HMGA-targeted phosphorothioate DNA aptamers increase sensitivity to gemcitabine chemotherapy in human pancreatic cancer cell lines

Elevated high mobility group A (HMGA) protein expression in pancreatic cancer cells is correlated with resistance to the chemotherapy agent gemcitabine. Here, we demonstrate use of HMGA-targeted AT-rich phosphorothioate DNA (AT-sDNA) aptamers to suppress HMGA carcinogenic activity. Cell growth of human pancreatic cancer cells (AsPC-1 and Miapaca-2) transfected with AT-sDNA were monitored after treatment with gemcitabine. Significant increases in cell death in AT-sDNA transfected cells compared to non-AT-rich sDNA treated cells were observed in both cell lines. The data indicate the potential use of HMGA targeted DNA aptamers to enhance chemotherapy efficacy in pancreatic cancer treatment.     

B淋巴瘤6号染色体微卫星不稳定性及杂合性缺失

目的:探讨6号染色体微卫星不稳定性(microsatelliteinstability,MSI)及杂合性缺失(lossofheterozygosity,LOH),碱基错配修复系统GTBP和hMLH1基因蛋白在B细胞淋巴瘤(Bcellnonhodgkin’slymphoma,BNHL)发生学上的意义。方法:选取6号染色体上7对多态微卫星标记,结合PCR及银染技术,采用凝胶成像图象分析系统,分别检测58例BNHL染色体微卫星MSI及LOH。对其中23例BNHL细胞进行EnVinsion法检测MMR的功能基因GTBP、hMLH1的表达情况。结果:弥漫性大B细胞淋巴瘤(diffuselargeBcelllymphoma,DLBCL)与滤泡性淋巴瘤(follicularlymphoma,FL)中GTBP和hMLH1蛋白表达差异无统计学意义,P值分别为0.98和1.30。原发生于淋巴结内与淋巴结外的GTBP、hMLH1蛋白表达差异无统计学意义,P值分别为0.54和0.67。GTBP蛋白在高、低度恶性表达之间差异无统计学意义,P=1.00;而hMLH1蛋白表达在低度恶性较高度恶性高,P=0.99。在位点D6S275MSI的发生率为7.5%(4/53),其中包括DLBCL2例,FL和BCLL/SLL各1例,LOH总的发生率达66.0%(35/53),其中包括DLBCL19例(19/21,90.5%),FL8例(8/13,61.5%),BCLL/SLL8例(8/19,42.1%),DLBCL的LOH率同BCLL/SLL和FL相比,差异有统计学意义,P=10.60。结论:hMLH1和GTBP错配修复基因蛋白表达与BNHL组织学类型、肿瘤的发生部位可能无关系。位点D6S275可能存在一个抑癌基因,该基因的缺失以及与错配修复基因hMLH1突变的关系对B细胞淋巴瘤的发生作用有待进一步研究。     

DNA Sequence Copy Number Aberrations Associated with Histological Subtypes and DNA Ploidy in Gastric Carcinoma

We have analyzed DNA sequence copy number aberrations (DSCNAs) and DNA ploidy by using comparative genomic hybridization and laser scanning cytometer in gastric carcinomas (GCs) to elucidate the genomic aberrations in relation to clinicopathological parameters. Thirty-two out of 33 cases showed one or more DSCNAs with a mean number of 11.7 per tumor. High-level gains were detected at 2p, 3q, 6p, 7p, 7q, 8q, 12p, 13q, 19q, and 20q. Frequency of gross genomic abnormalities and chromosome regions that have genomic aberrations were similar in both intestinal-and diffuse-type GCs, except aberrations at 8p, 9p, 12q, and 20q. The overall number of DSCNAs was significantly greater in DNA aneuploid tumors than that in DNA diploid tumors. We detected genomic aberrations characterized by histological subtype, tumor location, and DNA ploidy status: gain of 20q and losses of 8p and 9p in intestinal-type GCs, gains of 8p and 12q in diffuse-type GCs, gain of 20q in the lower third GCs, and loss of 5q, 9p, lOq, 16q, and 18q in DNA aneuploid GCs. Furthermore, 5q loss is associated with DNA aneuploidy ( P =0.0001) or the total number of losses ( P =0.001), gain+losses ( P =0.004), and high-level gains ( P =0.001) in GCs. Among these loci, chromosome 8p was unique. Gain of 8p was more common in diffuse-type GC, whereas loss of 8p was more frequently detected in intestinal-type GC. In conclusion, we describe chromosomal regions of 5q, 8p, and 20q, which are of interest for further investigation of GCs.     

