Infectious agents and cancer
10.29.09 by Sharmila Pejawar-Gaddy
Several cancers have been attributed to infectious agents. It is estimated that approximately 18% of all cancers worldwide are caused by infectious agents. 26% of these are in developing countries and 8% in developed countries. These figures and discrepancies between the developed and developing worlds point to differences in disease prevalence, either due to sanitary conditions or shortage of vaccines. Infectious agents can be classified as indirect or direct carcinogens. Indirect carcinogenic agents are those that cause chronic infection and thus chronic inflammation, which then leads to the advent of cancer. Examples of these include, Helicobacter pylori infection that is the an attributing factor to a majority of stomach/gastric cancers, as well as chronic hepatitis B and C infections that are causally linked to a majority of liver cancers. On the other hand, direct carcinogenic agents are those that can incorporate oncogenes into the cell’s genome. Examples of these are human papillomavirus that causes a majority of cervical cancers, as well as in some cases, penile cancer, vaginal cancer and genital warts; Epstein-Barr virus linked to a majority of Naso-pharengeal carcinomas and human herpes virus-8 linked to Kaposi’s sarcoma. This list grows every day. The good news is this: most of these infections, and thus the advent of several cancers, can be prevented by vaccination.
Adapted from Parkin, DM. 2006. Int J Cancer. 118:3030 and Dr. Douglas Lowy
Related articles
- Parkin, DM. 2006. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 118:3030.
- Campbell, K. 2006. The infectious causes of cancer. Nurs Times. 102(33):28.
- FDA approves Gardasil to prevent genital warts in boys (ctv.ca)
- FDA Approves Merck’s Gardasil for Boys (abcnews.go.com)
Fear the Flu More than the Flu Vaccine
10.20.09 by Daniel Gaddy
I have previously written on this site about the Influenza A(H1N1) virus and the possibility, however unlikely, of this virus becoming a catastrophic pandemic. In my first post, I was concerned that the general public was being driven toward unnecessary panic by a “media firestorm” of negative “swine flu” news coverage. Now, however, I have fears of the exact opposite. It seems that people may not be taking this virus seriously enough! As I said in my first article, we really do not know how deadly this virus will be, and the truth is that there is nothing about this virus, particularly its genome, that suggests it will be a catastrophic killer. However, influenza is always deadly and it needs to be taken seriously.
It seems that these days people are more terrified of vaccines than the diseases they are designed to prevent. This is, at least partially, due to a massive campaign to convince people that vaccines cause autism. However, there has been absolutely no scientific evidence of a vaccine-autism link. None. In relation to influenza vaccines, people are worried about a variety of issues, not the least of which is the speed at which the vaccine was produced and made available. An article in the NY Times last week by Paul Offit, a professor and expert on infectious diseases and vaccines at the University of Pennsylvania, addressed this and several other myths about the H1N1 vaccine.
…Here are some of those myths, and why they’re wrong:
SWINE FLU VACCINE IS UNSAFE The H1N1 virus revealed itself too late for it to be included in this year’s seasonal flu vaccine. But the H1N1-specific vaccine was manufactured in the same way as the regular vaccine: The shot form is made by growing the virus in hen’s eggs, purifying it and then treating it with a chemical that inactivates it. This technology has been used to make influenza vaccines for 60 years, and it has an excellent safety record. The nasal spray form is made by adapting the virus to temperatures below those typically found in the body. This allows it to reproduce in the relatively cool lining of the nose, but not in the lungs where it could cause harm. This technology has been used safely for more than 30 years. FluMist, a seasonal flu vaccine used since 2003, is made the same way.
THE VACCINE IS UNTESTED The H1N1 vaccine has already been given to thousands of volunteers to determine whether it could protect them from the virus and to make sure that it caused no adverse reactions. Only then did the Food and Drug Administration license it.
THE VACCINE CONTAINS A DANGEROUS ADJUVANT Some vaccines, like the hepatitis B and human papillomavirus vaccines, have substances called adjuvants, which are added to enhance the immune response, so that smaller quantities of vaccine can be given. Some people fear that the H1N1 vaccine contains, in particular, squalene, an adjuvant that, while included in other vaccines in Europe and Canada, has never been used in routine vaccines in the United States. But the H1N1 vaccine available in the United States has no adjuvant of any kind.
THE VACCINE HAS A DANGEROUS PRESERVATIVE Thimerosal, a preservative containing ethyl mercury that has been in vaccines since the 1930s, is used to prevent inadvertent bacterial and fungal contamination of multi-dose vials. H1N1 vaccine distributed in multi-dose vials will contain about 25 micrograms of ethyl mercury per dose. The issue of thimerosal received public attention in 1999 when the American Academy of Pediatrics and the United States Public Health Service took the precautionary step of asking that thimerosal be removed from single-dose vials of all vaccines. This was done in such a precipitous and frightening manner that it gave rise to the notion that thimerosal had led to autism or mercury poisoning. It hadn’t.
