Recent advances with cyclin-dependent kinase inhibitors: therapeutic agents for breast cancer and their role in immuno-oncology

Introduction: Collaborative interactions between several diverse biological processes govern the onset and progression of breast cancer. These processes include alterations in cellular metabolism, anti-tumor immune responses, DNA damage repair, proliferation, anti-apoptotic signals, autophagy, epithelial-mesenchymal transition, components of the non-coding genome or onco-mIRs, cancer stem cells and cellular invasiveness. The last two decades have revealed that each of these processes are also directly regulated by a component of the cell cycle apparatus, cyclin D1.

Area covered: The current review is provided to update recent developments in the clinical application of cyclin/CDK inhibitors to breast cancer with a focus on the anti-tumor immune response.

Expert opinion: The cyclin D1 gene encodes the regulatory subunit of a proline-directed serine-threonine kinase that phosphorylates several substrates. CDKs possess phosphorylation site selectivity, with the phosphate-acceptor residue preceding a proline. Several important proteins are substrates including all three retinoblastoma proteins, NRF1, GCN5, and FOXM1. Over 280 cyclin D3/CDK6 substrates have b\een identified. Given the diversity of substrates for cyclin/CDKs, and the altered thresholds for substrate phosphorylation that occurs during the cell cycle, it is exciting that small molecular inhibitors targeting cyclin D/CDK activity have encouraging results in specific tumors.     

氟苯咪唑CHL培养细胞染色体畸变研究

氟苯咪唑(Fludendazole)由Gelder于1969年合成,直到最近几年才受到各国重视,我国于1983年也合成了该化合物。该药经临床应用疗效显著,抗虫效力高,抗虫谱     

Mitotic and meiotic detection of radiation-induced translocations in mouse stem cell spermatogonia using fluorescencein situ hybridization

The efficiency of two methods of detection of translocations induced in mouse stem cell spermatogonia by X-ray doses of 2, 5 and 7 Gy was compared: classical multivalent analysis at diakinesis-metaphase I of meiosis and observation via fluorescencein situ hybridization analysis of mitotic or meiotic stages. Specific DNA libraries for chromosomes 1, 11 and 13 were used. The results obtained indicate that (a) chromosomes 1, 11 and 13 are more involved in multivalent formation than expected on the basis of DNA content and (b) if the mitotic FISH analysis data are corrected for the observed over-representation, the frequencies of induced translocations are similar to those recorded in the classical multivalent studies, suggesting equal scoring efficiencies in both systems.     

东莨菪碱诱发染色体畸变的剂量效应

东茛菪碱五个剂量(1、2、5、10、20μg/ml作用于12名健康成人外周血淋巴细胞培养液诱发染色体畸变,并设空白对照组(生理盐水)。染色体畸变率分别为3.±0.5,9.6±1.1,11.7±1.1,13.6±2.3,18.0±3.0和17.5±2.0％;细胞畸变率为3.1±0.6,9.2±0.6,10.0±0.8,10.8±1.5,11.6±1.8和12.2±14.％。各剂量组与对照组比较差异高度显著(P<0.01)。方差分析,各剂量组间变异的差异高度显著(P<0.01)。相关系数和回归系数也非常显著(P<0.01)。结果表明,东莨菪碱剂量与染色体畸变率和细胞畸变率有线性关系。     

Chromosomal Rearrangements in Three Infertile Men

Summary:  Three chromosomal rearrangements: a balanced reciprocal translocation, t(14;10) (q22;q13), a Y-autosome translocation, t(Y;16) (q11;p13) and a deleted Y chromosome, Yq- were detected among 100 infertile men. The autosomal translocation, associated with oligozoospermia was found to be familial with various effects on the female carriers and the proband's father. The patients with the chromosome Y abberations were found to be azoospermic and might have lost the genes necessary for normal sperma-togenesis.
Zusammenfassung:  Unter 100 infertilen Männern wurden drei Chromosomenneuan-ordnungen entdeckt: eine balancierte reziproke Translokation, t(14;10) (q22;q13), eine Y-autosome Translokation, t(Y;16) (q11;p13) und eine Deletion des Y-Chromosoms, Yq-. Die autosomale Translokation bei Oligozoospermie zeigte sich familiär mit verschiedenen Auswirkungen bei den weiblichen Überträgern und dem Vater des Probanden. Die Patien-ten mit chromosomalen Y-Aberrational wiesen eine Azoospermie auf und scheinen die zur normalen Spermatogenese notwendigen Gene verloren zu haben.     

