Numerous publications have stated that metastases are responsible for 90% of cancer deaths, but data underlying this assertion has been lacking. Our objective was to determine what proportions of ...cancer deaths are caused by metastases. Population‐based data from the Cancer Registry of Norway for the years 2005‐2015 was analyzed. We compared all deaths in the Norwegian population where a cancer diagnosis was registered as cause of death. Deaths caused by cancer, with and without metastases, were analyzed, by sex and tumor group. For solid tumors, 66.7% of cancer deaths were registered with metastases as a contributing cause. Proportions varied substantially between tumor groups. Our data support the idea that the majority of deaths from solid tumors are caused by metastases. Thus, a better understanding of the biology of metastases and identification of druggable targets involved in growth at the metastatic site is a promising strategy to reduce cancer mortality.
In publications on cancer research, a common statement is that 90% of cancer deaths are caused by metastases, data underlying this assertion has been lacking. Using the nation‐wide, population based Norwegian Cancer Registry, we found that two of three of the deaths from solid tumors were registered with metastases as contributing cause of death, with substantial variation between tumor groups.
Over the past half-century, community health workers (CHWs) have been a growing force for extending health care and improving the health of populations. Following their introduction in the 1970s, ...many large-scale CHW programs declined during the 1980s, but CHW programs throughout the world more recently have seen marked growth. Research and evaluations conducted predominantly during the past two decades offer compelling evidence that CHWs are critical for helping health systems achieve their potential, regardless of a country's level of development. In low-income countries, CHWs can make major improvements in health priority areas, including reducing childhood undernutrition, improving maternal and child health, expanding access to family-planning services, and contributing to the control of HIV, malaria, and tuberculosis infections. In many middle-income countries, most notably Brazil, CHWs are key members of the health team and essential for the provision of primary health care and health promotion. In the United States, evidence indicates that CHWs can contribute to reducing the disease burden by participating in the management of hypertension, in the reduction of cardiovascular risk factors, in diabetes control, in the management of HIV infection, and in cancer screening, particularly with hard-to-reach subpopulations. This review highlights the history of CHW programs around the world and their growing importance in achieving health for all.
Bisphosphonates (BP) are a class of calcium-binding drug used to prevent bone resorption in skeletal disorders such as osteoporosis and metastatic bone disease. They act by selectively targeting ...bone-resorbing osteoclasts and can be grouped into two classes depending on their intracellular mechanisms of action. Simple BPs cause osteoclast apoptosis after cytoplasmic conversion into toxic ATP analogues. In contrast, nitrogen-containing BPs potently inhibit FPP synthase, an enzyme of the mevalonate (cholesterol biosynthesis) pathway. This results in production of a toxic metabolite (ApppI) and the loss of long-chain isoprenoid lipids required for protein prenylation, a process necessary for the function of small GTPase proteins essential for the survival and activity of osteoclasts. In this review we provide a state-of-the-art overview of these mechanisms of action and a historical perspective of how they were discovered. Finally, we challenge the long-held dogma that BPs act only in the skeleton and highlight recent studies that reveal insights into hitherto unknown effects on tumour-associated and tissue-resident macrophages.
•Bisphosphonates target the skeleton and are selectively internalised by osteoclasts.•Simple bisphosphonates are metabolised intracellularly to toxic ATP analogues.•N-containing bisphosphonates inhibit the mevalonate pathway and prevent protein prenylation.•New approaches to measure prenylation reveal effects of bisphosphonates outside the skeleton.
Bisphosphonates are currently the most important and effective class of anti-resorptive drugs available, but the exact molecular mechanisms by which they inhibit osteoclast-mediated bone resorption ...have only recently been identified. Due to the targeting of bisphosphonates to bone mineral and the ability of osteoclasts to release bone-bound bisphosphonate, a direct effect on mature osteoclasts appears to be the most important route of action. As a result of recent discoveries concerning their molecular mechanism of action, bisphosphonates can be grouped into two classes. The simple bisphosphonates that closely resemble PPi (such as clodronate, etidronate and tiludronate) can be metabolically incorporated into non-hydrolysable analogues of ATP that accumulate intracellularly in osteoclasts, resulting in induction of osteoclast apoptosis. By contrast, the more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. Loss of bone-resorptive activity and osteoclast apoptosis is due primarily to loss of geranylgeranylated small GTPases. Identification of FPP synthase as the target of nitrogen-containing bisphosphonates has also helped explain the molecular basis for the adverse effects of these agents in the GI tract and on the immune system.
Numerous foods acquire their elastic properties (i.e., snap, mouth-feel, and hardness) from the colloidal fat crystal network comprised primarily of trans- and saturated fats. These hardstock fats ...contribute, along with numerous other factors, to the global epidemics related to metabolic syndrome and cardiovascular disease. A dire need for new technologies capable of structuring unsaturated edible oils, reducing the necessity for trans- and saturated fats, are required. At present, organogels are under-utilized in the food industry but numerous potential organogelators exist including: phytosterols and oryzanols, ceramides, monoglycerides and waxes. When examining these compounds as suitable ingredients for the food industry, they should be food grade, cost effective, have no negative health implications and one should be able to modify their physical properties. This review considers alternatives to colloidal fat crystal networks when structuring unsaturated oils as well as methods to modify their physical properties.