In fact, subsequent studies found that infants could safely receive eight times as much mercury as is contained in the H1N1 vaccine. But the public’s perception of thimerosal was damaged. This year, enough thimerosal-free vaccine is available to inoculate children under age 6, but that does not mean doses with thimerosal are unsafe.
New myths will inevitably arise as some of the millions of people who are inoculated against H1N1 flu suffer unrelated illnesses. Health officials will keep a close eye out for any real problems. One can only hope that the American public will understand that subsequence isn’t necessarily consequence, and not be scared away from a vaccine that can save lives.
The point of my first article was not to declare that we have nothing to fear from the H1N1 virus. To the contrary, since seasonal influenza kills more than 36,000 people in the United States alone, and between 250,000 and 500,000 people worldwide, if H1N1 is even as severe as seasonal flu, we certainly have something to fear! However, many if not most of these deaths are preventable by vaccination! A safe and effective seasonal flu vaccine is already available for everyone (I have already had my shot!) and the H1N1 vaccine, also proven safe and effective, is currently available for high-risk patients. When it is available to the general public, I will be in line to get mine! Will you?
Related articles
- Op-Ed Contributor: Nothing to Fear but the Flu Itself (NY Times)
- Key Facts About Seasonal Flu Vaccine (CDC)
- H1N1 Flu Vaccination Resources (CDC)
- Bill Maher vs. the Flu Vaccine (NY Times)
- Beck and Limbaugh weigh in on swine flu (Los Angeles Times)
Major breakthrough in stem cell therapeutics
10.11.09 by Atif Towheed
A team of Harvard Stem Cell Institute (HSCI) researchers have produced induced pluripotent (cells which have the capability to regenerate into any organ) stem (iPS) cells from adult cells.
…a patient with Parkinson’s disease might be treated with neurons created from his own cells, theoretically eliminating the need for immunosuppressive drugs, or the possibility of rejection of the transplanted cells. Similarly, patient-specific iPS cells could be used to create muscle for damaged hearts, or other individualized treatments.
http://www.sciencedaily.com/releases/2009/10/091008151715.htm
Measuring the Treatment of Evolution in Science Classes
08.13.09 by Daniel Gaddy
I recently wrote an Introduction to Evolution on this site outlining the basics of evolution and exploring the disconnect between the scientific community and the education system of the United States when it comes to the teaching of evolution. A new study by Louise Mead and Anton Mates, published in Evolution: Education and Outreach has performed a very thorough analysis of the teaching of evolution in science curricula, comparing each of the 50 states and the District of Columbia.
The authors compare their results to results of a similar analysis in 2000, which was referenced in my previous article. Essentially, 9 states (California, Florida, Indiana, Kansas, New Hampshire, New Jersey, New Mexico, Pennsylvania, and South Carolina) and the District of Columbia received grades of A, meaning the treatment of evolution in science classes was particularly good, while 5 states (Alabama, Louisiana, Oklahoma, Texas and West Virginia) received grades of F, meaning treatment of evolution was particularly poor. Kansas, in particular, is cited as a major success story. After several years of battling over standards for teaching evolution and intelligent design, Kansas “standards have improved immensely.”
While several states, including Kansas and Florida, improved their standards, several states, including Hawaii and Texas, actually regressed, often by the incorporation of creationist jargon. Overall conclusions from the study suggest that standards of teaching science in the United States public school system include more about evolution than in 2000. The authors also offer some advice on how to address science education standards in your state:
Get involved. Check to see when your state is next reviewing state standards, and ask your department of education or state educators’ associations how to participate in that process. Take a careful look at the language of your standards; check not only for explicit creationist claims but also for language that permits or encourages teaching material that makes such claims. Do not confine your attention to life science courses; check whether earth and space science courses discuss cosmological and geological evolution and whether human evolution is discussed in social studies or anatomy courses (as is sometimes the case). And make sure that the groundwork for all of these subjects is laid in K-8, rather than introduced for the first time in high school.
The Importance of Animal Research
08.7.09 by Daniel Gaddy
As a biomedical researcher, I firmly believe that the importance of animal research cannot be overstated. As eloquently expressed on the website of the Foundation for Biomedical Research:
Animal research has played a vital role in virtually every major medical advance of the last century – for both human and animal health. From antibiotics to blood transfusions, from dialysis to organ transplantation, from vaccinations to chemotherapy, bypass surgery and joint replacement, practically every present day protocol for the prevention, treatment, cure and control of disease, pain and suffering is based on knowledge attained through animal research.
Physicians and researchers overwhelmingly agree that animal systems provide invaluable and irreplaceable insights into human systems. The essential need for animal research is recognized and supported by medical societies and health agencies around the world.
