血清HE4水平对预测卵巢癌铂类化疗效果的临床观察

目的:探讨卵巢上皮癌患者血清中人附睾蛋白4(HE4)的水平与患者铂类化疗效果的关系。方法:回顾分析52例卵巢上皮癌患者的临床资料和随访信息,采用电化学发光法检测患者治疗前和随访时血清HE4及CA125水平,分析血清HE4及CA125水平与铂类化疗效果的关系。结果:52例患者中,31例铂类化疗敏感,21例铂类化疗抵抗。铂类化疗抵抗组患者治疗前血清HE4及CA125水平明显高于铂类化疗敏感组。治疗前血清HE4水平对卵巢癌铂类化疗疗效的预测效能高于CA125。铂类化疗抵抗组患者随访时血清HE4水平明显高于铂类化疗敏感组(276.5pmo/L vs 56.38pmo/L,P0.001)。随访时血清HE4可预测铂类化疗效果,当界值点为127.40pmo/L时,灵敏度达81%,特异度达93.5%,阳性预测值(PPV)为89.5%,阴性预测值(NPV)为87.9%,曲线下面积(AUC)为0.919。随访时血清CA125取界值点为76.4U/L时预测铂类化疗效果的灵敏度为95.2%,特异度为90.3%,PPV为85%,NPV为87.5%,AUC为0.876。随访时血清HE4预测铂类化疗效果的AUC也大于CA125。Logistic多因素回归分析结果显示,随访时血清HE4水平与发生铂类化疗抵抗密切相关(P=0.027)。结论:随访时血清HE4水平可以预测卵巢癌铂类化疗的反应。     

Urinary excretion of platinum (Pt) following skin and respiratory exposure to soluble Pt at South African precious metals refineries

Adverse respiratory and skin health effects have been associated with occupational exposure to soluble platinum (Pt). However, the relationship between skin exposure and urinary Pt excretion has not yet been investigated. In this study we examined the relationship between skin and respiratory exposure to soluble Pt and urinary Pt excretion at two South African precious metals refineries.The skin and respiratory exposure to soluble Pt as well as the urinary Pt excretion of forty precious metals refinery workers was assessed simultaneously using Ghostwipes?, Methods for the Determination of Hazardous Substances method 46/2 and spot urine tests, respectively.The geometric mean for skin exposure to soluble Pt on four anatomical positions (palm, wrist, neck and forehead) was 0.008?μg/cm² [95% confidence interval (CI): 0.005-0.013?μg/cm²], while the geometric mean for respiratory exposure was 0.301?μg/m³ (95%CI: 0.151-0.601?μg/m³) and the geometric mean for urinary Pt excretion was 0.212?μg/g creatinine (95%CI: 0.169-0.265?μg/g creatinine). Partial correlations identified significant positive correlations between skin exposure, respiratory exposure and urinary Pt excretion (r?=?0.580 to 0.754).Skin and respiratory exposures to soluble Pt were both positively correlated with urinary Pt excretion, and both exposure routes should be considered when investigating occupational exposure to soluble Pt.     

A newly synthesized platinum-based compound (PBC-II) increases chemosensitivity of HeLa ovarian cancer cells via inhibition of autophagy

There are many mechanisms of resistance, chemoresistance of HeLa cells to anti-cancer agents seems to be autophagy-mediated. While using very effective anti-cancers such as Doxorubicin and cisplatin, cells overcome the cytotoxicity of these drugs through promotion of what so-called cytoprotective autophagy. Here in this study, we sought to introduce a novel platinum-based compound PBC-II that possesses anti-cancer activity. Our data showed that PBC-II is able to induce apoptosis at relatively low concentrations, with no detectable reactive oxygen species (ROS). However, further experiments demonstrated that exposure of HeLa cells to PBC-II did not promote autophagy; rather, it resulted in accumulation of p62 and decrease in LC3-II levels. Autophagy was then promoted in HeLa cells pharmacologically by Doxorubicin and genetically by siRNA IL-10. In order to confirm promotion of autophagy in our model, we performed acridine orange staining to assess for autophagy under microscope as well as via flow cytometry. We then measured protein level of autophagy markers p62 and LC3 by western blot. Our data indicated that PBC-II interferes with therapy-induced autophagy. We also determined PI3K activity while co-incubation of PBC-II with autophagy inducers. It was clear that PI3K activation decreased when PBC-II was co-administered with autophagy inducers. Collectively, PBC-II exerts unique anti-proliferative effects associated with inhibition of autophagy, which indicates that PBC-II is potentially a promising agent to be used in resistant ovarian tumors.     