CYP1B1 and hormone-induced cancer

Cancers in hormone-responsive tissues (e.g., breast, ovary, endometrium, prostate) occur at high incidence rates worldwide. However, their genetic basis remains poorly understood. Studies to date suggest that endogenous/exogenous oestrogen and environmental carcinogens may play a role in development and/or progression of hormone-induced cancers via oxidative oestrogen metabolism. Cytochrome P450 1B1 is a key enzyme in its oestrogen metabolism pathway, giving rise to hydroxylation and conjugation. Although CYP1B1 is expressed in many cancers, particularly high levels of expression are observed in oestrogen-mediated disease. CYP1B1 is more readily found in tumour tissue compared to normal. Given the role of CYP1B1 in pro-carcinogen and oestrogen metabolism, polymorphisms in CYP1B1 could result in modifications in its enzyme activity and subsequently lead to hormone-mediated carcinogenesis. CYP1B1 may also be involved in progression of the disease by altering the tissue response to hormones and clinical response to chemotherapy. The exact mechanism behind these events is complex and unclear. Only a few functional single nucleotide polymorphisms of CYP1B1 are known to result in amino acid substitutions and have been extensively investigated. Studies examining the contribution of different CYP1B1 alleles to hormone-mediated cancer risks are inconsistent. The main focus of this review is to appraise the available studies linking the pathogenesis of the hormone-induced cancers to various CYP1B1 polymorphisms. Additionally, we explore the role of a neuronal protein, γ-synuclein, in CYP1B1-mediated pathogenesis.     

颅骨的性别判定研究 Ⅱ.上颌及硬腭径线的性别差异

本文对108例汉族成人上颌及硬腭的五个径线进行了测量,并做了男女各项平均值性别差异的t值检验和性别判别分析。性差检验结果,上齿槽弓长和腭长的性差高度显著,其余各项目性差不显著。性别判别分析结果,7种不同判别式性别判定的正确率为61.11～74.07％,各个判别式的显著性检验结果均高度显著。最理想的判别式是由腭长、腭宽、腭高三个项目组合成的判别式,判别率为74.07％。上颌及硬腭径线对性别判定有一定意义。     

气相色谱高温液晶固定液的合成和性能研究——Ⅲ.双-(对烷氧基苄叉)-4,4''-二氨基二苯乙烷薛夫碱类液晶

合成了十种文题所述液晶,其通式为: (其中R为CH_3、C_2H_5……C_(10)H_(21)) 测定了它们的元素分析、红外光谱、液晶相态和温度范围。应用为高温液晶固定液,对蒽油的组分分析和蒽、菲的分离,已取得较好结果。     

Propafenone and disopyramide enhance post-ischemic contractile and metabolic recovery of perfused hearts

The effects of sodium channel blockers, propafenone and disopyramide, on post-ischemic contractile dysfunction of perfused rat hearts were examined. Isolated hearts were subjected to 35 min ischemia, followed by 60 min reperfusion with and without administration of either drug during 3 min of pre-ischemia. Ischemia/reperfusion induced complete cardiac dysfunction, rise in left ventricular end-diastolic pressure, increase in perfusion pressure, accumulation of Na⁺ and Ca²⁺ and loss of K⁺ and Mg²⁺, and release of creatine kinase and purine nucleosides and bases from the heart. These observations suggest that ischemia/reperfusion in the current study induces cardiac cell necrosis or an increase in cell membrane permeability to ions, substrates and macromolecules. Treatment of perfused hearts with either propafenone at concentrations ranging from 5 to 70 μM, or disopyramide at concentrations of 100 μM or higher resulted in a pronounced contractile recovery of the heart, associated with suppression of reperfusion-induced tissue ion alteration and inhibition of reperfusion-induced release of creatine kinase and purine nucleosides and bases. Ischemic insult itself caused tissue Na⁺ accumulation and K⁺ loss without any change in tissue Ca²⁺ and Mg²⁺. The alterations in the electrolytes were attenuated by treatment with either agent. The results suggest that prevention of ischemia- and reperfusion-induced ionic disturbance of cardiac cells by propafenone and disopyramide plays a role in the improvement of post-ischemic contractile dysfunction.     