Unfortunately, not everyone gets this point. Animal rights activists have fought for many years to end the legal and moral use of animals in research, or what they deem animal cruelty. The truth is, treatment of research animals in the United States is far from cruel. In fact, every institution in the United States that conducts animal research must establish an Institutional Animal Care and Use Committee, which oversees the use of animals in research and establishes guidelines that guarantee safe and ethical treatment of research animals.
As for the activists, they do not simply protest and voice their opinions. Animal rights activists are becoming increasingly violent. The video below describes a recent attack against Novartis:
A vacation home belonging to Novartis CEO Daniel Vasella was burned in a suspected arson, a week after his mother’s grave was vandalized by animal rights protesters. The words “Drop HLS Now” were spray painted on the grave, CNBC reports. The protesters want Novartis to sever its ties to Huntingdon Life Sciences, a contract company that does animal testing for drug companies.
When considering animal research, there are a few points that are important to remember. First of all, both humans and animals benefit from animal research. The US Department of Health and Human Services estimates that animal research has helped extend the human lifespan by approximately 23.5 years. Furthermore, those of us who are animal lovers and love our pets will be happy to know that animal research has significantly helped advance veterinary medicine. Again from the FBR website:
Many people believe that research with animals is conducted for the exclusive benefit of humans. In fact, practically all biomedical research with lab animals also advances veterinary medicine and helps companion animals live longer, happier and healthier lives. Dozens of diseases, affecting both humans and animals, are prevented through the administration of vaccines. Many other conditions are successfully treated, in both humans and animals, with antibiotics. From asthma and epilepsy, from high blood pressure to cancer, people and their pets share myriad diseases and therapies. And thanks to animal research, effective new drugs have been designed, sophisticated medical devices have been developed and remarkable surgical procedures have been perfected – for human and veterinary medical care.
For years, there was basically one way to treat sick pets: Put them to sleep. But today they can live happy, long lives. Because animal research has resulted in medical advances for both you and your four-legged family members.
Another thing that is important to remember is that scientists are not crazed villains seeking to destroy animal-kind. Scientists who conduct animal research, including myself, view animal research as a necessary evil. Unfortunately, until better alternatives are found, animal models represent the best methods to study diseases of both human and animal origin.
Luckily, it seems that the majority of people understand this and disapprove of the violent actions of animal rights groups. CNBC currently has a blog post discussing the above-mentioned Novartis attacks. On the site is an unscientific poll asking readers whether they believe animal research is necessary or should be abolished. Currently, 89% of respondents believe animal research is necessary.
This is good news, suggesting that the vast majority of the readers of an economic blog support the ethical use of animals in research. However, one of the primary goals of FundScience is to raise money to support research projects. Since some of these projects will, undoubtedly, require the use of animals, we want to poll our own readers and potential donors. What do you think of animal research? Feel free to leave your thoughts and opinions in the comments. If you support the ethical use of animals in research, please sign the petition here.
[polldaddy poll=1852820]
The Obesity Epidemic
08.2.09 by Daniel Gaddy
The following is from an article in today’s Pittsburgh Post-Gazette describing the obesity epidemic in the United States and the repercussions on our current attempts at health care reform.
This article is very effective at stating the obvious: obesity is a growing problem in this country, and increasingly a problem around much of the developed world, but no one has any ideas of how to adequately address the issues. Just how bad is the problem?
The CDC estimates nearly 40 percent of American adults are considered obese based on their body mass index, a mathematical formula that considers a person’s height and weight. That extra weight frequently leads to additional health problems such as heart disease, diabetes, high blood pressure and pulmonary difficulties.
A RTI study estimates $1,429 a year is added to the nation’s health care costs for each obese patient. The overall cost is about 42 percent more annually for obese people and even higher for obese patients on Medicare. Obesity adds 9.1 percent to the annual cost of health care.
The truth is, far too many parties have too much invested in keeping America unhealthy. From the food industry to the health care industry, big profits are made when we are sick. The food is cheap, but poisoned by mass-production and cheap chemicals like high fructose corn syrup, which induces leptin resistance and leads directly to overeating.
The most expensive form of health care is treatment, while the most effective and inexpensive form is prevention. If the country wants to save money here, more effort needs to be placed on education and the prevention of obesity at an early age. Unfortunately, until fresh, healthy foods are cheaper than the unhealthy crap, far too many of us are going to continue to consume the poisons. If the poisons are all you can afford, at least they fill your belly! One part of the solution is to ban high fructose corn syrup or eliminate government corn subsidies, which would make the cost of high fructose corn syrup more than that of natural sugar. Another option on the table now is to tax soft drinks.
Regardless of the methods employeed, the change will not be overnight. This sickness is now ingrained in our society. Changes will require not only government regulation, but drastic changes to our social and psychological consciousness. Perhaps that is already starting to happen.
