Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy

FK506 binding proteins 12 and 12.6 (FKBP12 and FKBP12.6) are intracellular receptors for the immunosuppressant drug FK506 (ref. 1). The skeletal muscle ryanodine receptor (RyR1) is isolated as a hetero-oligomer with FKBP12 (ref. 2), whereas the cardiac ryanodine receptor (RyR2) more selectively associates with FKBP12.6 (refs 3, 4, 5). FKBP12 modulates Ca2+ release from the sarcoplasmic reticulum in skeletal muscle and developmental cardiac defects have been reported in FKBP12-deficient mice, but the role of FKBP12.6 in cardiac excitation-contraction coupling remains unclear. Here we show that disruption of the FKBP12.6 gene in mice results in cardiac hypertrophy in male mice, but not in females. Female hearts are normal, despite the fact that male and female knockout mice display similar dysregulation of Ca2+ release, seen as increases in the amplitude and duration of Ca2+ sparks and calcium-induced calcium release gain. Female FKBP12.6-null mice treated with tamoxifen, an oestrogen receptor antagonist, develop cardiac hypertrophy similar to that of male mice. We conclude that FKBP12.6 modulates cardiac excitation-contraction coupling and that oestrogen plays a protective role in the hypertrophic response of the heart to Ca2+ dysregulation.     

Efp targets 14-3-3 sigma for proteolysis and promotes breast tumour growth

Oestrogen exerts its influence on target organs through activating oestrogen receptors (ERs) and regulating downstream genes by means of their oestrogen-responsive elements. Efp, a target gene product of ER alpha, is a member of the RING-finger B-box coiled-coil (RBCC) motif family. Efp is predominantly expressed in various female organs as well as in breast cancers, and is thought to be essential for oestrogen-dependent cell proliferation and organ development Efp-disrupted mice display underdeveloped uteri and reduced oestrogen responsiveness. Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3 sigma, a negative cell cycle regulator that causes G2 arrest. We demonstrate that tumour growth of breast cancer MCF7 cells implanted in female athymic mice is reduced by treatment with antisense Efp oligonucleotide. Efp-overexpressing MCF7 cells in ovariectomized athymic mice generate tumours in the absence of oestrogen. Loss of Efp function in mouse embryonic fibroblasts results in an accumulation of 14-3-3 sigma, which is responsible for reduced cell growth. These data provide an insight into the cell-cycle machinery and tumorigenesis of breast cancer by identifying 14-3-3 sigma as a target for proteolysis by Efp, leading to cell proliferation.     

原发性子宫内膜癌与p16基因突变及蛋白表达关系的研究

目的研究p16蛋白表达与原发性子宫内膜癌发生发展的关系和p16基因缺失突变及点突变在原发性子宫内膜癌发生发展中的地位.方法利用免疫组织化学方法、聚合酶链反应和聚合酶链反应-单链构象多态性分析技术,分别检测正常子宫内膜组织、子宫内膜癌前病变组织及原发性子宫内膜癌组织,观察p16蛋白和p16基因缺失突变及点突变.结果1)p16蛋白阳性表达率在正常子宫内膜组织和子宫内膜癌前病变组织中表达率分别为92.78%和90.00%,两者相比无差异性;在原发性子宫内膜癌组织中为66.67%,明显低于正常子宫组织及癌前病变组织;2)在42例原发性性子宫内膜癌组织中有14例发生p16基因缺失突变,4例发生了p16基因点突变,突变率为分别为33.33%和9.6%,正常子宫颈组织和子宫内膜癌前病变组织未发现p16基因缺失突变和点突变.结论1)在原发性子宫内膜癌发生发展过程中,p16蛋白的表达在高分化癌明显低于低分化癌,表明p16蛋白缺乏与子宫颈细胞增殖失控及分化不良紧密相关.2)原发性子宫内膜癌存在p16基因点突变,以低分化癌多见,但不是较频繁的事件;原发性子宫内膜癌存在p16基因缺失突变,以低分化癌多见,是较频繁的事件.3)p16蛋白表达与p16基因突变的相关性未被发现.     

Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia

Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer.     

