Insulin Growth Factor 1 Receptor Expression Is Associated with NOTCH1 Mutation,Trisomy 12 and Aggressive Clinical Course in Chronic Lymphocytic Leukaemia

IGF1R is emerging as an important gene in the pathogenesis of many solid and haematological cancers and its over-expression has been reported as frequently associated with aggressive disease and chemotherapy resistance. In this study we performed an investigation of the role of IGF1R expression in a large and representative prospective series of 217 chronic lymphocytic leukaemia (CLL) patients enrolled in the multicentre O-CLL1 protocol (clinicaltrial.gov #NCT00917540). High IGF1R gene expression was significantly associated with IGHV unmutated (IGHV-UM) status (p<0.0001), high CD38 expression (p<0.0001), trisomy 12 (p<0.0001), and del(11)(q23) (p=0.014). Interestingly, higher IGF1R expression (p=0.002) characterized patients with NOTCH1 mutation (c.7541_7542delCT), identified in 15.5% of cases of our series by next generation sequencing and ARMS-PCR. Furthermore, IGF1R expression has been proven as an independent prognostic factor associated with time to first treatment in our CLL prospective cohort. These data suggest that IGF1R may play an important role in CLL biology, in particular in aggressive CLL clones characterized by IGHV-UM, trisomy 12 and NOTCH1 mutation.     

多基因模型在肝细胞癌预后中的应用

利用较少分子信息预测肝细胞癌类型对患者的个性化治疗十分关键。探索已知的与肝细胞癌预后相关的信号通路,共发现41个关键基因。随后,运用机器学习的方法对其构建风险预测模型,并在4个肝细胞癌数据集上进行验证。结果显示,该模型能将肝细胞癌患者分成两个预后差异显著的类型:癌症基因图谱(The cancer genome atlas,TCGA)数据集交叉验证的平均log rank P值为0.03;其他测试数据集的log rank P 值分别为0.000 38、0.002 1和0.01。生物信息学分析显示肝细胞癌的预后与细胞周期等信号通路显著相关,并筛选出12个潜在的肝细胞癌分子标志物。研究结果表明,基于41个基因构建的肝细胞癌预后模型具有较好的稳健性和准确的风险预测能力。     

条件启动子pCTR4在隐球菌基因表达调控中的应用

目的通过条件启动子pCTR4的质粒构建以及其在新生隐球菌中的同源置换,研究其在隐球菌基因表达调控中的应用。方法应用套叠PCR,构建含报告基因NEO的铜离子抑制性启动子质粒pNEO/CTR4和启动子同源重组框,并利用基因枪将其转化入新生隐球菌感受态细胞,常规及实时定量PCR检测条件启动子对目的基因的转录调控效应。结果成功构建了质粒pNEO/CTR和隐球菌条件启动子重建菌株,条件启动子pCTR4对目的基因具有预期的转录诱导和抑制效果。结论新建铜离子抑制性启动子质粒pNEO/CTR4可以应用于对隐球菌目的基因表达水平的调控;隐球菌泛素编码基因UBI 1并非致死性关键基因。我们的研究为今后新生隐球菌泛素系统的分子致病机制研究奠定了基础。     

华北石质山地侧柏人工林C、N、P生态化学计量特征的季节变化

以北京九龙山自然保护区幼龄侧柏人工林为研究对象,对其不同生长季节叶、枝、根(0—10 cm、10—20 cm土层)的碳(C)、氮(N)、磷(P)含量及其生态化学计量学特征进行了分析,深入探讨了生长季节与器官以及两因素交互作用对以上特征的影响,研究有助于理解植物各性状之间的相互作用以及植物生长过程中资源的利用和分配状况。结果表明:1)不同器官间C含量为414.97—461.58 g/kg,枝最大,根(0—10 cm)最小;N含量为6.57—14.28 g/kg,叶最大,枝最小;P含量为0.39—1.28 g/kg,叶最大,根(10—20 cm)最小;C∶N为31.76—70.98,枝最大,叶最小;C∶P为369.93—1099.20,根(10—20 cm)最大,叶最小;N∶P为9.21—23.81,根(0—10 cm)最大,枝最小。整个生长季节中侧柏各器官C含量最稳定,变异系数均小于7%;P含量变异性最大,变异系数均超过15%,N含量变异性介于两者之间;各器官中C∶N和N∶P较C∶P更为稳定,C、N与P具有较好的耦合协同性,C∶P和N∶P的变化主要取决于P的变化。2)器官对C、N、P含量及其化学计量关系均存在显著影响,生长季节对N和P含量存在显著影响,两者交互作用只对P含量存在显著影响,器官对侧柏C、N、P含量及其化学计量变异的贡献大于生长季节。3)侧柏各器官间C、N、P含量及其化学计量比相关性多数未达到显著性水平,仅有叶与枝中的P及C∶P显著相关,说明侧柏器官分化过程中各器官对元素的吸收利用具有特异性。侧柏叶片N∶P14,说明生长季节里幼龄侧柏人工林更多受到N限制。     

Lipotoxicity and the development of heart failure: moving from mouse to man

Intracardiac lipid accumulation can cause heart failure. A study in Journal of Clinical Investigation (Son et?al., 2010) found that cardiac-specific PPARγ overexpression caused heart failure with intracardiac triglyceride accumulation. Overexpressing PPARγ on a PPARα-/- background improved cardiac function, suggesting that specific lipid metabolites and lipid packaging determine cardiac lipotoxicity.     