Consumer demand led to $46 billion of global sales of organic food and drink products in 2007, with an average annual growth of $5 billion over the last decade. The European Union (EU) accounts for 54 percent of this revenue, and organic products make up 4-6 percent of food sales in some countries. The United States accounts for 43 percent of the global revenue stream, with organic now commanding 3.5 percent of total food and beverage sales, up 1 percent since 2005.
At least it is a move in the right direction. It is up to all of us to keep this momentum going, and reclaim our health from corporations seeking nothing but profit to the detriment of human welfare.
Related articles
- The decline and fall of high-fructose corn syrup. (slate.com)
- Food Companies Fight Soda Tax Proposal Despite Rising Obesity (Video) (takepart.com)
- King Corn – a belated review (bmimedical.blogspot.com)
- Healthy School Food (chefann.com)
- It’s time to declare our food source independence (timesunion.com)
- Rising Obesity Carries Hefty Price Tag (abcnews.go.com)
The Future of Brain Tumor Therapy
06.14.09 by Daniel Gaddy
A little over a year ago, the announcement that Senator Ted Kennedy was diagnosed with a malignant brain tumor brought a lot of attention to brain cancer research. Brain cancers are among the most perplexing types of cancers. Indeed, until now, it was not even known how brain cancers form. It was believed for many years that brain tumor metastasis, or the process whereby cancerous cells move from the location where a tumor has initially grown and spreads to other parts of the body, was the product of “brain-specific homing” of metastatic cancer cells from other areas of the body, followed by direct interactions of the cancer cells with neural tissues. However, recent research from Oxford University, published in the journal PLOS One, demonstrated that metastatic cancer cells in mouse and human tissue utilized “vascular cooption” for seeding brain tumors rather than invading and growing within the neural tissue. What this means is that cancer cells enter blood vessels, where they can then be transported throughout the body. This information is not new. What the Oxford researchers, led by Professor Ruth Muschel, showed is that once in the blood vessels, cancer cells can establish residence and begin to grow along the blood vessel walls. By thus co-opting blood vessels in the brain, tumors can utilize readily available nutrients and oxygen from the blood without having to grow their own blood vessels, which occurs via processes known as neovascularization and angiogenesis.
The normal course of treatment for malignant brain tumors is radiation and chemotherapy. The ability of newly established tumors to utilize existing vasculature may account for the resistance of some brain tumors to many chemotherapy drugs that target neovascularization and angiogenesis. Drug resistance, in part, leads to the poor prognosis for patients with malignant brain tumors. Because existing treatments are largely futile, novel therapies are always being investigated. The research of Dr. Muschel and her colleagues not only identified a novel mechanism of tumor metastasis to the brain, but also identified the integrin family of cellular adhesion proteins as the key molecules that mediate attachment of metastatic cancer cells to blood vessel walls. This discovery could, potentially, lead to novel brain tumor therapies.
Another novel therapy, which I have had the opportunity to work with, is the oncolytic virus, vesicular stomatitis virus (VSV). As a graduate student, I worked with a mutant VSV that had a preference for infecting and killing tumor cells, while sparing normal cells. A primary application for oncolytic VSV is in the treatment of brain tumors, because VSV naturally targets the brain. Many studies have successfully demonstrated the ability of VSV to kill brain cancer cells in vitro and in mouse models. To my knowledge, these studies have not been extended to human clinical trials, but the last I heard they were very close. Similar oncolytic (meaning they “lyse” or kill tumors) viruses have moved into clinical trials, with varying levels of success. Novel therapeutics such as oncolytic viruses, gene and cell therapies and immunotherapies offer the greatest promise for treatment, and potentially even cures, of some of mankind’s deadliest and most debilitating diseases. While these therapeutics are still met with some disdain in the United States (because genetically modified organisms are categorically evil!), other parts of the world are embracing them. These therapies are continuously being shown to be both safer and more effective than traditional therapies. While more research is certainly needed, the potential remains for these therapies to change the face of modern medicine.
Citation: Carbonell WS, Ansorge O, Sibson N, Muschel R (2009) The Vascular Basement Membrane as “Soil” in Brain Metastasis. PLoS ONE 4(6): e5857. doi:10.1371/journal.pone.0005857
New Embryonic Stem Cell Policy
05.15.09 by Daniel Gaddy
New guidelines for the use of embryonic stem cells have been proposed by the National Institutes of Health. Many scientists were excited when President Barack Obama announced on March 9th that restrictions enforced by the Bush administration would be overturned. Under the Bush administration policy, only 21 embryonic stem cell lines that had been established prior to August 2001 qualified for federal funding. The new policy draft was released April 18th and, after much scrutiny from the science community, has been deemed by many scientists to be even more restrictive than the Bush administration policy.