Gelatin-encapsulated iron oxide nanoparticles for platinum (IV) prodrug delivery,enzyme-stimulated release and MRI

A facile method for transferring hydrophobic iron oxide nanoparticles (IONPs) from chloroform to aqueous solution via encapsulation of FITC-modified gelatin based on the hydrophobic–hydrophobic interaction is described in this report. Due to the existence of large amount of active groups such as amine groups in gelatin, the fluorescent labeling molecules of fluorescein isothiocyanate (FITC) and platinum (IV) prodrug functionalized with carboxylic groups can be conveniently conjugated on the IONPs. The nanoparticles carrying Pt(IV) prodrug exhibit good anticancer activities when the Pt(IV) complexes are reduced to Pt(II) in the intracellular environment, while the pure Pt(IV) prodrug only presents lower cytotoxicity on cancer cells. Meanwhile, fluorescence of FITC on the surface of nanoparticles was completely quenched due to the possible Förster Resonance Energy Transfer (FRET) mechanism and showed a fluorescence recovery after gelatin release and detachment from IONPs. Therefore FITC as a fluorescence probe can be used for identification, tracking and monitoring the drug release. In addition, adding pancreatic enzyme can effectively promote the gelatin release from IONPs owing to the degradation of gelatin. Noticeable darkening in magnetic resonance image (MRI) was observed at the tumor site after in situ injection of nanoparticles, indicating the IONPs-enhanced T₂-weighted imaging. Our results suggest that the gelatin encapsulated Fe₃O₄ nanoparticles have potential applications in multi-functional drug delivery system for disease therapy, MR imaging and fluorescence sensor.     

High-Dose Etoposide Plus Granulocyte Colony-Stimulating Factor as an Effective Chemomobilization Regimen for Autologous Stem Cell Transplantation in Patients with Non-Hodgkin Lymphoma Previously Treated with CHOP-based Chemotherapy: A Study from the Consortium for Improving Survival of Lymphoma

We conducted a multicenter retrospective study to compare the efficacy and toxicity of various chemomobilization regimens: high-dose (HD) cyclophosphamide, HD etoposide (VP-16), and platinum-based chemotherapies. We reviewed the experiences of 10 institutions with 103 non-Hodgkin lymphoma patients who had previously only been treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy. The mobilization yields for each regimen were analyzed. HD VP-16 mobilized a significantly higher median number of CD34⁺ cells (16.22 × 10⁶ cells/kg) than HD cyclophosphamide (4.44 × 10⁶ cells/kg) or platinum-based chemotherapies (6.08 × 10⁶ cells/kg, P < .001). The rate of successful mobilization (CD34⁺ cell count ≥5.0 × 10⁶ cells/kg) was also significantly higher for HD VP-16 (86%) than for HD cyclophosphamide (45%) or platinum-based chemotherapies (61%, P = .004). The successful mobilization rate on day 1 of 72% for HD VP-16 was significantly higher than the rates for HD cyclophosphamide (13%) and platinum-based chemotherapies (26%, P < .001). In multivariate analysis, HD VP-16 was a significant predictor of successful mobilization (P = .014; odds ratio, 5.25; 95% confidence interval, 1.40 to 19.63). Neutropenic fever occurred in 67% of patients treated with HD VP-16. The incidence was similar for HD cyclophosphamide (58%, P = .454) but was significantly lower for platinum-based chemotherapies (12%, P < .001). However, fatal (grade ≥ 4) infection and treatment-related mortality were not observed in this study. In conclusion, the mobilization yield was significantly influenced by the chemomobilization regimen, and HD VP-16 was a highly effective mobilization regimen in patients with non-Hodgkin lymphoma.     

Characterization and bacterial anti-adherent effect on modified PMMA denture acrylic resin containing platinum nanoparticles

PURPOSE

This study characterized the synthesis of a modified PMMA (Polymethyl methacrylate) denture acrylic loading platinum nanoparticles (PtN) and assessed its bacterial inhibitory efficacy to produce novel antimicrobial denture base material.

MATERIALS AND METHODS

Polymerized PMMA denture acrylic disc (20 mm × 2 mm) specimens containing 0 (control), 10, 50, 100 and 200 mg/L of PtN were fabricated respectively. The obtained platinum-PMMA nanocomposite (PtNC) was characterized by TEM (transmission electron microscopy), SEM/EDX (scanning electron microscope/energy dispersive X-ray spectroscopy), thermogravimetric and atomic absorption spectrophotometer analysis. In antimicrobial assay, specimens were placed on the cell culture plate, and 100 µL of microbial suspensions of S. mutans (Streptococcus mutans) and S. sobrinus (Streptococcus sobrinus) were inoculated then incubated at 37℃ for 24 hours. The bacterial attachment was tested by FACS (fluorescence-activated cell sorting) analysis after staining with fluorescent probe.

