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Take your "M" time
No full textBoth entry and exit from mitosis are driven through the fine modulation of Cdk1 activity by several proteins or protein complexes. It is well established that to enter into the M-phase a cell requires Cdk1 to be fully activated in the nucleus by the Cdc25A, B and C phosphatases. Then, at the onset of anaphase Cdk1 activity suddenly drops mainly due to Cyclin B1 degradation, thus allowing exit from M-phase. Recent data demonstrate that high Cdk1 activity is necessary also for proper chromosome segregation, since its premature drop determines acceleration of the progression from prophase to metaphase eventually with incorrect division of the DNA content. A primary role in maintaining high Cdk1 activity during prophase and metaphase is played by Cdc25C phosphatase. During the M-phase, the activity of Cdc25C is regulated by the FEZ1/LZTS1 (LZTS1) tumor suppressor gene, which is able to prevent Cdc25C degradation in mitotic cells. As a consequence, Lzts1 absence in mice results in accelerated mitotic progression, improper chromosome segregation and, eventually, in increased incidence of both spontaneous and carcinogen-induced cancer formation. © 2007 Landes Bioscience
Abstract SY32-01: The new genetics and treatment of CLL
No full textAbstract
Loss of miR-15/16 on chromosome 13q14 is the most common genetic alteration in CLL. Recently, we discovered that miR-15/16 target BCL2, an antiaptoptic gene we discovered and named in 1984. Thus, loss of miR-15/16 leads to overexpression of BCL2 (the driver) and causes sensitivity of CLL cells to the antiBcl2 drug venetoclax that is capable of inducing complete remission of CLL in patients and was approved by the FDA in April 2016. The discovery of the involvement of miR-15/16 in CLL also indicated that alterations in genes not encoding proteins can cause cancer. Before our publication of 2002, the dogma was that alterations in protein coding genes, oncogenes, and suppressor genes, cause cancer. We speculate that by looking at other targets of miR-15/16 we might discover other biomarkers that are overexpressed because of miR-15/16 loss, providing novel opportunities to discover targetable targets. Since it seems likely that among the billions of leukemic cells in patients, there are a few that do not respond to the drug—for example, because of mutations in the Bcl2 pocket binding the drug—it is important to develop other drugs capable of killing CLL cells because they have lost miR-15/16. We propose to define whether loss of miR-15/16 may lead to overexpression of specific surface markers that can be targeted by specific monoclonal antibodies. The availability of these antibodies will allow the killing of the same leukemic cells by using a combination of the antibodies and venetoclax minimizing the possibility of drug resistance. Finally, we will assess the role of a new family of short noncoding RNAs we have discovered, ts-RNAs, in the pathogenesis of CLL.
Citation Format: Carlo M. Croce. The new genetics and treatment of CLL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY32-01. doi:10.1158/1538-7445.AM2017-SY32-01</jats:p
Critical role of the RB-E2F pathway in the generation of pituitary adenomas in transgenic mice overexpressing the HMGA2 gene
No full textThe HMGA2 protein plays a crucial role in the development of malignant and benign tumors through a mechanism still unknown. We have recently developed transgenic mice, which overexpress high levels of HMGA2 in all tissues. The large majority (85%) of female transgenic mice developed pituitary adenomas secreting prolactin (PRL) and growth hormone (GH) by the age of 6 months. This is consistent with our recent results showing amplification and overexpression of the HMGA2 gene in a large set of human prolactinomas. To investigate the mechanism by which HMGA2 is involved in pituitary tumorigenesis, we explored the RB/E2F pathway, both in vitro and in vivo, since RB has been shown to be implicated in pituitary tumorigenesis in animal models through a mechanism that involves the activation of E2F1. In our work, we demonstrate that HMGA2 interacts with RB and inhibits its growth suppressing function. Moreover, we show that the HMGA2 protein displaces HDAC1 from the RB/E2F complex in vitro and from the E2F target promoters in vivo, and enhances E2F1 activity. These findings indicate the existence of a pathway of RB regulation involving HMGA2. To validate the hypothesis that the increased E2F activity may be responsible for the onset of pituitary adenomas in HMGA2 mice, we have crossed HMGA2 mice with E2F1–/– mice. The resulting double mutant mice showed a significant reduction of the pituitary phenotype compared to the HMGA2 mice, indicating the critical role of the HMGA2-mediated enhancement of the E2F1 activity in the onset of these neoplasias
Differentially expressed genes execute zinc-induced apoptosis in precancerous esophageal epithelium of zinc-deficient rats
No full textZinc deficiency (ZD) in rats increases esophageal cell proliferation and the incidence of N-nitrosomethylbenzylamine-induced esophageal tumors. Conversely, zinc replenishment (ZR) rapidly induces apoptosis in esophageal epithelia and reverses cancer development. We investigated gene expression changes in ZR versus ZD esophageal epithelia to identify differentially expressed genes associated with the antitumor effect of ZR. Weanling rats were fed a ZD diet for 6 weeks to establish esophageal cell proliferation or a zinc-sufficient (ZS) diet. Then, 10 ZD rats were treated with zinc gluconate intragastrically and switched to ZS diet; the remaining 10 ZD and ZS animals were treated with saline. All animals were killed 26-28 h later. Using cDNA microarrays, real-time polymerase chain reaction amplification and RNA hybridization techniques, we identified novel differentially expressed genes, including a RNA-binding protein with two RNA recognition motifs and a zinc knuckle (ZD7), and a DNA/RNA helicase with a DEAD box (ZD10) with two splice variants, ZD10a and ZD10b. In situ hybridization detected increased mRNA expression of ZD7, ZD10a and ZD10b in ZR esophageal epithelia, which displayed markedly increased occurrence of apoptotic cells, relative to ZD epithelia. Overexpression of ZD7 in human esophageal cancer cells resulted in induction of apoptosis and activation of caspase-3 and -7, activities that were inhibited by caspase-specific inhibitors. In addition, ZD7 mRNA levels and zinc-induced apoptosis in rat squamous carcinoma cells were reduced by specific small interfering ribonucleic acids. Thus, ZR rapidly induces ZD7 and ZD10 expression, which in turn stimulates apoptosis. These results provide the beginnings of a molecular pathway for zinc-induced apoptosis under conditions that reverse esophageal tumor initiation
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
People
No full textAbstract
Michael A. Caligiuri, MD; Mina J. Bissell, PhD; and Carlo M. Croce, MD, are featured.</jats:p
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