The new policy requires consent forms that specifically mention human embryonic stem cell research, forbid donating eggs for the benefit of a specific person, and contain multiple other stipulations that were generally mentioned on older consent forms, but not specifically defined. The new rules are to be applied retroactively to existing embryonic stem cell lines, and therefore could have a serious impact on existing and proposed research. In fact, the vast majority of the 700+ existing embryonic stem cell lines would be ineligible for federal funding under the new policy.
The NIH has issued a Request for Comment in regards to the proposed “Draft National Institutes of Health Guidelines for Human Stem Cell Research Notice”. Prior to enacting these changes, the NIH must obtain public comment. These comments are taken seriously in determining whether the proposed changes will be enacted.
Stem cell research has been a hotly debated issue and responding to the request for comment is a way for individuals, scientists and lay-persons, to have a say in the discussion. We encourage you to make your voice heard.
The deadline for a response is May 26, 2009. The notice can be found at: http://edocket.access.gpo.gov/2009/E9-9313.htm. You may submit a comment through the following website: http://nihoerextra.nih.gov/stem_cells/add.htm.
Related articles
- Obama’s Stem Cell Guidelines Threaten Research
- Obama Lifts Ban on Stem Cell Research
- Draft of stem cell research guidelines unveiled
Cancer vaccines: a brief introduction
05.8.09 by Sharmila Pejawar-Gaddy
From the time of the first documented vaccine against smallpox by Edward Jenner, developing an effective vaccine to prevent deadly disease caused by existing or newly emerging pathogens has been the goal of many microbiologists and immunologists. With a single exception, that of the rabies vaccine, all vaccines developed previously have been prophylactic, meaning that they are administered in order to prevent the onset of disease. The concept of a vaccine has slowly evolved to currently include a therapeutic vaccine, meant to ameliorate an existing disease state by potentially strengthening an ongoing but not fully effective immune response against a pathogen. Further broadening of the concept of a vaccine has come about with the realization that in addition to eliciting an immune response where there was none, a vaccine could also be designed to change an existing immune response from one type to another. Most recently, vaccines are being considered not only for elicitation of immunity but also potentially for induction of tolerance [1, 2]. This concept has also increased potential targets of vaccines from diseases caused by pathogens to any disease that involves the immune system, such as cancer, autoimmunity and graft rejection. [3-6].
Challenges facing cancer vaccines
Choosing the right antigen and adjuvant are the sine qua non of an effective vaccine.
The “right” antigen: Antigens used in cancer vaccines should preferably be molecules that are different between normal cells and tumor cells ensuring that the immune response generated by vaccination will target for destruction antigen-bearing tumor cells and not normal cells [7, 8]. This requirement is satisfied more easily in the case of vaccines against pathogens because their antigens are all foreign to the host and thus immunity generated against them, in most instances, does not cross-react with normal host tissues. In cancer, most antigens are derived from mutated or modified self-proteins against which there is often a certain level of immune tolerance. This creates particular challenges for the appropriate design of vaccines that have to overcome this tolerance in order to elicit anti-tumor immunity without autoimmunity [9].
The “right” adjuvant: Adjuvants are diverse molecules that can activate antigen presenting cells (APC) to stimulate a potent and robust cellular immune response (T cells). Adjuvants can also activate natural killer cells or other cells of the innate immune system to produce cytokines that can promote survival of antigen-specific T cells [10]. Although at the present time, there are only two adjuvants approved worldwide for clinical use – aluminium-based salts (alum) and a squalene-oil-water emulsion (MF56) – many other molecules, such as cytokines, bacterial products (toll-like receptor (TLR) agonists), heat-shock proteins [11-13], microspheres [14, 15], virus-like particles [16, 17] and immunostimulatory complexes (ISCOMs) are being tested [18].
The “right” immune response: An effective vaccine must be able to generate and sustain a potent immune response that would ensure eradication and prevent recurrence of existing tumors, in the case of a therapeutic vaccine, or in the case of a prophylactic vaccine, prevent de novo tumor formation [19]. Thus the immune response generated must result in long-term memory to provide life-long protection from cancer. It is now clear that the generation of an immune response that can eliminate the tumor depends on the ability of a vaccine to activate both the innate and the adaptive immune system [20]. More importantly, the end result of this activation should be an immune response that is the “right” type for the tumor that is being treated. Different types of immune responses include systemic versus mucosal immunity, T-helper 1 (Th1) versus T-helper 2 (Th2), [21, 22] or primarily antibodies versus primarily cytotoxic T lymphocyte (CTL). Recent realization that every vaccine is capable of simultaneous induction of effector cells as well as regulatory T cells [23](reviewed in [24] has added another requirement, that of preferential induction of effector T cells.
Tumor antigens, candidates for cancer vaccines
Since the pioneering work of Boon and Rosenberg leading to the isolation of the first human melanoma antigens [25-27], work on the discovery of tumor antigens has been pursued by many researchers employing many different methods [28-31].
