The calcium signal is a powerful and multifaceted tool by which cells can achieve specific outcomes. Cellular machinery important in tumour progression is often driven or influenced by changes in ...calcium ions; in some cases this regulation occurs within spatially defined regions. Over the past decade there has been a deeper understanding of how calcium signalling is remodelled in some cancers and the consequences of calcium signalling on key events such as proliferation, invasion and sensitivity to cell death. Specific calcium signalling pathways have also now been identified as playing important roles in the establishment and maintenance of multidrug resistance and the tumour microenvironment.
The increasing number of approved nucleic acid therapeutics demonstrates the potential to treat diseases by targeting their genetic blueprints in vivo. Conventional treatments generally induce ...therapeutic effects that are transient because they target proteins rather than underlying causes. In contrast, nucleic acid therapeutics can achieve long-lasting or even curative effects via gene inhibition, addition, replacement or editing. Their clinical translation, however, depends on delivery technologies that improve stability, facilitate internalization and increase target affinity. Here, we review four platform technologies that have enabled the clinical translation of nucleic acid therapeutics: antisense oligonucleotides, ligand-modified small interfering RNA conjugates, lipid nanoparticles and adeno-associated virus vectors. For each platform, we discuss the current state-of-the-art clinical approaches, explain the rationale behind its development, highlight technological aspects that facilitated clinical translation and provide an example of a clinically relevant genetic drug. In addition, we discuss how these technologies enable the development of cutting-edge genetic drugs, such as tissue-specific nucleic acid bioconjugates, messenger RNA and gene-editing therapeutics.
To investigate the equity and policy implications of different methods to calculate catastrophic health spending.
We used routinely collected data from recent household budget surveys in 14 European ...countries. We calculated the incidence of catastrophic health spending and its distribution across consumption quintiles using four methods. We compared the budget share method, which is used to monitor universal health coverage (UHC) in the sustainable development goals (SDGs), with three other well-established methods: actual food spending; partial normative food spending; and normative spending on food, housing and utilities.
Country estimates of the incidence of catastrophic health spending were generally similar using the normative spending on food, housing and utilities method and the budget share method at the 10% threshold of a household's ability to pay. The former method found that catastrophic spending was concentrated in the poorest quintile in all countries, whereas with the budget share method catastrophic spending was largely experienced by richer households. This is because the threshold for catastrophic health spending in the budget share method is the same for all households, while the other methods generated effective thresholds that varied across households. The normative spending on food, housing and utilities method was the only one that produced an effective threshold that rose smoothly with total household expenditure.
The budget share method used in the SDGs overestimates financial hardship among rich households and underestimates hardship among poor households. This raises concerns about the ability of the SDG process to generate appropriate guidance for policy on UHC.
Increases in intracellular free Ca2+ play a major role in many cellular processes. The deregulation of Ca2+ signaling is a feature of a variety of diseases, and modulators of Ca2+ signaling are used ...to treat conditions as diverse as hypertension to pain. The Ca2+ signal also plays a role in processes important in cancer, such as proliferation and migration. Many studies in cancer have identified alterations in the expression of proteins involved in the movement of Ca2+ across the plasma membrane and subcellular organelles. In some cases, these Ca2+ channels or pumps are potential therapeutic targets for specific cancer subtypes or correlate with prognosis.
Natural disasters disrupt the nature of work, promoting an urgent review of where work is performed. Home‐based telework (HbTW), a common form of telework, is increasingly promoted as a means to ...ensure continuity of operations in an emergency situation. While widely advocated, little is known of the challenges and outcomes of HbTW when employed in disaster situations. This article explores the organisational and employee experiences of HbTW in the aftermath of a disaster, drawing on data from over 240 public sector workers and their managers who worked from home following a series of earthquakes in Christchurch, New Zealand. Findings point to critical factors shaping the experiences and outcomes of HbTW in disaster situations. Significant variation in the experiences and perceptions of HbTW for team leaders highlights their pivotal role and heightened pressures to maintain control in complex disaster situations.
The B7 family represents one of the best-studied subgroups within the Ig superfamily, yet new interactions continue to be discovered. However, this binding promiscuity represents a major challenge ...for defining the biological contribution of each specific interaction. We developed a strategy for addressing these challenges by combining cell microarray and high-throughput FACS methods to screen for promiscuous binding events, map binding interfaces, and generate functionally selective reagents. Applying this approach to the interactions of mPD-L1 with its receptor mPD-1 and its ligand mB7-1, we identified the binding interface of mB7-1 on mPD-L1 and as a result generated mPD-L1 mutants with binding selectivity for mB7-1 or mPD-1. Next, using a panel of mB7-1 mutants, we mapped the binding sites of mCTLA-4, mCD28 and mPD-L1. Surprisingly, the mPD-L1 binding site mapped to the dimer interface surface of mB7-1, placing it distal from the CTLA-4/CD28 recognition surface. Using two independent approaches, we demonstrated that mPD-L1 and mB7-1 bind in cis, consistent with recent reports from Chaudhri A et al. and Sugiura D et al. We further provide evidence that while CTLA-4 and CD28 do not directly compete with PD-L1 for binding to B7-1, they can disrupt the cis PD-L1:B7-1 complex by reorganizing B7-1 on the cell surface. These observations offer new functional insights into the regulatory mechanisms associated with this group of B7 family proteins and provide new tools to elucidate their function in vitro and in vivo.
