Transforming growth factor β (TGF-β) is a secreted cytokine that regulates cell proliferation, migration, and the differentiation of a plethora of different cell types. Consistent with these findings, TGF-β plays a key role in controlling embryogenic development, inflammation, and tissue repair, as well as in maintaining adult tissue homeostasis. TGF-β elicits a broad range of context-dependent cellular responses, and consequently, alterations in TGF-β signaling have been implicated in many diseases, including cancer. During the early stages of tumorigenesis, TGF-β acts as a tumor suppressor by inducing cytostasis and the apoptosis of normal and premalignant cells. However, at later stages, when cancer cells have acquired oncogenic mutations and/or have lost tumor suppressor gene function, cells are resistant to TGF-β-induced growth arrest, and TGF-β functions as a tumor promotor by stimulating tumor cells to undergo the so-called epithelial-mesenchymal transition (EMT). The latter leads to metastasis and chemotherapy resistance. TGF-β further supports cancer growth and progression by activating tumor angiogenesis and cancer-associated fibroblasts and enabling the tumor to evade inhibitory immune responses. In this review, we will consider the role of TGF-β signaling in cell cycle arrest, apoptosis, EMT and cancer cell metastasis. In particular, we will highlight recent insights into the multistep and dynamically controlled process of TGF-β-induced EMT and the functions of miRNAs and long noncoding RNAs in this process. Finally, we will discuss how these new mechanistic insights might be exploited to develop novel therapeutic interventions.

Members of the Inhibitor of Apoptosis Protein (IAP) family block activation of the intrinsic cell death machinery by binding to and neutralizing the activity of pro-apoptotic caspases. In Drosophila melanogaster, the pro-apoptotic proteins Reaper (Rpr), Grim and Hid (head involution defective) all induce cell death by antagonizing the anti-apoptotic activity of Drosophila IAP1 (DIAP1), thereby liberating caspases. Here, we show that in vivo, the RING finger of DIAP1 is essential for the regulation of apoptosis induced by Rpr, Hid and Dronc. Furthermore, we show that the RING finger of DIAP1 promotes the ubiquitination of both itself and of Dronc. Disruption of the DIAP1 RING finger does not inhibit its binding to Rpr, Hid or Dronc, but completely abrogates ubiquitination of Dronc. Our data suggest that IAPs suppress apoptosis by binding to and targeting caspases for ubiquitination.

Chemoresistance remains a major complication of cancer treatments. Recent data provide strong evidence that chemoresistance is linked to epithelial-mesenchymal transition (EMT), a latent developmental process, which is re-activated during cancer progression. EMT involves transcriptional reprogramming and is driven by specific EMT transcription factors (EMT-TFs). In this review, we provide support for the idea that EMT-TFs contribute to the development of resistance against cancer therapy and discuss how EMT-TFs might be targeted to advance novel therapeutic approaches to the treatment of cancer.

The evolutionarily conserved Ras/mitogen-activated protein kinase (MAPK) cascade is an integral part of the processes of cell division, differentiation, movement and death. Signals received at the cell surface are relayed into the nucleus, where MAPK phosphorylates and thereby modulates the activities of a subset of transcription factors. Here we report the cloning and characterization of a new component of this signal transduction pathway called Mae (for modulator of the activity of Ets). Mae is a signalling intermediate that directly links the MAPK signalling pathway to its downstream transcription factor targets. Phosphorylation by MAPK of the critical serine residue (Ser 127) of the Drosophila transcription factor Yan depends on Mae, and is mediated by the binding of Yan to Mae through their Pointed domains. This phosphorylation is both necessary and sufficient to abrogate transcriptional repression by Yan. Mae also regulates the activity of the transcriptional activator Pointed-P2 by a similar mechanism. Mae is essential for the normal development and viability of Drosophila, and is required in vivo for normal signalling of the epidermal growth factor receptor. Our study indicates that MAPK signalling specificity may depend on proteins that couple specific substrates to the kinase.

An extensive clinical trial program combined with 5 years' postmarketing experience with valacyclovir provides evidence of favorable safety and efficacy in herpes simplex virus (HSV) management. Valacyclovir enhances acyclovir bioavailability compared with orally administered acyclovir. Long-term use of acyclovir for up to 10 years for HSV suppression is effective and well tolerated. Acyclovir is also approved for use in children, is available in some countries over the counter in cream formulation for herpes labialis, and has been monitored in over 1000 pregnancies. Safety monitoring data from clinical trials of valacyclovir, involving over 3000 immunocompetent and immunocompromised persons receiving long-term therapy for HSV suppression, were analyzed. Safety profiles of valacyclovir (

Continuous nevirapine may be associated with increased toxicity among HIV-1-infected pregnant women with CD4 cell counts greater than 250 cells/microL, as has been observed in non-pregnant women.

To prevent mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission, it is important to identify its determinants. Because HIV-1 RNA levels can be reduced by antiviral therapy, we examined the role of maternal plasma HIV-1 RNA level in mother-to-child transmission. We used quantitative competitive PCR to measure HIV-RNA in 30 infected pregnant women and then followed their infants prospectively; 27% of the women transmitted HIV-1 to their infants and maternal plasma HIV-1 RNA level correlated strikingly with transmission. Eight of the 10 women with the highest HIV-1 RNA levels at delivery (190,400-1,664,100 copies per ml of plasma) transmitted, while none of the 20 women with lower levels (500-155,800 copies per ml) did (P = 0.0002). Statistical analysis of the distribution of HIV-1 RNA loads in these 30 women projected a threshold for mother-to-child transmission in a larger population; the probability of a woman with a viral RNA level of < or = 100,000 copies per ml not transmitting is predicted to be 97%. Examination of serial HIV-1 RNA levels during pregnancy showed that viral load was stable in women who did not initiate or change antiviral therapy. These data identify maternal plasma HIV-1-RNA level as a major determinant of mother-to-child transmission and suggest that quantitation of HIV-1 RNA may predict the risk of transmission.

The U.S. Departmentof Energy recently published an interimdose limit of I rad d"I for controllingthe radiationexposure of native aquatic organisms. A computer program named CRITR, developed previouslyfor calculating radiationdoses to aquatic organismsand their predators,has been updated as an activity of the Hanford Site Surface EnvironmentalSurveillance. Project to facilitatedemonstrationof compliancewith this limit. This report presents the revised models and the updated computer program, CRITR2,-for the assessmentof radiologicaldoses to aquatic organisms and their predators;tables of the required input parametersare also provided. Both internal and external doses to fish, crustacea,mollusks, and algae, as well as organisms that subsist on them, such as muskrats, raccoons, and ducks, may be estimated using CRITR2. Concentrationsof radionuclides in the water to which the organisms are exposed may be entered directly into the user-input file or may be calculatedfrom a source term and standard dilution models developed for the National Council on Radiation Protectionand Measurements.