Tumor antigens can be broadly classified into two categories: shared tumor antigens and unique tumor antigens. Shared tumor antigens are expressed by many tumors and either not on normal tissues or expressed by normal tissue in a quantitatively and qualitatively different form. Examples of such shared tumor antigens are the cancer testes antigens (MAGE, GAGE and NY-ESO1) (reviewed in [32]). Unique tumor antigens, on the other hand, are products of random mutations induced by physical or chemical carcinogens, and therefore expressed uniquely by individual tumors [33]. These include specific mutations in oncogenes, such as p53 and Kras (reviewed in [32]). An interesting variation on this theme are tumor-derived heat shock proteins that are being developed as cancer vaccines [34, 35]. The heat shock proteins themselves are conserved proteins but the tumor peptides bound to them are derived from both shared and unique tumor antigens.
Undefined tumor antigen-based vaccines
A recent report shows that colon and breast cancers contain on an average at least 11 different mutations in proteins involved in a wide range of cellular functions, including transcription, adhesion and invasion [36]. Many of these mutations are candidates for tumor antigens. This supports a long-held notion that one way to expose the immune system to many potential tumor antigens is to immunize with whole tumor cells. This approach mimics many vaccines against infectious diseases that use the whole, attenuated forms of the pathogens. The benefit of such vaccines is that it allows the immune system rather than the vaccinologist to select most immunogenic tumor specific antigens. The danger is that in the presence of adjuvants, tolerance to normal molecules might be broken resulting in autoimmunity.
Bibliography
1. Yates SF, Paterson AM, Nolan KF, Cobbold SP, Saunders NJ, Waldmann H, Fairchild PJ. Induction of regulatory T cells and dominant tolerance by dendritic cells incapable of full activation. J Immunol 2007,179:967-976.
2. Xiao BG, Huang YM, Link H. Dendritic cell vaccine design: strategies for eliciting peripheral tolerance as therapy of autoimmune diseases. BioDrugs 2003,17:103-111.
3. Finn OJ. Cancer vaccines: between the idea and the reality. Nat Rev Immunol 2003,3:630-641.
4. Dranoff G. GM-CSF-based cancer vaccines. Immunol Rev 2002,188:147-154.
5. Bar-Or A, Vollmer T, Antel J, Arnold DL, Bodner CA, Campagnolo D, et al. Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial. Arch Neurol 2007,64:1407-1415.
6. Young JW, Merad M, Hart DN. Dendritic cells in transplantation and immune-based therapies. Biol Blood Marrow Transplant 2007,13:23-32.
7. Parmiani G, De Filippo A, Novellino L, Castelli C. Unique human tumor antigens: immunobiology and use in clinical trials. J Immunol 2007,178:1975-1979.
8. Graziano DF, Finn OJ. Tumor antigens and tumor antigen discovery. Cancer Treat Res 2005,123:89-111.
9. Pardoll DM. Inducing autoimmune disease to treat cancer. Proc Natl Acad Sci U S A 1999,96:5340-5342.
10. McKee AS, Munks MW, Marrack P. How do adjuvants work? Important considerations for new generation adjuvants. Immunity 2007,27:687-690.
11. Roman LD, Wilczynski S, Muderspach LI, Burnett AF, O’Meara A, Brinkman JA, et al. A phase II study of Hsp-7 (SGN-00101) in women with high-grade cervical intraepithelial neoplasia. Gynecol Oncol 2007,106:558-566.
12. Zhang X, Yu C, Zhao J, Fu L, Yi S, Liu S, et al. Vaccination with a DNA vaccine based on human PSCA and HSP70 adjuvant enhances the antigen-specific CD8+ T-cell response and inhibits the PSCA+ tumors growth in mice. J Gene Med 2007,9:715-726.
13. Einstein MH, Kadish AS, Burk RD, Kim MY, Wadler S, Streicher H, et al. Heat shock fusion protein-based immunotherapy for treatment of cervical intraepithelial neoplasia III. Gynecol Oncol 2007,106:453-460.
14. Gupta RK, Singh M, O’Hagan DT. Poly(lactide-co-glycolide) microparticles for the development of single-dose controlled-release vaccines. Adv Drug Deliv Rev 1998,32:225-246.
15. Sapin A, Clavreul A, Garcion E, Benoit JP, Menei P. Evaluation of particulate systems supporting tumor cell fractions in a preventive vaccination against intracranial rat glioma. J Neurosurg 2006,105:745-752.
16. Lo-Man R, Rueda P, Sedlik C, Deriaud E, Casal I, Leclerc C. A recombinant virus-like particle system derived from parvovirus as an efficient antigen carrier to elicit a polarized Th1 immune response without adjuvant. Eur J Immunol 1998,28:1401-1407.
