KEAPing tumor cells susceptible to chemotherapy
Lung cancer is the most common cause of cancer-related death worldwide, in part because these tumors often are or become resistant to chemotherapy. A study by Shyam Biswal and colleagues, published in the international open-access journal PLoS Medicine, now shines some light on what causes this resistance.
Cancer cells acquire resistance by making high levels of proteins that destroy chemotherapeutic agents (detoxification enzymes) or pump them out of cells (efflux pumps), and by making antioxidants that protect cells against the oxidative damage caused by some chemotherapy drugs. All of those proteins have normal functions as well; they protect cells from environmental toxins and from oxidants produced by the chemical processes of life.
Their production is regulated by NRF2, a transcription factor (a protein that controls the expression of other proteins) that is in turn controlled by a protein called KEAP1. Biswal and colleagues investigated whether changes in KEAP1 might underlie the drug resistance seen in many lung cancers. The researchers examined the KEAP1 gene in tissue taken from lung tumors and in several lung cancer cell lines and found mutations in KEAP1 in half the cell lines and a fifth of the tumor samples. They also found that about half of the samples had lost one copy of the KEAP1 gene--cells usually have two copies of each gene. Five of the six tumors with KEAP1 mutations had lost the other (functional) copy of KEAP1--geneticists call this biallelic inactivation--leaving them without any functional KEAP1.
As would be expected, the tumor cells had more NRF2 than normal cells and also made more detoxification enzymes, efflux proteins, and antioxidants than normal cells. And Biswal and colleagues showed that lung cancer cells with KEAP1 mutations were more resistant to chemotherapy drugs than normal lung cells.
These results indicate that biallelic inactivation of KEAP1 is a frequent genetic alteration in lung cancer and suggest that the loss of KEAP1 activity is one way that lung tumors can increase their NRF2 activity and develop resistance to chemotherapeutic drugs. If other studies confirm that high NRF2 activity is associated with a poor response to chemotherapy, then the development of NRF2 inhibitors might help to improve treatment outcomes in patients with chemotherapy-resistant tumors.
Citation: Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, et al.(2006) Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med 3(10): e420.
PLEASE ADD THE LINK TO THE PUBLISHED ARTICLE IN ONLINE VERSIONS OF YOUR REPORT: http://dx.doi.org/10.1371/journal.pmed.0030420
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Caption: Immunohistochemical staining of Nrf2 in NSCLC tumor tissue harboring KEAP1 mutation
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Comparing influenza vaccine strategies: shots for those at high risk of catching the flu or those most likely to die if they do?
Most countries target flu vaccination efforts towards the people most at risk of dying from influenza, and to health-care workers who are likely come into contact with flu patients. A new study by Lauren Meyers and colleagues (University of Texas) published in the international open access journal PLoS Medicine now suggests that this might not be the best strategy under all circumstances.
Annual vaccination with vaccines based on the currently circulating viruses controls seasonal flu epidemics; to control a pandemic caused by a new strain against which few people have immunity, vaccines based on the antigenically altered virus would have to be quickly developed and deployed. But what is the best way to reduce the burden of illness (morbidity) and death (mortality) caused by influenza, particularly at the start of a pandemic, when vaccine would be limited? Old people and infants are much less likely to catch and spread influenza than school children, students, and employed adults, so could vaccination of these sections of the population--instead of those most at risk of death--be the best way to contain influenza outbreaks?
The researchers used an analytical method called "contact network epidemiology" to compare two types of vaccination strategies: the currently favored mortality-based strategy, which targets high-risk individuals, and a morbidity-based strategy, which targets those segments of the community in which most influenza cases occur. Using information from Vancouver, British Columbia, Canada, on household size, age distribution, and occupations, and other factors such as school sizes, the researchers built a model population of a quarter of a million interconnected people. They then investigated how different vaccination strategies controlled the spread of influenza in this population.
The optimal strategy depended on the level of viral transmissibility--the likelihood that an infectious person transmits influenza to a susceptible individual with whom he or she has contact. For moderately transmissible flu viruses, a morbidity-based vaccination strategy, in which the people most likely to catch the flu are vaccinated, was more effective at containing seasonal and pandemic outbreaks than a mortality-based strategy, in which the people most likely to die if they caught the flu are vaccinated. For highly transmissible strains, this situation was reversed. The level of transmissibility at which this reversal occurred depended on several factors, including whether vaccination was delayed and how many times influenza was introduced into the community.
Meyers and colleagues tested their models by checking that they could replicate real influenza epidemics and pandemics, but, as with all mathematical models, they included many assumptions about influenza in their calculations, which might need to be adjusted for any new outbreaks. Also, because the contact network used data from Vancouver, their results might not be applicable to other cities, or to nonurban areas. Nevertheless, their findings have important public health implications. When there are reasonable estimates of the viral transmission rate, and it is known how often influenza is being introduced into a community, contact network models could help public health officials choose between morbidity- and mortality-based vaccination strategies.
Citation: Bansal S, Pourbohloul B, Meyers LA (2006) A comparative analysis of influenza vaccination programs. PLoS Med 3(10): e387.
PLEASE ADD THE LINK TO THE PUBLISHED ARTICLE IN ONLINE VERSIONS OF YOUR REPORT: http://dx.doi.org/10.1371/journal.pmed.0030387
PRESS-ONLY PREVIEW OF THE ARTICLE: http://www.plos.org/press/plme-03-10-meyers.pdf
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Assessing groups of genetic variants improves prediction of type 2 diabetes
Looking at groups of genetic changes may help to predict who will get type 2 diabetes according to a study led by scientists from the Peninsula Medical School in Exeter. In the study published in the open access medical journal PLoS Medicine, researchers from four centres in the UK looked at three common genetic variants in three genes that have previously been shown to increase the chance of developing diabetes, and assessed whether the three variants together were likely to be more predictive than any one. In a study of more than 6000 participants (2409 people with diabetes and 3668 healthy controls) they showed that each increase in the number of abnormal gene variants carried increased the chance of having diabetes. Each risk variant increased the risk of developing diabetes by 28% and the risk multiplied with each additional risk variant inherited. This meant people with six abnormal genetic variants had a risk of diabetes over 5 times higher than people who had inherited none.