Shaping ability of the M4 handpiece and Safety Hedstrom Files in simulated root canals

The aim of this study was to assess the shaping ability of the M4 reciprocating handpiece and Safety Hedstrom files in simulated canals. A total of 40 simulated canals of various angles and positions of curvature were prepared with an M4 handpiece using Safety Hedstrom files oriented with the ground, flattened surface towards the inner aspect of the curve. A standard regimen was adopted throughout. Pre- and post-operative longitudinal images of the canals were taken with a video camera and stored and manipulated in a computer with image analysis software. The presence of canal aberrations and the amount and location of resin material removed as a result of preparation were determined from composite images of superimposed pre- and post-operative views. Preparation time varied significantly (P<0.001) between the canal types; overall, 20° canals were prepared more quickly than 40° canals. Zips and elbows were observed in 16 out of the 40 canals with most (11) being created in 40° specimens. Ledges were found in 19 canals and perforations in only 1. There were no significant differences between canal shapes for these aberrations. Excessive removal of material from the inner aspect of the canal at the curve to create a danger zone was found in 20 canals, but only in those with 40° curves. Significant differences in total canal width between the canal types were seen at the zips (P<0.05), elbows (P<0.05) and danger zones (P<0.001). Transportation at the danger zones varied significantly (P<0.001) between canal types. Under the conditions of this study, the M4 handpiece and Safety Hedstrom files created hour-glass preparations in a substantial proportion of canals. In reality, the Safety Hedstrom file with its one flattened surface was ineffective at reducing removal of material along the inner aspect of canal curves in severely curved specimens and clearly has the potential to create strip perforations in teeth.     

Absent chondrodysplasia punctata in a male with an Xp terminal deletion involving the putative region for CDPX1 locus

This is a follow-up report on a male patient with a 46, Y, r(X) karyotype. Although he had no clinico-radiological features of X-linked recessive chondrodysplasia punctata (CDPX1), molecular studies revealed an Xp terminal deletion involving the putative region for the CDPX1 locus (PABX-DXS31). We suspect that the absence of CDPX1 may be attributable to the nature of the disease and the extreme short stature of the patient (mean – 5.6 S.D.). © 1993 Wiley-Liss, Inc.     

Investigation of aneuploidy induction in mouse oocytes following exposure to vinblastine-sulfate,pyrimethamine, diethylstilbestrol diphosphate,or chloral hydrate

The various causative and mechanistic phenomena associated with aneuploidy induction require considerable investigation to better understand the etiology of chromosome missegregation. We investigated the potential of vinblastine sulfate, pyrimethamine, diethylstilbestrol diphosphate, and chloral hydrate to induce numerical and structural chromosome changes in female mouse germ cells. Superovulated ICR mice were administered the compounds either by intraperitoneal injection or oral gavage, and oocytes were collected and processed for cytogenetic analysis 17 hr later. Vinblastine sulfate, administered i.p., induced a significant increase in the frequency of ovulated Ml oocytes and of hyperploid Mll oocytes compared to controls, but did not increase the frequency of structural aberrations. Pyrimethamine, diethylstilbestrol diphosphate, and chloral hydrate did not increase the frequency of numerical or structural chromosome changes in female mouse germ cells. © 1993 Wiley-Liss, Inc.     

信号核素134Cs诱发体细胞和生殖细胞畸变效应比较研究

对１３４Ｃｓ诱发体细胞和生殖细胞的畸变效应进行了比较研究。方法观察内污染不同放射性活度１３４Ｃｓ时诱发同体骨髓细胞和精原细胞染色体畸变的量效关系，以及同一放射性活度１３４Ｃｓ作用不同时间诱发上述两种细胞的染色体畸变产额。结果研究发现，１３４Ｃｓ内照射诱发的骨髓细胞染色体畸变产额显著高于精原细胞，而其诱发的染色体畸变类型均以染色单体型畸变为主。结论由不同放射性活度１３４Ｃｓ所诱发的染色体畸变产额而言，骨髓细胞要比精原细胞高出１．５～５倍。