Survivin在子宫腺肌病中的表达及与VEGF相关性研究

目的探讨凋亡抑制基因Survivin在子宫腺肌病的表达及其与VEGF的相关性。方法应用免疫组织化学S—P法,检测50例子宫腺肌病异位及在位内膜组织中Survivin、VEGF蛋白的表达,并与正常在位子宫内膜组织30例进行对照。结果子宫腺肌病异位内膜组织中Survivin蛋白阳性表达率为80％,明显高于正常内膜及在位内膜组织的表达率16．67％、16％（P〈0．05）;子宫腺肌病异位内膜组织中VEGF蛋白阳性表达率为56％,明显高于正常内膜及在位内膜组织的表达率38％、20％（P〈0．05）;Survivin蛋白表达与VEGF蛋白呈正相关（P〈0．01）。结论Survivin可通过抑制异位内膜细胞凋亡,参与血管形成对子宫腺肌病的发生、发展起作用;Survivin与VEGF在子宫腺肌病的发生、发展中起协同作用。     

子宫内膜癌组织中COX-2、iNOS的表达

采用免疫组化EnVision法,测定了55例子宫内膜癌、24例不典型增生子宫内膜及20例正常子宫内膜中COX-2i、NOS蛋白的表达情况,探讨COX-2i、NOS蛋白在子宫内膜癌组织中的表达及子宫内膜癌发生和进展的关系。结果显示：1）COX-2蛋白在子宫内膜癌中的表达明显高于正常子宫内膜及不典型增生子宫内膜中的表达（P〈0.05）,与子宫内膜癌肌层浸润程度及淋巴结转移无相关。2）iNOS蛋白在子宫内膜癌中的表达明显高于正常子宫内膜及不典型增生子宫内膜中的表达（P〈0.05）,且与子宫内膜癌肌层浸润程度显著相关。这表明,子宫内膜癌患者COX-2和iNOS的表达水平明显上调,其表达与子宫内膜癌的发生发展有关。     

Superoxide dismutase as a target for the selective killing of cancer cells

Superoxide dismutases (SOD) are essential enzymes that eliminate superoxide radical (O2-) and thus protect cells from damage induced by free radicals. The active O2- production and low SOD activity in cancer cells may render the malignant cells highly dependent on SOD for survival and sensitive to inhibition of SOD. Here we report that certain oestrogen derivatives selectively kill human leukaemia cells but not normal lymphocytes. Using complementary DNA microarray and biochemical approaches, we identify SOD as a target of this drug action and show that chemical modifications at the 2-carbon (2-OH, 2-OCH3) of the derivatives are essential for SOD inhibition and for apoptosis induction. Inhibition of SOD causes accumulation of cellular O2- and leads to free-radical-mediated damage to mitochondrial membranes, the release of cytochrome c from mitochondria and apoptosis of the cancer cells. Our results indicate that targeting SOD may be a promising approach to the selective killing of cancer cells, and that mechanism-based combinations of SOD inhibitors with free-radical-producing agents may have clinical applications.     

Common non-hormone binding component in non-transformed chick oviduct receptors of four steroid hormones

Steroid hormones produce a response in target cells by binding to hormone-specific soluble receptors, which undergo a transformational change, leading to their interaction with chromatin and to modified gene expression. In a previous paper, we described a monoclonal antibody, BF4, that specifically recognizes and binds the non-transformed '8S' form of chicken oviduct progesterone receptor (8S-PR). We now show that BF4 does not form an immune complex with the 4S transformed form of 3H-progestin-labelled progesterone receptor, but does interact with the 8S non-transformed forms of the oestrogen, androgen and glucocorticosteroid receptors. Our results suggest that the antigenic determinant recognized by BF4 is present on a non-hormone binding unit, which we identify as a polypeptide of molecular weight (MW) 90,000 in the case of the progesterone receptor, and that this unit is common to other 8S non-transformed chicken steroid receptors.     

乳腺密度自动测量与乳腺癌术后他莫昔芬治疗预后方法

乳腺癌严重威胁人类生命健康,乳腺癌患者手术后辅以他莫昔芬治疗是常用的治疗方法。然而患者治疗后仍然面临复发或转移的风险,所以需要有效的预后方法来预测疗效。为了探索一种基于钼靶X线影像的乳腺癌术后他莫昔芬治疗预后分析方法,通过基于通道注意力机制的压缩激励卷积神经网络(squeeze-and-excitation convolutional neural network, SE-CNN)方法研究钼靶X线影像中的乳腺密度自动提取模型,提出预后影像标志物：乳腺密度变化率(mammographic density change ratio, MDCR),并进行生存分析,研究其对乳腺癌术后他莫昔芬治疗的预后能力。结果表明：SE-CNN的阈值绝对误差为9.92±4.78,决对系数为0.77,表明所提方法能够准确提取阈值。生存分析中得到无进展生存期为风险比率(hazard ratio, HR):2.654[95%CI(置信区间),1.102～6.395],P=0.030。MDCR值高的患者预后较好,反之则较差。可见乳腺密度变化率可以作为乳腺癌术后他莫昔芬治疗预后影像标志物。     