Type 2 diabetes is becoming increasingly common. Many factors influence a person's chance of getting diabetes and these can be broadly grouped into two categories: environmental and genetic. Environmental risk factors for developing type 2 diabetes in later life are obesity, poor diet and a sedentary lifestyle. The genetic risk of diabetes results from inheriting a number of variants in many different genes. Most of these gene variants are common in the population but each gene variant only mildly increases the risk that a person possessing it will develop the disease.
This analysis suggests that using information on multiple variants, rather than just one, is likely to be more accurate in predicting future risk of diabetes. This could provide a tool to help target members of the population who are at highest risk and hence the most likely to benefit from approaches aimed at preventing diabetes. Precisely how this genetic information should be used alongside the established preventative measure of intensive lifestyle intervention requires further study, but the authors conclude that "This approach may have a role in future preventative measures for common, polygenic diseases."
Citation: Weedon MN, McCarthy MI, Hitman G, Walker M, Groves CJ, et al. (2006) Combining information from common type 2 diabetes risk polymorphisms improves disease prediction. PLoS Med 3(10): e374.
PLEASE ADD THE LINK TO THE PUBLISHED ARTICLE IN ONLINE VERSIONS OF YOUR REPORT: http://dx.doi.org/10.1371/journal.pmed.0030374
PRESS-ONLY PREVIEW OF THE ARTICLE: http://www.plos.org/press/plme-03-10-weedon.pdf
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THE FOLLOWING RESEARCH ARTICLE WILL ALSO BE PUBLISHED ONLINE
Tuberculosis Recurrence and Mortality after Successful Treatment: Impact of Drug Resistance
A study of tuberculosis treatment in Uzbekistan found there were high rates of disease recurrence among patients whose treatment had initially been successful. Uzbekistan has long had a major TB problem and, as recommended by the World Health Organization, it introduced the DOTS (directly observed treatment short-course) form of treatment beginning in 1998. An international team of researchers followed the condition of some 200 patients with TB over a period of several months. The death rate was high, with 15% of patients dying per year. While 74% of new cases were "successfully" treated, 34% of these patients were subsequently rediagnosed with TB. Many cases of drug-resistant forms of TB were found. The researchers concluded that, where TB is common and many cases are drug resistant, DOTS treatment alone will not be sufficient to control the spread of the disease.
Citation: Cox H, Kebede Y, Allamuratova S, Ismailov G, Davletmuratova Z, et al. (2006) Tuberculosis recurrence and mortality after successful treatment: Impact of drug resistance. PLoS Med 3(10): e384. DOI: 10.1371/journal.pmed.0030384.
PLEASE ADD THE LINK TO THE PUBLISHED ARTICLE IN ONLINE VERSIONS OF YOUR REPORT: http://dx.doi.org/10.1371/journal.pmed.0030384
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Unhealthy myths about the HIV epidemic in Asia
A group of health experts who have worked with HIV/AIDS programs in Asia say that they are "concerned about a number of misinformed beliefs, or myths, about the epidemic--myths that are widely circulating in Asia."
Writing in the open access health journal PLoS Medicine, Peter Godwin (National Centre for HIV/AIDS, Dermatology and STD, Phnom Penh, Cambodia) and colleagues set out what they believe to be a number of important myths.
It is a myth, they say, that there is a major risk that the epidemic in many Asian countries will have the same disastrous 'development impact' as in Sub-Saharan Africa.
The authors argue that there are crucial differences in the nature of the epidemics in sub-Saharan Africa and Asia, and these differences make it unlikely that the Asian epidemic will have a major development impact. Instead, they say, "its main impact will rather be in presenting countries in Asia with particularly difficult problems of ensuring effective, equitable services, both for prevention and for care, for a series of generally marginalized populations," such as sex workers and drug users. "Attention to these challenges, rather than the mythical generalised developmental challenges, is urgently required."
Another myth, say Godwin and colleagues, is that most of the most of the progress made in controlling the epidemic in Asia has been made by non-governmental organizations (NGOs) and that the government contribution has been limited, clumsy, and hesitating.
"While NGOs may have a role as innovators, as watchdogs for human rights, and as advocates for more progressive policies on behaviour change," they say," it is the public sector that has the primary responsibility, and capability, for establishing policy, regulation, accountability, strategy and, by and large, the bulk of service delivery. It is thus essential to recognize the importance of public sector institutions, the roles they have to play, and the importance of strengthening them."
Citation: Godwin P, O'Farrell N, Fylkesnes K, Misra S (2006) Five myths about the HIV epidemic in Asia. PLoS Med 3(10): e426.
PLEASE ADD THE LINK TO THE PUBLISHED ARTICLE IN ONLINE VERSIONS OF YOUR REPORT: http://dx.doi.org/10.1371/journal.pmed.0030426
PRESS-ONLY PREVIEW OF THE ARTICLE: http://www.plos.org/press/plme-03-10-godwin.pdf
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About PLoS Medicine
PLoS Medicine is an open access, freely available international medical journal. It publishes original research that enhances our understanding of human health and disease, together with commentary and analysis of important global health issues. For more information, visit http://www.plosmedicine.org
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The Public Library of Science (PLoS) is a non-profit organization of scientists and physicians committed to making the world's scientific and medical literature a freely available public resource. For more information, visit http://www.plos.org
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