burn cases in the proliferative stage. 30 samples of normal skin were taken as the control. The expressions of TRAIL receptors in the fibroblasts of hypertrophic burn scar and the normal skin were assayed by semiquantitative RT-PCR and flowcytometry. RESULTS: The expression level of DR5 in the fibroblasts of hypertrophic burn scar is much lower than the control (P < 0.05); the expression level of DcR1 in the fibroblasts of hypertrophic burn scar is much higher than the control (P < 0.05). CONCLUSIONS: The down-regulated DR5 expression and elevated DcR1 expressions in the fibroblasts of hypertrophic burn scar may attribute to the apoptosis change induced by TRAIL and explain the apoptosis differences between the fibroblasts of hypertrophic scar and normal skin to a certain extent.