Oxysterols are oxygenated forms of cholesterol generated via autooxidation by free radicals and ROS, or formed enzymically by a variety of enzymes such as those involved in the synthesis of bile ...acids. Although found at very low concentrations in vivo, these metabolites play key roles in health and disease, particularly in development and regulating immune cell responses, by binding to effector proteins such as LXRα, RORγ and Insig and directly or indirectly regulating transcriptional programmes that affect cell metabolism and function. In this review, we summarise the routes by which oxysterols can be generated and subsequently modified to other oxysterol metabolites and highlight their diverse and profound biological functions and opportunities to alter their levels using pharmacological approaches.
LINKED ARTICLES
This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc
The development and deployment of several SARS-CoV-2 vaccines in a little over a year is an unprecedented achievement of modern medicine. The high levels of efficacy against transmission for some of ...these vaccines makes it feasible to use them to suppress SARS-CoV-2 altogether in regions with high vaccine acceptance. However, viral variants with reduced susceptibility to vaccinal and natural immunity threaten the utility of vaccines, particularly in scenarios where a return to pre-pandemic conditions occurs before the suppression of SARS-CoV-2 transmission. In this work we model the situation in the United States in May-June 2021, to demonstrate how pre-existing variants of SARS-CoV-2 may cause a rebound wave of COVID-19 in a matter of months under a certain set of conditions. A high burden of morbidity (and likely mortality) remains possible, even if the vaccines are partially effective against new variants and widely accepted. Our modeling suggests that variants that are already present within the population may be capable of quickly defeating the vaccines as a public health intervention, a serious potential limitation for strategies that emphasize rapid reopening before achieving control of SARS-CoV-2.
The capacity of Homo sapiens for the intergenerational accumulation of complex technologies, practices, and beliefs is central to contemporary accounts of human distinctiveness. However, the actual ...antiquity and evolutionary origins of cumulative culture are not known. Here we propose and exemplify a research program for studying the origins of cumulative culture using archaeological evidence. Our stepwise approach disentangles assessment of the observed fidelity of behavior reproduction from inferences regarding required learning mechanisms (e.g., teaching, imitation) and the explanation of larger-scale patterns of change. It is empirically grounded in technological analysis of artifact assemblages using well-validated experimental models. We demonstrate with a case study using a toolmaking replication experiment to assess evidence of behavior copying across three 2.6 Ma Oldowan sites from Gona, Ethiopia. Results fail to reveal any effects of raw material size, shape, quality, or reduction intensity that could explain the observed details of intersite technological variation in terms of individual learning across different local conditions. This supports the view that relatively detailed copying of toolmaking methods was already a feature of Oldowan technological reproduction at ca. 2.6 Ma. We conclude with a discussion of prospects and implications for further research on the evolution of human cumulative culture.
A comprehensive review of the features driving self-assembly of 12-hydroxystearic acid (12-HSA), a low-molecular-weight gelator, and its applications in drug delivery and as other soft innovative ...materials are presented herein. 12-HSA is obtained via hydrogenation of ricinoleic acid naturally found in high concentrations in castor oil. The ability of 12-HSA to self-assemble is associated with the presence, position, and enantiomeric purity of the hydroxy group along the fatty acid chain. The polarity and position of the hydroxyl group facilitates more interaction possibilities leading to its exceptional self-assembly behavior giving rise to fibers, ribbons, and tubes in a variety of solvents. Upon self-assembly, 12-HSA undergoes crystallization resulting in the formation of high aspect ratio fibrillar structures due to noncovalent, intermolecular interactions forming self-spanning, three-dimensional networks (called self-assembled fibrillar networks) in both aqueous and organic solvents. Herein, emphasis is placed on emerging applications of 12-HSA supramolecular assemblies (i.e. responsive aqueous foams, gelled complex fluids, drug delivery systems, hydrogels, organogels, xerogels, and aerogel). The vast literature is compiled associated with 12-HSA self-assembly exploring supramolecular assemblies based on one ambidextrous gelator capable of assembling in aqueous and nonaqueous solvent.
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•Molecular features that facilitate 12-hydroxystearic acid (12-HSA) as a hydrogelator and organogelator.•Design features of 12-hydroxystearic gels that lead to innovative soft materials.•Production methods of responsive gels and foams using chemical engineering approaches.•12-HSA drug delivery systems in aqueous and organic solvents.•12-HSA formulations obtaining gelled complex fluids.
Abstract
While pest management decisions are made at the farm level, a distinctive characteristic of the pest management of invasive species is its public-good nature. Here, we examine the challenges ...that a vector-disease pathosystem such as Diaphorina citri Kuwayama (Hemiptera: Liviidae)—citrus greening, creates for the adoption of prevention and collective management practices from an economic perspective. Those economic challenges originate from the choices and behavior of individual growers, which can impact not only their own payoff but also the choices, behavior and payoffs of other growers; influencing, for example, the spread of the disease, the vector population dynamics, and the adoption of proposed scientific solutions. While for most people the economics of invasive species is limited to calculating damage or control costs, economics is more than that. Economics can provide insights on the interactions between human behavior and natural processes, enabling a better understanding of the rationale of individual growers’ choices, which are key for the design and implementation of effective public policies to deal with invasive pests and diseases.
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