RESULTS

PtN were successfully loaded and uniformly immobilized into PMMA denture acrylic with a proper thermal stability and similar surface morphology as compared to control. PtNC expressed significant bacterial anti-adherent effect rather than bactericidal effect above 50 mg/L PtN loaded when compared to pristine PMMA (P=.01) with no or extremely small amounts of Pt ion eluted.

CONCLUSION

This is the first report on the synthesis and its antibacterial activity of Pt-PMMA nanocomposite. PMMA denture acrylic loading PtN could be a possible intrinsic antimicrobial denture material with proper mechanical characteristics, meeting those specified for denture bases. For clinical application, future studies including biocompatibility, color stability and warranting the long-term effect were still required.     

Electrodeposition of Pt nanoparticles on undoped nanodiamond powder for methanol oxidation electrocatalysts

Undoped nanodiamond (ND) powder with average particle sizes of 5 and 100 nm were modified with platinum (Pt) nanoparticles by electrodeposition from 1.1 mM chloroplatinic acid solution. The structure and morphology of the composites were characterized by field emission-scanning electron microscopy and X-ray diffraction. The results showed that Pt nanoparticles were well-dispersed on the facet surfaces of ND particles. The electrooxidation of methanol on Pt-modified ND powders was investigated by cyclic voltammetry, which indicated its good electrocatalytic activity. Compared with 100 nm ND powder, the 5 nm ND powder modified with Pt nanoparticles exhibited better electrocatalytic activity.     

Thermal enhancement of melphalan and oxaliplatin cytotoxicity in vitro

It has been established that hyperthermia can enhance cytotoxicity of some chemotherapeutic agents. This has led to various clinical trials of thermochemotherapy, although many questions remain unanswered. The effects of various agents have been studied on animal tumours with different histopathology at elevated temperatures. These studies indicated that alkylating agents were most effective to all tumours at a moderately elevated temperature. Cisplatin was also effective to all tumours, but its effectiveness at 41.5°C was less than that of alkylating agents. To quantitatively study these findings, the magnitude of thermal enhancement of melphalan, an alkylating agent, and that of oxaliplatin, a new platinum compound, were studied at 37-44.5°C by the colony formation assay. The dose of each agent was kept constant, and cell survival was determined as a function of treatment time. The cell survival curve was exponentially related with treatment time at all test temperatures, and the T 0 (the time to reduce survival from 1 to 0.37) decreased with an increasing temperature. These results suggested that the cytotoxic effect of these agents occurred with a constant rate at 37°C, and the rate was facilitated with an increasing temperature. This suggests that heat can accelerate the cytotoxic chemical reaction, leading to substantial thermal enhancement. The thermal enhancement ratio (TER, the ratio of the T 0 at 37°C to the T 0 at an elevated temperature) increased with an increase in the temperature. The activation energy for melphalan at moderately elevated temperatures was largest among the agents tested in the laboratory and that for oxaliplatin was approximately half of the melphalan activation energy. This suggests that the thermal enhancement for the cytotoxicity of melphalan or alkylating agents might be the greatest. Potential mechanisms of thermal enhancement of cytotoxicity were discussed.     

Combined oral cyclophosphamide and bevacizumab in heavily pre-treated ovarian cancer

Introduction Metronomic chemotherapy combined with bevacizumab has proved to be effective in various tumour types. The aim of this study is to review our experience in recurrent ovarian carcinomas treated with low-dose cyclophosphamide and bevacizumab. Materials and methods Retrospective analysis of pre-treated ovarian cancer patients, i.e., >/=2 previous chemotherapy regimens who received treatment with oral cyclophosphamide 50 mg/day and bevacizumab 10 mg/kg IV every two weeks. Patients with a performance status 0-2 were included. The endpoints were response rates, progressionfree disease and safety profile. Results Nine patients with advanced, measurable ovarian cancer were included. Of these, 8 were platinum-resistant and had received prior regimens with gemcitabine (88%), topotecan (77%) and liposomal doxorubicin (66%). There was a mean of 5 previous lines of chemotherapy, range 2-7. Applying RECIST criteria, the efficacy data were as follows: objective response (OR) 44%; 4/9 (CR 2/9 and PR 2/9), SD 2/9 and DP 3/9. At 6 months, 33% of patients were progression free. Response lasted for 12.5 months in three patients treated for 12 months; a further two patients who were re-treated achieved complete response. Mean time to progression was 5.5 months (95% CI 4.5-5.5). No severe adverse effects were reported. Only one patient had to delay several cycles due to G3 haematuria. Other toxicities observed include G3 abdominal pain (1 case); G2 mucositis and G2 dyspnoea in one patient. Conclusions Combined bevacizumab and metronomic oral cyclophosphamide is a safe and effective regimen for heavily pre-treated ovarian cancer patients. Further research is needed on predictive factors to screen for those patients who will benefit from anti-angiogenic therapy.