培美曲塞+顺铂方案诱导化疗联合同期放化疗对局部晚期非小细胞肺癌的近期疗效及安全性观察

目的:探究培美曲塞+顺铂方案诱导化疗联合同期放化疗对局部晚期非小细胞肺癌的近期疗效及安全性。方法:收集我院肿瘤科2009年7月到2011年7月住院治疗的局部晚期非鳞癌非小细胞癌患者54例,按照随机数字表法分为研究组和对照组,每组27例,研究组给予培美曲塞+顺铂方案诱导化疗联合同期放化疗,对照组仅给予培美曲塞+顺铂方案化疗联合同期放疗,治疗2个周期,随访2年,对比两组患者的近期疗效及安全性。结果:研究组的近期有效率和控制率分别为55.56%、77.78%,高于对照组的50.33%和59.26%,有效率和控制率差异具有统计学意义(P0.05)。随访2年,研究组的中位生存期为12.77个月,1年生存率为48.15%,高于对照组中位生存期11.28个月,1年生存率40.74%,但差异无统计学意义(P0.05),研究组2年生存率为43.46%,高于对照组的25.38%,差异具有统计学意义(P0.05);研究组白细胞减少以及脱发发生率分别为37.0%、25.9%,低于对照组的81.5%和55.5%,差异具有统计学意义(均P0.05);研究组中血小板减少、血红蛋白减少、呕吐、肝功能损害、肾功能损耗、皮疹等发生率分别为40.7%、22.2%、59.2%、11.1%、7.4%、14.8%,高于对照组中各不良反应发生率分别为33.3%、18.5%、55.5%、14.8%、11.1%、7.4%,但两组间差异无统计学意义(P0.05)。结论:培美曲塞+顺铂方案诱导化疗联合同期放化疗对局部晚期非小细胞肺癌治疗效果明显,且不良反应少,可作为临床上晚期非小细胞肺癌化疗一线药物。     

S100 to receptor for advanced glycation end-products binding assay: Looking for inhibitors

Secreted by tumor and stromal cells, S100 proteins exert their biological functions via the interaction with surface receptors. The most described receptor is the receptor for advanced glycation end-products (RAGE), thereby participating in the S100-dependent cell migration, invasion, tumor growth, angiogenesis and metastasis. Several approaches have been described for determining this interaction. Here we describe an easy, specific and highly reproducible ELISA-based method, by optimizing several parameters such as the binding and blocking buffer, interaction time and concentrations, directed to screen chemical and biological inhibitors of this interaction for S100A4, S100A7 and S100P proteins. The efficiency of the protocol was validated by using well described neutralizing agents of the RAGE receptor and of the S100A4 activity. The methodology described here will allow future works with other members of the S100 protein family and their receptors.     

Ascorbic acid prevents high glucose-induced apoptosis in human brain pericytes

High glucose concentrations due to diabetes increase apoptosis of vascular pericytes, impairing vascular regulation and weakening vessels, especially in brain and retina. We sought to determine whether vitamin C, or ascorbic acid, could prevent such high glucose-induced increases in pericyte apoptosis. Culture of human microvascular brain pericytes at 25 mM compared to 5 mM glucose increased apoptosis measured as the appearance of cleaved caspase 3. Loading the cells with ascorbate during culture decreased apoptosis, both at 5 and 25 mM glucose. High glucose-induced apoptosis was due largely to activation of the receptor for advanced glycation end products (RAGE), since it was prevented by specific RAGE inhibition. Culture of pericytes for 24 h with RAGE agonists also increased apoptosis, which was completely prevented by inclusion of 100 μM ascorbate. Ascorbate also prevented RAGE agonist-induced apoptosis measured as annexin V binding in human retinal pericytes, a cell type with relevance to diabetic retinopathy. RAGE agonists decreased intracellular ascorbate and GSH in brain pericytes. Despite this evidence of increased oxidative stress, ascorbate prevention of RAGE-induced apoptosis was not mimicked by several antioxidants. These results show that ascorbate prevents pericyte apoptosis due RAGE activation. Although RAGE activation decreases intracellular ascorbate and GSH, the prevention of apoptosis by ascorbate may involve effects beyond its function as an antioxidant.     

