Survivin study: What is the next wave?

Survivin, a novel member of inhibitor of apoptosis (IAP) protein family, is aberrantly expressed in cancer but undetectable in normal, differentiated adult tissues. Current studies suggest that survivin is implicated in both control of apoptosis and regulation of cell division. However, due to some inconsistent observations on survivin subcellular localization, there is debate about survivin's function in regulating apoptosis, cell division, or both. This review will discuss concepts, experimental methods, and interesting results that unify the different notions about survivin localization and function or point out gaps of knowledge about controversial issues. The author also intends to review various aspects of survivin studies, which were not emphasized or sufficiently discussed in previous reviews on survivin, and update recent developments that may reveal new applications of disease-oriented therapeutics in the coming years.     

Tumour vasculature: Friend or foe of oncolytic viruses?

In the past two decades there have been substantial advances in understanding the anti-cancer mechanisms of oncolytic viruses (OVs). OVs can mediate their effects directly, by preferentially infecting and killing tumour cells. Additionally, OVs can indirectly generate anti-tumour immune responses. These differing mechanisms have led to a paradoxical divergence in strategies employed to further increase the potency of oncolytic virotherapies. On one hand, the tumour neovasculature is seen as a vital lifeline to the survival of the tumour, leading some to use OVs to target the tumour vasculature in hopes to starve cancers. Therapeutics causing vascular collapse can potentiate tumour hypoxia, nutrient restriction and pro-inflammatory cytokine release, which has shown promise in oncological studies. On the other hand, the same vasculature plays an important role for the dissemination of OVs, trafficking of effector cells and other therapeutics, which has prompted researchers to find ways of normalizing the vasculature to enhance infiltration of leukocytes and delivery of therapeutic agents. This article describes the recent developments of therapies aimed to shut down versus normalize tumour vasculature in order to inform researchers striving to optimize OV-based therapies.     

Nitrosylation: the next phosphorylation?

Vitamin D3 plays an important role in the regulation of mineral homeostasis, cell differentiation, and proliferation. However, the exact role of vitamin D3 in vascular smooth muscle cells remains unclear. In the present study, we investigated whether vitamin D3 induces vascular endothelial growth factor (VEGF) release in aortic smooth muscle A10 cells. 1,25-Dihydroxyvitamin D3 (1,25(OH)2VD3), an active form of vitamin D3, stimulated the VEGF release while 24,25-dihydroxyvitamin D3 (24,25(OH)2VD3), an inactive form of vitamin D3, had little effect on the release. The stimulatory effect of 1,25(OH)2VD3 was dose dependent in the range between 10 pM and 10 nM. 1,25(OH)2VD3 induced the phosphorylation of p38 mitogen-activated protein (MAP) kinase but 24,25(OH)2VD3 did not. PD169316 and SB203580, specific inhibitors of p38 MAP kinase, significantly reduced the 1,25(OH)2VD3-stimulated release of VEGF. On the contrary, SB202474, a negative control for p38 MAP kinase inhibitor, had little effect on the VEGF release. PD169316 attenuated the 1,25(OH)2VD3-induced phosphorylation of p38 MAP kinase. These results strongly suggest that 1,25(OH)2VD3 stimulates the release of VEGF in aortic smooth muscle cells via p38 MAP kinase activation.     

ROS signaling: the new wave?

Reactive oxygen species (ROS) play a multitude of signaling roles in different organisms from bacteria to mammalian cells. They were initially thought to be toxic byproducts of aerobic metabolism, but have now been acknowledged as central players in the complex signaling network of cells. In this review, we will attempt to address several key questions related to the use of ROS as signaling molecules in cells, including the dynamics and specificity of ROS signaling, networking of ROS with other signaling pathways, ROS signaling within and across different cells, ROS waves and the evolution of the ROS gene network.     

RNA nanomedicines: the next generation drugs?

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Antibacterial monoclonal antibodies: the next generation?

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Pseudonormalisation of the T wave: old wine?

A 74-year-old woman with documented coronary artery disease presented with symptoms of angina at rest. During these episodes of angina, the initial abnormal terminal negative T waves converted to normal positive T waves. In this article the significance of pseudonormalisation as a sign of ischaemia is reviewed. The underlying electropathological basis of this phenomenon is discussed as well. (Neth Heart J 2007;15:257-9.)     

Two pacing spikes on the T wave in a single-chamber pacemaker: What is the mechanism?

We report a case of a 54-year-old female, known symptomatic sick sinus syndrome, who had undergone a single-chamber pacemaker (VVI, St. Jude Medical, VERITY ADxXL SC SN 2413520) implantation in 2011. Electrocardiography (ECG) performed on a recent visit to the pacemaker clinic showed intermittent double pacing spikes on top of the T wave (Fig. 1A). What is the mechanism?     

