Fluorescence in situ hybridization of three oncogenes on a leiomyoma

Using fluorescence in situ hybridization technique, expression of three oncogenes, C-myc, RARa, and cyclin-D was tested on a uterine leiomyoma. C-myc and RARa were amplified in approximately 30% and 90% of the cells, respectively. Numerous small signals of C-myc were indicative of the presence of double minutes. Amplification of RARa is being reported for the first time in a leiomyoma. Cyclin-D was normal in diploid cells while it was highly amplified in polyploid cells. Low levels of amplified C-myc and cyclin-D cells seem to be the reason for this tumor to be benign, while RARa could not be effective without the association of some other gene such as PML. Information presented here are significant toward developing new curative strategies such as gene-specific drugs and molecular manipulation to stop the activity of cancer gene. Further study may elucidate that how fibroids grow and maintain their rare benign nature.     

Critical Players and Therapeutic Targets in Chronic Itch

Chronic itch is one of the most prominent clinical characteristics of diverse systematic diseases. It is a devastating sensation in pathological diseases. Despite its importance, there are no FDA-labelled drugs specifically geared toward chronic itch. The associated complex pathogenesis and diverse causes escalate chronic itch to being one of the top challenges in healthcare. Humanized antibodies against IL-13, IL-4, and IL-31 proved effective in treatment of itch-associated atopic dermatitis but remain to be validated in chronic itch. There are still no satisfactory anti-itch therapeutics available toward itch-related neuropeptides including GRP, BNP, SST, CGRP, and SP. The newly identified potential itch targets including OSM, NMB, glutamate, periostin, and Serpin E1 have opened new avenues for therapeutic development. Proof-of-principle studies have been successfully performed on antagonists against these proteins and their receptors in itch treatment in animal models. Their translational interventions in humans need to be evaluated. It is of great importance to summarize and compare the newly emerging knowledge on chronic itch and its pathways to promote the development of novel anti-itch therapeutics. The goal of this review is to analyze the different physiologies and pathophysiologies of itch mediators, whilst assessing their suitability as new targets and discussing future therapeutic development.     

Effects of Sulforaphane-Induced Cell Death upon Repeated Passage of Either P-Glycoprotein-Negative or P-Glycoprotein-Positive L1210 Cell Variants

The expression of the membrane ABCB1 transporter in neoplastic cells is one of the most common causes of reduced sensitivity to chemotherapy. In our previous study, we investigated the effect of a single culture of ABCB1-negative (S) and ABCB1-positive variants of L1210 cells (R and T) in the presence of sulforaphane (SFN). We demonstrated that SFN induces the onset of autophagy more markedly in S cells than in R or T cells. In the current study, we focused on the effect of the repeated culture of S, R and T cells in SFN-containing media. The repeated cultures increased the onset of autophagy compared to the simple culture, mainly in S cells and to a lesser extent in R and T cells, as indicated by changes in the cellular content of 16 and 18 kDa fragments of LC3B protein or changes in the specific staining of cells with monodansylcadaverine. We conclude that SFN affects ABCB1-negative S cells more than ABCB1-positive R and T cells during repeated culturing. Changes in cell sensitivity to SFN appear to be related to the expression of genes for cell-cycle checkpoints, such as cyclins and cyclin-dependent kinases.     

靶向抑制CDK4/6的肿瘤治疗基础研究与临床应用进展

周期蛋白依赖性激酶4/6(cyclin-dependent kinase 4/6,CDK4/6) 是一类丝氨酸/苏氨酸激酶,通过与细胞周期蛋白D（cyclin D）结合,调节视网膜母细胞瘤蛋白(Rb)的磷酸化状态,Rb磷酸化后与E2F转录因子分离,释放的E2F可以自由激活一系列基因表达,参与DNA复制和细胞分裂,从而介导细胞G1/S期转换,影响细胞周期的进程。近年研究发现CDK4/6在多种肿瘤发生和发展过程中起着核心作用,已成为临床多种肿瘤治疗的重要分子靶点。本文将对CDK4/6与肿瘤的关系以及CDK4/6抑制剂临床应用的最新研究进展做一综述。     

Betel Nut Arecoline Induces Different Phases of Growth Arrest between Normal and Cancerous Prostate Cells through the Reactive Oxygen Species Pathway

Prostate cancer (PCa) is a reproductive system cancer in elderly men. We investigated the effects of betel nut arecoline on the growth of normal and cancerous prostate cells. Normal RWPE-1 prostate epithelial cells, androgen-independent PC-3 PCa cells, and androgen-dependent LNCaP PCa cells were used. Arecoline inhibited their growth in dose- and time-dependent manners. Arecoline caused RWPE-1 and PC-3 cell cycle arrest in the G2/M phase and LNCaP cell arrest in the G0/G1 phase. In RWPE-1 cells, arecoline increased the expression of cyclin-dependent kinase (CDK)-1, p21, and cyclins B1 and D3, decreased the expression of CDK2, and had no effects on CDK4 and cyclin D1 expression. In PC-3 cells, arecoline decreased CDK1, CDK2, CDK4, p21, p27, and cyclin D1 and D3 protein expression and increased cyclin B1 protein expression. In LNCaP cells, arecoline decreased CDK2, CDK4, and cyclin D1 expression; increased p21, p27, and cyclin D3 expression; had no effects on CDK1 and cyclin B1 expression. The antioxidant N-acetylcysteine blocked the arecoline-induced increase in reactive oxygen species production, decreased cell viability, altered the cell cycle, and changed the cell cycle regulatory protein levels. Thus, arecoline oxidant exerts differential effects on the cell cycle through modulations of regulatory proteins.     

REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors

We describe a drug-design strategy termed REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) in which nonpeptidic surrogates for specific determinants of known peptide ligands are identified in silico by using a core peptide-bound protein structure as a design anchor. In the REPLACE application example, we present the effective replacement of two critical binding motifs in a lead protein-protein interaction inhibitor pentapeptide with more druglike phenyltriazole and diphenyl ether groups. These were identified through docking of fragment libraries into the volume of the cyclin-binding groove of CDK2/cyclin A vacated through truncation of the inhibitor peptide-binding determinants. Proof of concept for this strategy was obtained through the generation of potent peptide-small-molecule hybrids and by the confirmation of inhibitor-binding modes in X-ray crystal structures. This method therefore allows nonpeptide fragments to be identified without the requirement for a high-sensitivity binding assay and should be generally applicable in replacing amino acids as individual residues or groups in peptide inhibitors to generate pharmaceutically acceptable lead molecules.     

基于改进CPD算法的SPECT-B超甲状腺图像配准

为了获得更多甲状腺肿瘤的诊断信息,文章提出了一种基于改进CPD算法的甲状腺肿瘤的SPECT图像和B超图像自动配准方法。首先,将参考图像(SPECT图像)和待配准图像(B超图像)分别通过阈值分割和图割的方法提取轮廓特征点;然后,用遗传算法和粒子群算法相结合的优化算法对CPD的权重参数进行自动寻优,利用改进的CPD算法对提取出的两组特征点进行匹配,得到两幅图像的空间变换参数;最后,将待配准图像按所求得的变换参数旋转、平移,从而获得配准后图像。实验结果表明,该方法能实现SPECT与B超甲状腺肿瘤图像的良好配准,具有参数少、精度高、鲁棒性好等特点。     

Cyclin d1 expression and the inhibitory effect of celecoxib on ovarian tumor growth in vivo

The report aims to investigate the relationship between the expression of cyclin D1 and Cyclooxgenase-2 (COX-2), thus to explore the molecular mechanisms of the antitumor efficacy of Celecoxib, a COX-2 inhibitor. Human ovarian SKOV-3 carcinoma cell xenograft-bearing mice were treated with Celecoxib by infusing gaster (i.g.) twice/day for 21 days. The mRNA levels of COX-2 and cyclin D1 were determined by RT-PCR. The expression of cyclin D1 at the protein level was detected by immunohistochemistry, while COX-2 protein expression was determined by Western blot. A high-dose of Celecoxib (100 mg/kg) significantly inhibited tumor growth (P < 0.05), and the expression of cyclin D1 was reduced by 61%. Celecoxib decreased the proliferation cell index by 40% (P < 0.001) and increased apoptotic index by 52% (P < 0.05) in high-dose Celecoxib treated group. Our results suggest that the antitumor efficacy of Celecoxib against ovarian cancer in mice may in part be mediated through suppression of cyclin D1, which may contribute to its ability to suppress proliferation.     

IGFs对小鼠乳腺IGFBP-5和cyclin D1表达的影响

运用荧光显微镜技术，采用小鼠乳腺组织培养及免疫荧光组化方法，对IGFs在乳腺发育和乳腺功能调控中的作用进行研究。结果表明：①IGFs能抑制各时期小鼠乳腺中IGFBP-5的表达，并且IGF—Ⅰ对小鼠乳腺中IGFBP-5表达的抑制作用强于IGF—Ⅱ，说明IGFs抑制小鼠乳腺细胞凋亡，延缓小鼠乳腺退化过程；②IGFs能促进各时期小鼠乳腺cyclin D1的表达，并且IGF—Ⅰ对小鼠乳腺cyclin D1表达的促进作用强于IGF—Ⅱ．证明IGFs可促进小鼠乳腺腺泡的发育。     

天然和饱水状态B类角砾岩的力学性质及其对地下厂房稳定性的影响

 从现场勘查、室内试验和数值计算的角度对某厂房出露的B类角砾岩的岩体特性、力学性质与开挖卸荷后围岩稳定性做系统的分析。室内试验结果表明,0～15 MPa围压下B类角砾岩表现典型的弹脆塑性;饱水试样在相对较高围压下加载时,试样的变形趋于均匀化,此时弹性模量不再随围压增大而增大。峰值强度的离散性较大,这是由于试样中方解石含量不同,随方解石含量增大,试样峰值强度增大;饱水状态试样较天然状态内摩擦角小而黏聚力大,体现水对角砾岩黏结强度的提高和内摩擦因数的弱化作用;利用角砾岩区域的三维数值模型计算得到开挖卸荷条件下B类角砾岩区域围岩的基本力学响应。计算结果与现场监测数据吻合较好。经过对B类角砾岩出露区域系统地加强支护,确保了施工期角砾岩区域的稳定性。