Sequencing and cardiac expression of natriuretic peptide receptor 2 (NPR-B) in Sus Scrofa

The cardiovascular actions of the C-type natriuretic peptide (CNP) are mainly mediated by the interaction with natriuretic peptide receptor-B (NPR-B). The aim of this study was to identify the sequence of NPR-B in Sus Scrofa, which is not present in GenBank, to verify the expression of NPR-B in the different cardiac chambers of normal pigs and evaluate its homology with murine and human species. Using the guanidinium thyocyanate-phenol-chloroform method, we extracted total RNA from samples obtained from heart of mouse and from the atrium, ventricle, and septum of normal pigs. Pig NPR-B mRNA was sequenced using polymerase chain reaction primers designed from mouse consensus sequences. Sus Scrofa natriuretic peptide receptor 2 mRNA, 1-396 bp, was submitted to GenBank (accession number DQ487044). The presence of NPR-B at mRNA level was detected in all the cardiac chambers; moreover, the bands obtained from pig cardiac tissue shared a 93% sequence homology with a region of the mouse NPR-B and a 95% sequence homology with Homo sapiens. Therefore, NPR-B sequencing provides a new tool to investigate the role of CNP under physiological and pathological conditions in the experimental and clinical setting.     

Phase II study of interleukin-2 and 13-cis-retinoic acid as maintenance therapy in metastatic colorectal cancer

Purpose We have previously shown that low-dose interleukin-2 (IL-2) and 13-cis-retinoic acid (13-cis-RA) improved lymphocyte and natural killer (NK) cell count of patients with advanced tumors showing a clinical benefit from chemotherapy. The primary endpoint of this study was to ask whether IL-2 and 13-cis-RA improved (≥30%) lymphocyte and NK cell count in patients with metastatic colorectal cancer (MCRC) that had a clinical benefit from induction chemotherapy. Secondary endpoint was the evaluation of toxicity, progression-free survival (PFS), and overall survival (OS). Patients and methods Forty patients with MCRC, showing a clinical benefit from chemotherapy, were treated with subcutaneous low-dose IL-2 (1.8 × 10⁶ IU) and oral 13-cis-RA (0.5 mg/kg) in order to maintain responses and improve survival through the increase of lymphocyte and NK cells. The biological parameters and the clinical outcome of these patients were compared with those of a control group of patients (80) with a similar disease status, including clinical benefit from chemotherapy. Results The most common adverse events were mild cutaneous skin rash and fever. After 4 months and 2 years of biotherapy, a statistically significant improvement was observed in lymphocyte and number of NK cells with respect to baseline values and to controls. After a median follow-up of 36 months, median PFS was 27.8 months, while median OS was 52.9 months. Conclusion These data show that maintenance immunotherapy with low-dose IL-2 and oral 13-cis-RA in patients with MCRC showing a clinical benefit from chemotherapy is feasible, has a low toxicity profile, improves lymphocyte and NK cell count. An improvement in the expected PFS and OS was also observed. A randomized trial is warranted.     

The cholesterol metabolite 25-hydroxycholesterol activates estrogen receptor α-mediated signaling in cancer cells and in cardiomyocytes

Background

The hydroxylated derivatives of cholesterol, such as the oxysterols, play important roles in lipid metabolism. In particular, 25-hydroxycholesterol (25HC) has been implicated in a variety of metabolic events including cholesterol homeostasis and atherosclerosis. 25HC is detectable in human plasma after ingestion of a meal rich in oxysterols and following a dietary cholesterol challenge. In addition, the levels of oxysterols, including 25HC, have been found to be elevated in hypercholesterolemic serum.

Methodology/Principal Findings

Here, we demonstrate that the estrogen receptor (ER) α mediates gene expression changes and growth responses induced by 25HC in breast and ovarian cancer cells. Moreover, 25HC exhibits the ERα-dependent ability like 17β-estradiol (E2) to inhibit the up-regulation of HIF-1α and connective tissue growth factor by hypoxic conditions in cardiomyocytes and rat heart preparations and to prevent the hypoxia-induced apoptosis.

Conclusions/Significance

The estrogen action exerted by 25HC may be considered as an additional factor involved in the progression of breast and ovarian tumors. Moreover, the estrogen-like activity of 25HC elicited in the cardiovascular system may play a role against hypoxic environments.