Processes that are important in cancer progression, such as sustained cell growth, invasion to other organs, and resistance to cell death inducers, have a clear overlap with pathways regulated by Ca
...signaling. It is therefore not surprising that proteins important in Ca
signaling, sometimes referred to as the "Ca
signaling toolkit," can contribute to cancer cell proliferation and invasiveness, and the ability of agents to induce cancer cell death. Ca
signaling is also critical in other aspects of cancer progression, including events in the tumor microenvironment and processes involved in the acquisition of resistance to anticancer therapies. This review will consider the role of Ca
signaling in tumor progression and highlight areas in which a better understanding of the interplay between the Ca
-signaling toolkit and tumorigenesis is still required.
Herpes virus entry mediator (HVEM) regulates positive and negative signals for T cell activation through co-signaling pathways. Dysfunction of the HVEM co-signaling network is associated with ...multiple pathologies related to autoimmunity, infectious disease, and cancer, making the associated molecules biologically and therapeutically attractive targets. HVEM interacts with three ligands from two different superfamilies using two different binding interfaces. The engagement with ligands CD160 and B- and T-lymphocyte attenuator (BTLA), members of immunoglobulin superfamily, is associated with inhibitory signals, whereas inflammatory responses are regulated through the interaction with LIGHT from the TNF superfamily. We computationally redesigned the HVEM recognition interfaces using a residue-specific pharmacophore approach, ProtLID, to achieve switchable-binding specificity. In subsequent cell-based binding assays the new interfaces, designed with only single or double mutations, exhibited selective binding to only one or two out of the three cognate ligands.
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•A residue-based pharmacophore approach is used to design specific protein interfaces•Designed point mutations of HVEM introduced six-way selectivity•Cell-based assays confirmed selectivity of mutants
Shrestha et al. use a residue-based pharmacophore as a computational approach to design mutations for the interface of HVEM to make it selective to one or two of its three cognate ligands. In cell assay experiments, 15 of the 25 designed single and double point mutants proved to introduce statistically significant selectivity.
Financial crisis, austerity, and health in Europe Karanikolos, Marina, MSc; Mladovsky, Philipa, MSc; Cylus, Jonathan, MSc ...
The Lancet (British edition),
04/2013, Letnik:
381, Številka:
9874
Journal Article
Recenzirano
The financial crisis in Europe has posed major threats and opportunities to health. We trace the origins of the economic crisis in Europe and the responses of governments, examine the effect on ...health systems, and review the effects of previous economic downturns on health to predict the likely consequences for the present. We then compare our predictions with available evidence for the effects of the crisis on health. Whereas immediate rises in suicides and falls in road traffic deaths were anticipated, other consequences, such as HIV outbreaks, were not, and are better understood as products of state retrenchment. Greece, Spain, and Portugal adopted strict fiscal austerity; their economies continue to recede and strain on their health-care systems is growing. Suicides and outbreaks of infectious diseases are becoming more common in these countries, and budget cuts have restricted access to health care. By contrast, Iceland rejected austerity through a popular vote, and the financial crisis seems to have had few or no discernible effects on health. Although there are many potentially confounding differences between countries, our analysis suggests that, although recessions pose risks to health, the interaction of fiscal austerity with economic shocks and weak social protection is what ultimately seems to escalate health and social crises in Europe. Policy decisions about how to respond to economic crises have pronounced and unintended effects on public health, yet public health voices have remained largely silent during the economic crisis.
One of the hallmarks of the tumour microenvironment is hypoxia resulting from increased oxygen consumption by proliferative cancer cells and altered vasculature. Hypoxic tension initiates various ...cellular signals and can drive epithelial to mesenchymal transition (EMT), a process important in cancer progression. In this study, using the antioxidant N-acetylcysteine (NAC), we show that hypoxia-induced reactive oxygen species (ROS) in MDA-MB-468 breast cancer cells, selectively regulate hypoxia-induced increases in N-cadherin and SERPINE1, two proteins involved in cell adhesion. Treatment of cells with NAC also attenuated hypoxia-mediated activation of EGFR, but did not have any effect on hypoxia-mediated induction of HIF1α. Exogenous hydrogen peroxide phenocopied the effects of hypoxia on N-cadherin and SERPINE1 expression and EGFR activation, suggesting its possible involvement in these hypoxia-mediated events. Reflective of their effect on cell adhesion proteins and EGFR (associated with migratory phenotypes), NAC also reduced cell migration under hypoxic conditions, a crucial event in metastasis. Our findings suggest a selective role for redox signalling in the regulation of specific components of the responses to hypoxia and induction of EMT in breast cancer cells. This study provides new evidence supporting the potential of targeting ROS as a therapeutic strategy for the control of breast cancer metastasis.
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