Low-Substituted Hydroxypropylcellulose as a Sustained-Drug Release Matrix Base or Disintegrant Depending on Its Particle Size and Loading in Formulation

Tablets of acetaminophen as a model drug were prepared with low-substituted hydroxypropylcellulose (L-HPC) of various particle sizes at various loadings in the formulation. Drug release into an aqueous dissolution medium (pH 1.2) was remarkably sustained from tablets prepared with fine L-HPC (LH41) at loadings of more than 20%. Tablets prepared with less than 20% LH41 or with coarse L-HPCs (LH11, LH21, and LH31) disintegrated in the medium, resulting in rapid release of the drug. The difference in behavior could not be explained in terms of differences in tablet strength, but in swelling and water uptake abilities of the tablet's polymer. Swelling work (swelling force), water penetration speed, and water uptake of LH41 (4.4-µm average particle size) were much smaller than those of coarse L-HPCs. The formation of a continuous gel-like layer on the surface of tablets containing more than 20% LH41 was another factor to sustain the drug release rate.     

Cadmium and T cell differentiation: limited impact in vivo but significant toxicity in fetal thymus organ culture

DNA lesions, including oxydated bases, nucleotide damage and double strand breaks, are continuously produced in living cells and represent a threat for genetic stability. Highly conserved repair processes have evolved to maintain DNA integrity. Cadmium (Cd) is an environmental carcinogenic pollutant known to inactivate several proteins involved in DNA repair systems while at the same time creating an oxidative stress that can result in additional DNA lesions. Cd also has potent immunotoxic effects. DNA repair by non-homologous end joining (NHEJ) is absolutely required for T lymphocyte differentiation. In this study, we examined the impact of Cd on non-homologous end joining pathway by analyzing T cell development in the thymus of mice that received Cd-supplemented drinking water. In vivo, the absence of major alteration indicates that Cd does not affect NHEJ, despite its accumulation in the thymus. Cd contamination affects only a discrete population of developing thymocytes. However, these cells are functional as the cellular response observed in mice following gamma-radiation exposure is identical in treated and control mice. Furthermore, Cd diet did not perturb the redox status in thymocytes and more importantly did not generate significant DNA lesions in organs that accumulate the highest concentration of Cd. Our results show that in vivo, Cd does not affect NHEJ or base and nucleotide repair, and that Cd toxicity to T cells is rather linked to cell cycle perturbations.     

Synthesis of 4'-hydroxy-3'-piperidinomethylchalcone derivatives and their cytotoxicity against PC-3 cell lines

A new series of mono Mannich bases of 4'-hydroxychalcones 2a-e carrying a variety of aryl groups was synthesized and the in vitro cytotoxic activities of the new compounds were screened against PC-3 cell lines. Bioactivities of 2a-e, which are reported for the first time in this study, were compared against their precursor 4'-hydroxychalcones 1a-e. Compound 2b was found to be the most potent (IC(50 )= 3.7 microM) among the compounds synthesized. In addition, the compounds 1a-c and 2d showed moderate cytotoxicity. Incorporation of the 3'-piperidinomethyl group in 1b and 1d raised the potency by 1.68 and 2.19 times respectively and, therefore, seemed to be a noteworthy molecular modification. Correlations were noted between cytotoxicity and one or more physiochemical constants of the aryl ring as well as log P values for the compounds 2a-e. The significant improvement of cytotoxicity of 2b, 2d, and 2e against PC-3 cell lines compared with their chalcone precursors suggests that the incorporation of a piperidinomethyl group is a useful molecular modification and further development of these compounds as candidate cytotoxic agents may be warranted.