Glucocorticoid and progesterone receptors bind to the same sites in two hormonally regulated promoters

The glucocorticoid receptor of rat liver recognizes nucleotide sequences near the promoter of mouse mammary tumour virus (MMTV) required for hormonal induction in gene transfer experiments. Similar nucleotide sequences have been found in the human metallothionein gene IIA and in the chicken lysozyme gene, the later induced also by oestrogen, progesterone and androgens. In microinjection experiments, deletion of only 44 base pairs (bp) of the lysozyme promoter (from -208 to -164) results in coordinated loss of progesterone and glucocorticoid-dependent gene expression. We show here that purified glucocorticoid receptor from rat liver and progesterone receptor from rabbit uterus yield similar or overlapping exonuclease III footprints in the promoter regions of MMTV and chicken lysozyme. Thus, the regulatory elements for different steroid hormones may be similar or at least share structural features.     

bFGF调控CD34对子宫内膜癌细胞生长的影响

目的探讨碱性成纤维细胞生长因子（bFGF）调控CD34对子宫内膜癌细胞生长的影响。方法免疫组化法检测正常子宫内膜和子宫内膜癌组织中bFGF、微血管密度（MVD）和增殖细胞核抗原（PCNA）的表达。用TUNEL原位凋亡法检测细胞凋亡并计算凋亡率（AR）。结果子宫内膜癌组织中bFGF、MVD和PCNA表达均明显高于正常子宫内膜组织,而AR低于正常子宫内膜组织。bFGF、MVD和PCNA均呈正相关。bFGF和MVD与AR均呈负相关。结论bFGF促进肿瘤细胞增殖,抑制肿瘤细胞凋亡。     

VEGF、COX-2、HIF-1α在子宫内膜癌中的表达及其意义

应用免疫组化SP法检测46例子宫内膜癌、22例子宫内膜不典型增生和19例正常子宫内膜组织中VEGF、COX-2与HIF-1α蛋白的表达情况.结果显示：VEGF、COX-2与HIF-1α在子宫内膜癌中表达升高,且随分级分期的升高而升高,三者在子宫内膜病变发生、发展中起促进作用;在子宫内膜组织中,COX-2和HIF-1α可能分别对VEGF起调控作用,有望成为内膜肿瘤抗血管治疗的有效靶标.     

Functional identification of an aggression locus in the mouse hypothalamus

Electrical stimulation of certain hypothalamic regions in cats and rodents can elicit attack behaviour, but the exact location of relevant cells within these regions, their requirement for naturally occurring aggression and their relationship to mating circuits have not been clear. Genetic methods for neural circuit manipulation in mice provide a potentially powerful approach to this problem, but brain-stimulation-evoked aggression has never been demonstrated in this species. Here we show that optogenetic, but not electrical, stimulation of neurons in the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) causes male mice to attack both females and inanimate objects, as well as males. Pharmacogenetic silencing of VMHvl reversibly inhibits inter-male aggression. Immediate early gene analysis and single unit recordings from VMHvl during social interactions reveal overlapping but distinct neuronal subpopulations involved in fighting and mating. Neurons activated during attack are inhibited during mating, suggesting a potential neural substrate for competition between these opponent social behaviours.     

原位和子宫腺肌病异位内膜Bcl-2的表达

目的：研究原位子宫内膜和子宫腺肌病异位内膜Ｂｃｌ－２在月经周期中的表达情况,并探讨子宫腺肌病和子宫内膜异位症Ｂｃｌ－２不同表达的原因。方法：应用免疫组织化学ＬＳＡＢ方法研究２０例原位子宫内膜和子宫腺肌病异位内膜的Ｂｃ１－２表达。结果：原位子宫内膜腺体的Ｂｃｌ－２表达在月经周期中存在周期性变化：从增生早期至分泌早期,腺上皮细胞均呈Ｂｃｌ－２阳性反应,增生中晚期Ｂｃｌ－２表达最强,至分泌中晚期则表达基