Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells

Reversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged time to response observed in patients. We show that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically relevant nanomolar doses, without causing immediate cytotoxicity, produce an antitumor "memory" response, including inhibition of subpopulations of cancer stem-like cells. These effects are accompanied by sustained decreases in genomewide promoter DNA methylation, gene reexpression, and antitumor changes in key cellular regulatory pathways. Low-dose decitabine and azacitidine may have broad applicability for cancer management.     

响应面法优化超声提取益母草中多酚工艺及其抗氧化作用研究

目的：优选出益母草中多酚提取工艺,并对其进行抗氧化活性研究。方法：在单因素实验基础上,以没食子酸标准品为对照,以乙醇浓度、料液比、超声时间为自变量,以益母草多酚得率为响应值,运用响应面法优化超声辅助提取工艺参数;并通过DPPH、ABTS自由基法研究益母草多酚体外抗氧化作用。结果：益母草中多酚最优工艺为：乙醇浓度42%,料液比1:8(g/mL),超声时间15 min,此时得率为3.78%,与理论得率3.82%,相差0.04%,工艺稳定、可行,可用于益母草中多酚提取。抗氧化实验可知,益母草多酚和维生素C对DPPH、ABTS的清除率均随二者在测试浓度（4~14 mg/mL）范围内正相关;当浓度为14 mg/mL时,维生素C和益母草多酚对DPPH的平均清除率分别是89.34%和75.96%,差异不明显;对ABTS的平均清除率分别是79.52%和61.81%,差异在高浓度时较为显著。结论：益母草多酚具有一定的抗氧化作用。该研究为益母草资源广泛开发提供参考。     

Uncoupling of fatty acid and glucose metabolism in malignant lymphoma: a PET study.

Increased use of glucose through glycolysis is characteristic for neoplastic growth while the significance of serum-free fatty acids for regulation of energy metabolism in cancer is poorly understood. We studied whether serum-free fatty acids (FFA) interfere with glycolytic metabolism of lymphoproliferative neoplasms as assessed with 2-F18-fluoro-2-deoxy-D-glucose ([F18]FDG) and positron emission tomography (PET). Twelve patients with newly diagnosed non-Hodgkin's lymphoma (n = 9) or Hodgkin's disease (n = 3) participated in this study before start of oncologic treatment. Each patient underwent two [F18]FDG PET studies within 1 week after overnight fast: once during high fasting serum FFA concentrations and once after reduction of serum FFA by administration of acipimox. Acipimox is a nicotinic acid derivative that inhibits lipolysis in peripheral tissues and induces a striking reduction in circulating FFA concentration. In all cases, dynamic PET imaging over the tumour area was performed for 60 min after injection of [F18]FDG. Both graphical analysis (rMR(FDG)) and single scan approach (SUV) were used to compare tumour uptake of [F18]FDG under high fasting FFA concentrations and after pharmacologically decreased FFA concentrations. Serum FFA concentrations were reduced significantly from 0.92+/-0.42 mmol I(-1)at baseline to 0.26+/-0.31 mmol I(-1) after acipimox administration (P = 0.0003). Plasma glucose, serum insulin and lactate concentrations were similar during both approaches. The retention of glucose analogue [F18]FDG in tumour was similar between baseline and acipimox studies. Median rMR(FDG) of a total of 12 involved lymph nodes in 12 patients was 21.9 micromol 100 g(-1) min(-1) (range 8.7-82.5) at baseline and 20.1 micromol 100 g(-1) min(-1)(range 10.7-81.7) after acipimox. The respective values for median SUV were 7.8 (range 3.6-18.6) and 6.0 (range 4.1-20.2). As expected, [F18]FDG uptake in myocardium was clearly enhanced by acipimox due to reduction of circulating FFAs. In conclusion, blood fatty acids appear to have minor significance for [F18]FDG uptake in lymphoma. This suggests that glucose utilization is uncoupled of FFA metabolism and indicates that glucose-free fatty acid cycle does not operate in lymphomatous tissue. Glucose appears to be the preferred substrate for energy metabolism in tumours, in spite of the high supply of FFAs in the fasting state. Although acipimox and other anti-lipolytic drugs have potential for treatment of catabolic state induced by cancer, they are not likely to interfere with tumour energy metabolism which is fuelled by glucose.     

天津市男男性行为人群随访干预的效果评价

目的 评价天津市MSM人群随访干预效果,为后续研究的开展提供参考依据。方法 2013年4月至2017年9月,在天津市通过MSM活动场所和移动互联网招募MSM,建立前瞻性开放队列,并每6个月施加随访干预,评价随访干预效果。结果 基线共招募MSM 1 822人,符合纳入标准1 007人,累积随访干预时间为2 216.96人年,HIV共阳转39例,HIV阳转密度为1.76/100人年。梅毒阴性934人,累计随访观察时间为1 959.94人年,梅毒阳转100例,梅毒阳转密度为5.10/100人年。艾滋病知识知晓率随着宣传和干预活动很快发生改善;与同性性伴、同性固定性伴、同性临时性伴发生肛交的比例在干预后增加,但肛交安全套的使用率也有所增加;随访干预超过3次后安全套使用率有所下降。广义估计方程（GEE）分析结果显示,大专及以上文化程度（aOR=0.81,95% CI：0.68～0.98）,艾滋病知识知晓（aOR=0.52,95% CI：0.36～0.75）,最近6个月曾接受过安全套宣传（aOR=0.60,95% CI：0.49～0.74）,样本来源为移动互联网（aOR=0.85,95% CI：0.73～1.00）,累计干预1次（aOR=0.55,95% CI：0.45～0.66）、2次（aOR=0.38,95% CI：0.30～0.49）、3次（aOR=0.26,95% CI：0.20～0.35）、≥4次（aOR=0.24,95% CI：0.17～0.33）是无保护肛交的保护因素;最近6个月曾被诊断为性病（aOR=1.43,95% CI：1.06～1.96）,最近6个月使用过助性剂（aOR=1.22,95% CI：1.02～1.47）是无保护肛交的危险因素。结论 经过随访干预后,天津市MSM队列HIV和梅毒感染处于低水平;艾滋病知识知晓率发生改善,肛交安全套使用率有所提升;但MSM人群发生无保护肛交的影响因素很多,建议专门开展MSM人群无保护肛交的持续干预。     

