Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascade Inhibitors: How Mutations Can Result in Therapy Resistance and How to Overcome Resistance

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and premature aging. This review will evaluate more recently described potential uses of MEK, PI3K, Akt and mTOR inhibitors in the proliferation of malignant cells, suppression of CICs, cellular senescence and prevention of aging. Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways play key roles in the regulation of normal and malignant cell growth. Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The audit process : principles, practice and cases, 6th ed./ Gray

xxiii, p.920.: ill.; 25 c

The audit process : principles, practice and cases, 6th ed./ Gray

xxiii, p.920.: ill.; 25 c

Leptomycin B induces apoptosis in cells containing the whole HPV 16 genome

Cervical cancer is a major cause of death in women worldwide and is strongly associated with human papillomavirus (HPV) infection. Integration of HPV is thought to be a key step in malignant progression, and is associated with loss of regulation of the viral E6 and E7 oncogenes. Leptomycin B (LMB), a nuclear export inhibitor, has previously been shown to induce apoptosis in primary keratinocytes transduced with the HPV 16 E7 or E6/E7 genes, but not in normal cells. We show here that LMB can also induce apoptosis in derivatives of the W12 cell line that contain either episomal or integrated HPV 16. Cells transduced with HPV 16 E7 or E6/E7, and the episomal and integrated W12 derivatives showed distinct temporal expression patterns of the apoptotic markers activated caspase-3 and M30. The expression of both markers occurred later in the episomal derivatives than in either transduced cells or W12 derivatives containing integrated HPV. These findings suggest that, although LMB can induce apoptosis in keratinocytes containing episomal or integrated HPV 16, genome status is likely to influence the response of HPV-associated anogenital lesions to LMB treatment.</p

Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes

Human papillomavirus (HPV) infection is strongly associated with the development of anogenital neoplasia, particularly cervical cancer. It has been estimated that 99.7% of all cervical carcinomas are attributable to infection with HPV, and types 16 and 18 account for the vast majority of such cases. Both of these 'high risk' HPV types encode the oncoproteins E6 and E7, which exert multiple effects on many proteins involved in cell-cycle regulation, including p53. The nuclear export protein inhibitor leptomycin B (LMB) has been shown to cause the nuclear sequestration of p53 in cervical carcinoma cells. We demonstrate that LMB induces apoptosis selectively at nanomolar concentrations in primary human keratinocytes (PHKs) expressing HPV oncogenes. Both monolayer and organotypic raft cultures of transduced PHKs were highly susceptible to treatment with LMB. By contrast, although LMB stimulated p53 accumulation in normal PHKs, no significant induction of apoptosis was detected on Western blots or immunostained monolayer/raft cells, or following pulsed exposure to the drug. Furthermore, topical application of mu M concentrations of LMB to mouse skin was non-toxic. These data suggest that the topical application of LMB to HPV-infected intra-epithelial lesions may represent a specific and effective therapeutic strategy against HPV-associated anogenital neoplasia. (c) 2007 Wiley-Liss, Inc.</p