17. Kaufmann AM, Nieland JD, Jochmus I, Baur S, Friese K, Gabelsberger J, et al. Vaccination trial with HPV16 L1E7 chimeric virus-like particles in women suffering from high grade cervical intraepithelial neoplasia (CIN 2/3). Int J Cancer 2007,121:2794-2800.
18. Takahashi H, Takeshita T, Morein B, Putney S, Germain RN, Berzofsky JA. Induction of CD8+ cytotoxic T cells by immunization with purified HIV-1 envelope protein in ISCOMs. Nature 1990,344:873-875.
19. Ryan SO, Gantt KR, Finn OJ. Tumor antigen-based immunotherapy and immunoprevention of cancer. Int Arch Allergy Immunol 2007,142:179-189.
20. Chang CC, Ferrone S. NK cell activating ligands on human malignant cells: molecular and functional defects and potential clinical relevance. Semin Cancer Biol 2006,16:383-392.
21. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989,7:145-173.
22. Tatsumi T, Kierstead LS, Ranieri E, Gesualdo L, Schena FP, Finke JH, et al. Disease-associated bias in T helper type 1 (Th1)/Th2 CD4(+) T cell responses against MAGE-6 in HLA-DRB10401(+) patients with renal cell carcinoma or melanoma. J Exp Med 2002,196:619-628.
23. Conroy H, Marshall NA, Mills KH. TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours. Oncogene 2008,27:168-180.
24. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol 2008,8:59-73.
25. Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Sakaguchi K, Appella E, et al. Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci U S A 1994,91:6458-6462.
26. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 1991,254:1643-1647.
27. Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Rivoltini L, Topalian SL, et al. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci U S A 1994,91:3515-3519.
28. Hunt DF, Henderson RA, Shabanowitz J, Sakaguchi K, Michel H, Sevilir N, et al. Pillars article: Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 1992. 255: 1261-1263. J Immunol 2007,179:2669-2671.
29. Kao H, Marto JA, Hoffmann TK, Shabanowitz J, Finkelstein SD, Whiteside TL, et al. Identification of cyclin B1 as a shared human epithelial tumor-associated antigen recognized by T cells. J Exp Med 2001,194:1313-1323.
30. Kao H, Amoscato AA, Ciborowski P, Finn OJ. A new strategy for tumor antigen discovery based on in vitro priming of naive T cells with dendritic cells. Clin Cancer Res 2001,7:773s-780s.
31. Barnd DL, Lan MS, Metzgar RS, Finn OJ. Specific, major histocompatibility complex-unrestricted recognition of tumor-associated mucins by human cytotoxic T cells. Proc Natl Acad Sci U S A 1989,86:7159-7163.
32. Mocellin S, Mandruzzato S, Bronte V, Lise M, Nitti D. Part I: Vaccines for solid tumours. Lancet Oncol 2004,5:681-689.
33. Srivastava PK, Old LJ. Individually distinct transplantation antigens of chemically induced mouse tumors. Immunol Today 1988,9:78-83.
34. Srivastava PK. Therapeutic cancer vaccines. Curr Opin Immunol 2006,18:201-205.
35. Parmiani G, Testori A, Maio M, Castelli C, Rivoltini L, Pilla L, et al. Heat shock proteins and their use as anticancer vaccines. Clin Cancer Res 2004,10:8142-8146.
36. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, et al. The consensus coding sequences of human breast and colorectal cancers. Science 2006,314:268-274.
Influenza A(H1N1)
05.4.09 by Daniel Gaddy
A media firestorm has been unleashed over the last few weeks regarding the so-called “swine flu.” If you pay attention to CNN or any mainstream media outlet, you are bombarded with dire warnings and panic-inducing reports of swine flu deaths and the resulting mayhem. I want to write this post to put things into perspective. Keep in mind that the news outlets have one thing in mind: ratings. The more fear they can strike into you, the more likely you are to watch. This is not to say that there is no reason to be concerned. As with any influenza outbreak, the more you know, the better prepared you are to handle it. However, the media consistently compare the current outbreak with previous pandemics, particularly the 1918 pandemic. The chances of such a disastrous pandemic are rare. Here, I will explain why that is, as well as provide some insight into this disease and some resources that will help you prepare should you come into contact with anyone infected with influenza.
First of all, the nomenclature “swine flu” is inaccurate. I am not saying this because I have been paid by the pork lobby. The truth is, this virus is part swine, part avian, and part human. This description is, in and of itself, probably confusing for a lay-person. Influenza virus biology is too complicated to get into here in real detail. Basically, influenza virus has a segmented genome. These segments are similar to chromosomes in humans, in that they are nucleic acids (RNA in the case of flu) and each segment codes for a different viral protein. The process of segments from different strains of virus (eg. swine, avian and human) coming together to form a new strain of virus is called re-assortment. This occurs when multiple viruses infect the same cell, and a basic example is illustrated in the figure below. This process occurs frequently, particularly in animals such as pigs and birds, but rarely results in super-virulent strains of influenza.
