Interaction between γ-radiation and dietary folate starvation metabolically reprograms global hepatic histone H3 methylation at lysine 4 and lysine 27 residues

The objective of the present study was to investigate the regulatory control of histone H3 methylation at lysine 4 (H3K4) and lysine 27 (H3K27) residues in response to the effect of folate deficiency and gamma (γ)-radiation. Male Swiss mice maintained on folate sufficient diet (FSD) and folate free diet (FFD) based on AIN-93M formula, were subjected to 2-4 Gy total body γ-irradiation. There was a significant decrease in liver folate levels with concomitant depletion of S-adenosylmethionine (SAM) reserves. Folate deficiency and γ-radiation together induced H3K4 histone methyltransferase (H3K4HMTase) and suppressed H3K27 histone methyltransferase (H3K27HMTase) activities in a dose and time dependent manner. Our studies suggested radiation induced metabolic reprogramming of H3K4/H3K27 methylation patterns in FFD animals. We showed that radiation toxicity diverted one-carbon (C1) flux in FFD fed animals towards H3K4 methylation. Present work on methylation pattern of histone lysine residues gains particular importance as methylation of H3K4 residues is associated with euchromatin while methylated H3K27 residues promote gene silencing. In conclusion, our study suggests that maintenance of genomic histone methylation under γ-radiation stress might be a very dynamic, progressive process that could be modulated by dietary folate deficiency leading to formation of epigenetically reprogrammed cells.     

基于7次跨膜受体的药物发现基本方法——细胞检测

随着检测技术进步,含7个跨膜α螺旋结构的受体性质已渐为人们所了解。7次跨膜（7TM）受体不仅具有开关功能,更类似于信息微处理器;特定配体只能参与特定受体介导的部分信号机制,这就为药物发现开拓了一个新领域。为进一步发现7TM受体与配体间的新行为并量化评价药物对这一复杂系统的作用效能,进而指导药物化学研究,药理学检测已成为关注焦点。本文阐述从还原重组体到整体系统测定方法的回归,讨论药物效价与评价其效应的特定检测方法间的联系,强调新的检测方法在药物发现过程中的价值。     

Pancreaticoduodenectomy with vascular reconstruction for adenocarcinoma of the pancreas with borderline resectability

AIM: To analyze whether pancreaticoduodenectomy with simultaneous resection of tumor-involved vessels is a safe approach with acceptable patient survival.METHODS: Between January 2001 and March 2012, 136 patients received pancreaticoduodenectomy for adenocarcinoma at our hospital. Seventy-eight patients diagnosed with pancreatic head carcinoma were included in this study. Among them, 46 patients received standard pancreaticoduodenectomy (group 1) and 32 patients received pancreaticoduodenectomy with simultaneous resection of the portal vein or the superior mesenteric vein or artery (group 2) followed by reconstruction. The immediate surgical outcomes and survivals were compared between the groups. Fifty-five patients with unresectable adenocarcinoma of the pancreas without liver metastasis who received only bypass operations (group 3) were selected for additional survival comparison.RESULTS: The median ages of patients were 67 years (range: 37-82 years) in group 1, and 63 years (range: 35-86 years) in group 2. All group 2 patients had resection of the portal vein or the superior mesenteric vein and three patients had resection of the superior mesenteric artery. The pancreatic fistula formation rate was 21.7% (10/46) in group 1 and 15.6% (5/32) in group 2 (P = 0.662). Two hospital deaths (4.3%) occurred in group 1 and one hospital death (3.1%) occurred in group 2 (P = 0.641). The one-year, three-year and five-year overall survival rates in group 1 were 71.1%, 23.6% and 13.5%, respectively. The corresponding rates in group 2 were 70.6%, 33.3% and 22.2% (P = 0.815). The one-year survival rate in group 3 was 13.8%. Pancreaticoduodenectomy with simultaneous vascular resection was safe for pancreatic head adenocarcinoma.CONCLUSION: The short-term and survival outcomes with simultaneous resection were not compromised when compared with that of standard pancreaticoduodenectomy.     

双能量X线骨质密度测量仪监测小儿下肢骨延长骨矿物质的变化

目的　在儿童骨延长的患儿中 ,为了能够有效地控制骨延长的速率 ,达到骨延长的目的 ,采用双能量X线骨质密度测量仪 (dualenergyX Rayabsorptiometry ,DEXA)监测延长断端骨矿含量 (bonemineralcontent,BMC)的变化。方法　 30例患儿中有 5 0处下肢作了骨延长术 ,平均年龄10 .9岁 (5～ 17岁 ) ,引起短肢的病因不同。术后 7～ 10d开始行骨延长 ,每次延长 0 .2 5mm ,每天 4次。牵引延长期间每周扫描一次 ,拆除外固定器后每 2周扫描一次到术后 2年。DEXA扫描的分辨率是 1mm× 1mm ,扫描速度 30mm/s。比较不同延长时期中骨矿含量的变化。分析不同病因和不同外固定器之间骨矿含量变化的差别。结果　不同固定器之间骨矿含量的差别无著性意义。根据骨延长区BMC增加速率 ,将患儿分为快速组、一般组和慢速组。快速组每日BMC增加速率为 0 .3%～ 0 .6 % ,新骨生长快速 ;一般组每日BMC增加 0 .1%～ 0 .3% ,新骨中速生长 ;慢速组每日增加 <0 .1% ,新骨生成缓慢。骨矿化速率与原发病因相关。结论　DEXA能动态监测骨延长中新生骨的骨矿含量的变化 ,根据骨矿含量变化的程度 ,能够调整骨延长的速率 ,从而达到预期骨延长的目的。     