Premature aging in uremia

Guanidinosuccinic acid is an aberrant metabolite isolated 40 years ago in the blood and urine of uremic subjects and a suspect in the toxicity associated with renal failure. It plays a minor role in the bleeding diathesis of uremia, contributes to the methyl group deficiency of dialysis patients, and is a factor in the premature atherosclerosis of end stage renal disease through the induction of hyperhomocysteinemia. As a major player, however, in the diversity and severity of uremic symptoms, it is a disappointment. Recently its source has been identified. It results from the superoxidation of argininosuccinic acid, which leads, also, to the production of gamma glutamic semialdehyde, an advanced glycation end product (AGE), which normally results from from the Maillard reaction, the non-enzymatic browning of protein. AGEs stimulate cross-linkages in protein that lead ultimately to loss of function, phagocytosis, and removal, and are important elements in the premature aging characteristic of renal disease, and diabetes.     

Plasma protein advanced glycation end products, carboxymethyl cysteine, and carboxyethyl cysteine, are elevated and related to nephropathy in patients with diabetes

In Diabetes Mellitus (DM), glucose and the aldehydes glyoxal and methylglyoxal modify free amino groups of lysine and arginine of proteins forming advanced glycation end products (AGEs). Elevated levels of these AGEs are implicated in diabetic complications including nephropathy. Our objective was to measure carboxymethyl cysteine (CMC) and carboxyethyl cysteine (CEC), AGEs formed by modification of free cysteine sulfhydryl groups of proteins by these aldehydes, in plasma proteins of patients with diabetes, and investigate their association with the albumin creatinine ratio (ACR, urine albumin (mg)/creatinine (mmol)), an indicator of nephropathy. Blood was collected from forty-two patients with type 1 and 2 diabetes (18–36 years) and eighteen individuals without diabetes (17–35 years). A liquid chromatography-mass spectrophotometric method was developed to measure plasma protein CMC and CEC levels. Values for ACR and hemoglobin A1C (HbA1C) were obtained. Mean plasma CMC (μg/l) and CEC (μg/l) were significantly higher in DM (55.73 ± 29.43, 521.47 ± 239.13, respectively) compared to controls (24.25 ± 10.26, 262.85 ± 132.02, respectively). In patients with diabetes CMC and CEC were positively correlated with ACR, as was HbA1C. Further, CMC or CEC in combination with HbA1C were better predictors of nephropathy than any one of these variables alone. These results suggest that glucose, glyoxal, and methylglyoxal may all be involved in the etiology of diabetic nephropathy.     

The denatured state of HIV-1 protease under native conditions

The denatured state of several proteins has been shown to display transient structures that are relevant for folding, stability, and aggregation. To detect them by nuclear magnetic resonance (NMR) spectroscopy, the denatured state must be stabilized by chemical agents or changes in temperature. This makes the environment different from that experienced in biologically relevant processes. Using high-resolution heteronuclear NMR spectroscopy, we have characterized several denatured states of a monomeric variant of HIV-1 protease, which is natively structured in water, induced by different concentrations of urea, guanidinium chloride, and acetic acid. We have extrapolated the chemical shifts and the relaxation parameters to the denaturant-free denatured state at native conditions, showing that they converge to the same values. Subsequently, we characterized the conformational properties of this biologically relevant denatured state under native conditions by advanced molecular dynamics simulations and validated the results by comparison to experimental data. We show that the denatured state of HIV-1 protease under native conditions displays rich patterns of transient native and non-native structures, which could be of relevance to its guidance through a complex folding process.     

Aberrant Expression of Osteopontin and E-Cadherin Indicates Radiation Resistance and Poor Prognosis for Patients with Cervical Carcinoma

Radiotherapy is the first-line treatment for all stages of cervical cancer, whether it is used for radical or palliative therapy. However, radioresistance of cervical cancer remains a major therapeutic problem. Consequently, we explored if E-cadherin (a marker of epithelial-mesenchymal transition) and osteopontin could predict radioresistance in patients with locally advanced cervical squamous cell carcinoma (LACSCC). Patients were retrospectively reviewed and 111 patients divided into two groups (radiation-resistant and radiation-sensitive groups) according to progression-free survival (PFS). In pretreated paraffin-embedded tissues, we evaluated E-cadherin and osteopontin expression using immunohistochemical staining. The percentage of patients with high osteopontin but low E-cadherin expression in the radiation-resistant group was significantly higher than those in the radiation-sensitive group (p<0.001). These patients also had a lower 5-year PFS rate (p<0.001). Our research suggests that high osteopontin but low E-cadherin expression can be considered as a negative, independent prognostic factor in patients with LACSCC ([Hazard ratios (95% CI) 6.766 (2.940, 15.572)], p<0.001).