Influenza viruses are further subdivided based on their surface proteins, hemagglutinin (HA) and neuraminidase (NA). To date, 16 unique HA subtypes (H1-16) and 9 unique NA subtypes (N1-9) have been identified. The virus in the current outbreak has subtypes H1 and N1, leading to the appropriate Influenza A(H1N1) designation.
When thinking about outbreaks of viruses such as influenza, which occur annually, it is important to maintain a level head and not fly into a frenzy, as it seems the mainstream media would like for you to do. When the Vice-President of the United States goes on television and essentially tells people to not go outside and to avoid crowded places, it not only demonstrates his ignorance on the subject, but spreads that ignorance to everyone who listens to his nonsense. This causes undue panic, and makes people think they may die just by getting on a bus, subway or airplane. The truth is, no one really knows how serious this outbreak will be. But to compare it to the 1918 influenza pandemic, largely because they both happen to be H1N1 strains, is ridiculous. By all estimations, the 2009 outbreak is already a pandemic, as cases have been reported around the world. A map of laboratory-confirmed cases is shown in the next figure.
However, a pandemic only means that cases have been reported in various countries around the world. It by no means suggests that this disease is going to be as severe as the 1918 virus. It is estimated that between 70 million and 100 million people died in the 1918 pandemic. So far, only 26 people have died worldwide as a result of this virus, 25 in Mexico and 1 in the United States. Compare these figures to the annual death toll caused by “regular” influenza: in the United States alone, more than 36,000 deaths occur annually as a result of influenza, and between 250,000 and 500,000 deaths occur worldwide. Clearly, the 2009 Influenza A(H1N1) virus has a long way to go to reach either of these statistics.
In my opinion, for what it is worth, it is unlikely that this virus reaches anywhere near the severity of the 1918 pandemic. First of all, the disease reporting is far better today than in 1918. When cases occur practically anywhere in the world, those cases are reported and everyone around the world knows about it quickly. A disease as severe as the 1918 influenza is not going to sneak up on us. This gives us time to prepare. One of the good things that has arisen from the media firestorm is that people are taking the outbreak seriously enough to go to the hospital as soon as symptoms arise. While there is no cure for influenza, early treatment is key to preventing the development of severe complications due to influenza infection. Furthermore, we actually know how to care for patients now, unlike in 1918. A virus would have to be extremely virulent to cause as many deaths as the 1918 flu, and this virus has thus far given no signs of being that virulent.
Finally, there are a number of things everyone can do to reduce your chances of becoming sick and to avoid spreading the infection to others. This may be boring, but it is important. First and foremost, wash your hands! This seems so basic, yet it seems that people must be constantly reminded. If you are in a crowded place, be it a bus, subway, etc, the first thing you should do when you reach your destination is wash your hands. Other people carry a variety of germs, not just influenza, and the primary means of contracting these germs is to touch a contaminated surface, then touch your face. So wash your hands! Secondly, get the annual flu vaccine. It will not protect you from this ongoing Influenza A(H1N1) outbreak, but it typically does a very good job of protecting against the very serious seasonal flu virus that kills over 36,000 people annually in the US.
Symptoms of influenza infection are:
- fever (usually high)
- headache
- extreme tiredness
- dry cough
- sore throat
- runny or stuffy nose
- muscle aches
- Stomach symptoms, such as nausea, vomiting, and diarrhea, also can occur but are more common in children than adults.
If you experience these symptoms, seek medical treatment. If treated early, antiviral therapeutics may help reduce the severity of the disease. After seeking treatment, avoid crowded places so as not to spread the infection to other people. When you cough or sneeze, cover your mouth and nose with your arm, not your hands. If you sneeze in your hands then touch something, other people may come along and touch the same surface, thereby risking transmission of the virus.
The bottom line is, no one knows how severe this outbreak of influenza will be, but influenza is always serious! However, by thinking rationally and following some basic, common sense principles, we can aid in reducing the severity of this outbreak and others.
Related Articles
- NIAID Influenza Fact Sheet
- CDC: Influenza
- CDC: H1N1 Flu
- ASM: Influenza A(H1N1) Resources
- Swine Flu: To Panic Or Not — That Is The Question
- Why the Current Swine Flu Virus Is Not Bioterrorism
- Swine flu: How afraid should we be?
- Assessing the Danger of New Flu
- New virus lacks killer genes of 1918 flu
- W.H.O. Gives Virus a Name That’s More Scientific and Less Loaded
- Virologists Developing More Potent Vaccine Technology That Could Apply To Many Viruses
- Swine Flu Genes Show Virus May Be Weak
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