Emergency embolization of spontaneous ruptured hepatocellular carcinoma: Correlation between survival and Child−Pugh classification

From February 1994 to April 2000, 29 emergency gelfoam embolizations for spontaneous ruptured hepatocellular carcinoma (HCC) performed in 28 patients were retrospectively reviewed. There were 11 patients in Child's A , 11 in Child's B and six in Child's C classification of cirrhosis. The duration of the procedure, artery embolized and complications were reviewed, and the Child?Pugh classification of each patient was correlated with their mean survival period. Embolization was done in 12 right hepatic arteries, two left hepatic arteries and 15 proper hepatic arteries. In one patient, the left hepatic artery was embolized initially but the proper hepatic artery was also embolized because another subcapsular liver tumour was found after reviewing the preangiogram CT scan. The entire procedure took 40?170 min (mean = 86 min) with no periprocedural complication. Following embolization, the mean survival period for Child's A class was 218.3 days, Child's B class was 83.4 days and Child's C class was 11.0 days. Transcatheter embolization is an effective treatment to arrest bleeding in spontaneous ruptured HCC. Patients with Child's A class cirrhosis have the longest survival. Selective embolization of either the right or the left hepatic artery alone carries the potential risk of missing multifocal HCC that might not be easily appreciated during angiography.     

OFLOXACIN VERSUS TRIMETHOPRIM AND CO-TRIMOXAZOLE IN THE TREATMENT OF UNCOMPLICATED URINARY TRACT INFECTION IN GENERAL PRACTICE

A large-scale, randomised, multicentre single-blind clinical trial was conducted to assess the comparative efficacy and tolerance of ofloxacin, trimethoprim and co-trimoxazole in the treatment of uncomplicated urinary tract infection in general practice. A total of 1,069 patients from 76 centres across the UK were enrolled in the study, and randomised to one of the following treatment groups: ofloxacin (200 mg od), trimethoprim (200 mg bd) or co-trimoxazole (trimethoprim 160 mg and sulphamethoxazole 800 mg bd). Each patient received five days of medication. Clinically, ofloxacin was as effective as trimethoprim and co-trimoxazole. However, the bacteriological cure rate was significantly better for ofloxacin, with eradication of the initial causative pathogen by the end of treatment in 92% of patients in the ofloxacin group, compared with 81% for trimethoprim and co-trimoxazole (P = 0.0002). There was also a lower relapse rate for ofloxacin. Ofloxacin was well tolerated: adverse events were reported by 67 (12.4%) patients in the ofloxacin group, compared with 48 (18.7%) patients in the co-trimoxazole group and 37 (13.6%) patients in the trimethoprim group. Ofloxacin can therefore be considered a suitable alternative for the treatment of uncomplicated urinary tract infection.     

Candidate colorectal cancer predisposing gene variants in Chinese early-onset and familial cases

AIM: To investigate whether whole-exome sequencing may serve as an efficient method to identify known or novel colorectal cancer(CRC) predisposing genes in early-onset or familial CRC cases.METHODS: We performed whole-exome sequencing in 23 Chinese patients from 21 families with nonpolyposis CRC diagnosed at ≤ 40 years of age, or from multiple affected CRC families with at least 1 firstdegree relative diagnosed with CRC at ≤ 55 years of age.Genomic DNA from blood was enriched for exome sequences using the Sure Select Human All Exon Kit, version 2(Agilent Technologies) and sequencing was performed on an Illumina Hi Seq 2000 platform.Data were processed through an analytical pipeline to search for rare germline variants in known or novel CRC predisposing genes.RESULTS: In total, 32 germline variants in 23 genes were identified and confirmed by Sanger sequencing.In 6 of the 21 families(29%), we identified 7 mutations in 3 known CRC predisposing genes including MLH1(5 patients), MSH2(1 patient), and MUTYH(biallelic, 1 patient), five of which were reported as pathogenic.Inthe remaining 15 families, we identified 20 rare and novel potentially deleterious variants in 19 genes, six of which were truncating mutations.One previously unreported variant identified in a conserved region of EIF2AK4(p.Glu738_Asp739insA rgA rg) was found to represent a local Chinese variant, which was significantly enriched in our early-onset CRC patient cohort compared to a control cohort of 100 healthy Chinese individuals scored negative by colonoscopy(33.3% vs 7%, P 0.001).CONCLUSION: Whole-exome sequencing of early-onset or familial CRC cases serves as an efficient method to identify known and potential pathogenic variants in established and novel candidate CRC predisposing genes.