Cerebral glucose metabolism in survivors of childhood acute lymphoblastic leukemia

BACKGROUND: Cranial radiation therapy (CRT) has been suggested to be a principal factor responsible for long term neurocognitive deficits in survivors of acute lymphoblastic leukemia (ALL). However, neither reduction of the irradiation dose nor the elimination of irradiation entirely appear to have abolished neurocognitive impairment in long term ALL survivors. Positron emission tomography (PET) and [(18)F]-fluorodeoxyglucose (FDG) can be used to quantitate cerebral glucose metabolism, a potential indicator of treatment-induced adverse central nervous system (CNS) effects. The purpose of this study was to assess whether CRT is associated with defects in cerebral glucose metabolism in long term ALL survivors. The authors also studied whether chemotherapy and/or the severity of disease have deleterious effects on glucose metabolism. METHODS: Forty long-term survivors of childhood ALL were studied using FDG PET. All subjects went through an elaborate neurocognitive assessment. In 20 of these children, the prophylactic treatment of the CNS had been CRT combined with methotrexate (MTX), and it was MTX only in the remaining 20 children. RESULTS: No major differences were found in the regional cerebral glucose utilization or in neurocognitive performance between the irradiated and nonirradiated groups. A high leukocyte count at the time of diagnosis was found to be associated inversely with cerebral glucose utilization. CONCLUSIONS: CRT does not appear to affect cerebral glucose metabolism in long term survivors of ALL. By contrast, the association between the leukocyte count and glucose utilization implies that disease severity may be partly responsible for adverse CNS effects in long term survivors of childhood ALL.     

Granulocyte macrophage-colony stimulating factor (GM-CSF) and sucralfate in prevention of radiation-induced mucositis: a prospective randomized study

PURPOSE: To compare subcutaneously given molgramostim (GM-CSF) and sucralfate mouth washings to sucralfate mouth washings in prevention of radiation-induced mucositis. METHODS AND MATERIALS: Forty head and neck cancer patients were randomly assigned to use either GM-CSF and sucralfate (n = 20) or sucralfate alone (n = 20) during radiotherapy. Sucralfate was used as 1.0 g mouth washing 6 times daily after the first 10 Gy of radiotherapy, and 150-300 microg GM-CSF was given subcutaneously. The grade of radiation mucositis and blood cell counts were monitored weekly. Salivary lactoferrin was measured as a surrogate marker for oral mucositis. RESULTS: We found no significant difference between the molgramostim and the control groups in the oral mucositis grade, oral pain, use of analgesic drugs, weight loss, or survival. The median maximum neutrophil counts (median, 9.2 x 10(9)/L vs. 5.9 x 10(9)/L, p = 0.0005), eosinophil counts (median, 1.3 x 10(9)/L vs. 0.2 x 10(9)/L, p = 0.0004), and salivary lactoferrin concentrations were higher in patients who received GM-CSF. The most common toxicities in the GM-CSF plus sucralfate group were skin reactions at the GM-CSF injection site (65%), fever (30%), bone pain (25%), and nausea (15%), whereas the toxicity of sucralfate given alone was minimal. CONCLUSION: We found no evidence indicating that subcutaneously given GM-CSF reduces the severity of radiation-induced mucositis.     

Treatment of squamous cell carcinoma of the oral cavity, oropharynx and hypopharynx--an analysis of 174 patients in south western Finland

The purpose of this study was to determine the efficacy and feasibility of full-dose preoperative radiation therapy (RT) in head and neck cancer presenting in the oral cavity, oro- and hypopharynx, within a single university hospital district. During a seven-year period, 1989 to 1995, 174 patients with squamous cell carcinoma (SCC) of the oral cavity (OC, 70% of all patients), oropharynx (OP, 15%) and hypopharynx (HP, 15%) were referred to Turku University Central Hospital. All patients were seen by a tumor board consisting of an ENT (ear-nose-throat) head and neck surgeon, a radiation oncologist and a dentist. Potentially curative treatment was given to 142 patients. Of these, 88 (62%) had preoperative RT, 6 (4%) postoperative RT, 34 (24%) definitive RT and 14 patients (10%) were treated with surgery only. The radiation dose was ≥50 Gy, averagely 64 Gy. The major endpoints of the study were local control, overall survival and major complications of the combined treatment. The 5-year relative survival rate (RSR) was 40% for all, and 43% for patients treated with curative intent. For these, the local control at 5 years was 60%; the disease-specific 5-year survival rate was 65% for the patients with lingual SCC, 45% for those with other oral tumor localizations, 64% for the oropharynx patients and 47% for those with tumor in their hypopharynx, while it was 55% for all patients. The preoperative radiotherapy was fairly well tolerated. Ten (7%) of the patients treated with curative intent suffered major complications, and four patients had evidence of osteoradionecrosis. With the exception of patients with early SCC the outcome remains rather poor in this group of cancer patients who often have marked co-morbidity. In our opinion, preoperative radiotherapy to a dose of 62-64 Gy can safely be given, and remains a feasible means to treat patients with oral, oropharyngeal or hypopharyngeal cancer.