Characterization of H9 subtype influenza viruses from the ducks of southern China: a candidate for the next influenza pandemic in humans?

A current view of the emergence of pandemic influenza viruses envisages a gene flow from the aquatic avian reservoir to humans via reassortment in pigs, the hypothetical "mixing vessel." Understanding arising from recent H5N1 influenza outbreaks in Hong Kong since 1997 and the isolation of avian H9N2 virus from humans raises alternative options for the emergence of a new pandemic virus. Here we report that H9N2 influenza viruses established in terrestrial poultry in southern China are transmitted back to domestic ducks, in which the viruses generate multiple reassortants. These novel H9N2 viruses are double or even triple reassortants that have amino acid signatures in their hemagglutinin, indicating their potential to directly infect humans. Some of them contain gene segments that are closely related to those of A/Hong Kong/156/97 (H5N1/97, H5N1) or A/Quail/Hong Kong/G1/97 (G1-like, H9N2). More importantly, some of their internal genes are closely related to those of novel H5N1 viruses isolated during the outbreak in Hong Kong in 2001. This study reveals a two-way transmission of influenza virus between terrestrial and aquatic birds that facilitates the generation of novel reassortant H9N2 influenza viruses. Such reassortants may directly or indirectly play a role in the emergence of the next pandemic virus.     

RhoGAP: the next big thing for small mice?

The size of an organism is determined by the number and size of its constituent cells. The insulin/IGF-1 signaling systems have been long recognized to play a critical role in the determination of body size. Now the generation of mice deficient for a RhoGAP suggests that this small G protein might also regulate the growth of animals.     

Survivin study: An update of “What is the next wave?”

Studies on survivin over the past 2-3 years have shown that survivin possesses multiple subcellular localizations and is a multifunctional molecule involved in many aspects of cellular processes and/or behaviors. The subcellular localization and function of the survivin splice variants, however, have not yet been well elucidated. We have, therefore, provided additional observations on several survivin splice variants for further exploration. This review article will update the role of survivin, and its splice variants in the mitosis/cell cycle, apoptosis, tumorigenesis, chemoprevention, drug/radiation resistance, and cancer therapeutics.     

Eradicating multiple invasive species on inhabited islands: the next big step in island restoration?

Invasive species are the greatest threat to island ecosystems, which harbour nearly half the world’s endangered biodiversity. However, eradication is more feasible on islands than on continents. We present a global analysis of 1,224 successful eradications of invasive plants and animals on 808 islands. Most involve single vertebrate species on uninhabited islands, but plant and invertebrate eradications occur more often on inhabited islands. Inhabited islands are often highly modified and support numerous introduced species. Consequently, targeting a single invasive species can be ineffective or counterproductive. The impacts of other pests will continue and, in some cases, be exacerbated. The presence of people also creates regulatory, logistical and socio-political constraints. Real or perceived health risks to inhabitants, pets and livestock may restrict the use of some eradication tools, and communities or individuals sometimes oppose eradication. Despite such challenges, managing invasive species is vital to conserve and restore the unique biodiversity of many inhabited islands, and to maintain or improve the welfare and livelihoods of island residents. We present a brief case study of the Juan Fernández Archipelago, Chile, and discuss the feasibility of eradicating large suites of invasive plants and animals from inhabited islands while managing other invaders for which eradication is not feasible or desirable. Eradications must be planned to account for species interactions. Monitoring and contingency plans must detect and address any ‘surprise effects’. Above all, it is important that the local community derives social, cultural and/or economic benefits, and that people support and are engaged in the restoration effort.     

HIV and Mature Dendritic Cells: Trojan Exosomes Riding the Trojan Horse?

Exosomes are secreted cellular vesicles that can induce specific CD4⁺ T cell responses in vivo when they interact with competent antigen-presenting cells like mature dendritic cells (mDCs). The Trojan exosome hypothesis proposes that retroviruses can take advantage of the cell-encoded intercellular vesicle traffic and exosome exchange pathway, moving between cells in the absence of fusion events in search of adequate target cells. Here, we discuss recent data supporting this hypothesis, which further explains how DCs can capture and internalize retroviruses like HIV-1 in the absence of fusion events, leading to the productive infection of interacting CD4⁺ T cells and contributing to viral spread through a mechanism known as trans-infection. We suggest that HIV-1 can exploit an exosome antigen-dissemination pathway intrinsic to mDCs, allowing viral internalization and final trans-infection of CD4⁺ T cells. In contrast to previous reports that focus on the ability of immature DCs to capture HIV in the mucosa, this review emphasizes the outstanding role that mature DCs could have promoting trans-infection in the lymph node, underscoring a new potential viral dissemination pathway.