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Population genetics is the study of the distribution and change in frequency of alleles within populations, and as such it sits firmly within the field of evolutionary biology. The main processes of evolution are natural selection, genetic drift, gene flow, mutation, and genetic recombination and they form an integral part of the theory that underpins population genetics. Studies in this branch of biology examine such phenomena as adaptation, speciation, population subdivision, and population structure.

Population genetics was a vital ingredient in the emergence of the modern evolutionary synthesis. Its primary founders were Sewall Wright, J. B. S. Haldane and Ronald Fisher, who also laid the foundations for the related discipline of quantitative genetics.

Traditionally a highly mathematical discipline, modern population genetics encompasses theoretical, lab and field work. Computational approaches, often utilising coalescent theory, have played a central role since the 1980s.

Population genetics began as a reconciliation of Mendelian inheritance and biostatistics models. A key step was the work of the British biologist and statistician Ronald Fisher. In a series of papers starting in 1918 and culminating in his 1930 book The Genetical Theory of Natural Selection, Fisher showed that the continuous variation measured by the biometricians could be produced by the combined action of many discrete genes, and that natural selection could change allele frequencies in a population, resulting in evolution. In a series of papers beginning in 1924, another British geneticist, J.B.S. Haldane worked out the mathematics of allele frequency change at a single gene locus under a broad range of conditions. Haldane also applied statistical analysis to real-world examples of natural selection, such as the Peppered moth evolution and industrial melanism, and showed that selection coefficients could be larger than Fisher assumed, leading to more rapid adaptive evolution.[1][2]

The American biologist Sewall Wright, who had a background in animal breeding experiments, focused on combinations of interacting genes, and the effects of inbreeding on small, relatively isolated populations that exhibited genetic drift. In 1932, Wright introduced the concept of an adaptive landscape and argued that genetic drift and inbreeding could drive a small, isolated sub-population away from an adaptive peak, allowing natural selection to drive it towards different adaptive peaks.

The work of Fisher, Haldane and Wright founded the discipline of population genetics. This integrated natural selection with Mendelian genetics, which was the critical first step in developing a unified theory of how evolution worked.[1][2]John Maynard Smith was Haldane's pupil, whilst W.D. Hamilton was heavily influenced by the writings of Fisher. The American George R. Price worked with both Hamilton and Maynard Smith. American Richard Lewontin and Japanese Motoo Kimura were heavily influenced by Wright.

The mathematics of population genetics were originally developed as the beginning of the modern evolutionary synthesis. According to Beatty (1986), population genetics defines the core of the modern synthesis. In the first few decades of the 20th century, most field naturalists continued to believe that Lamarckian and orthogenic mechanisms of evolution provided the best explanation for the complexity they observed in the living world. However, as the field of genetics continued to develop, those views became less tenable.[3] During the modern evolutionary synthesis, these ideas were purged, and only evolutionary causes that could be expressed in the mathematical framework of population genetics were retained.[4] Consensus was reached as to which evolutionary factors might influence evolution, but not as to the relative importance of the various factors.[4]

Theodosius Dobzhansky, a postdoctoral worker in T. H. Morgan's lab, had been influenced by the work on genetic diversity by Russian geneticists such as Sergei Chetverikov. He helped to bridge the divide between the foundations of microevolution developed by the population geneticists and the patterns of macroevolution observed by field biologists, with his 1937 book Genetics and the Origin of Species. Dobzhansky examined the genetic diversity of wild populations and showed that, contrary to the assumptions of the population geneticists, these populations had large amounts of genetic diversity, with marked differences between sub-populations. The book also took the highly mathematical work of the population geneticists and put it into a more accessible form. Many more biologists were influenced by population genetics via Dobzhansky than were able to read the highly mathematical works in the original.[5]

Fisher and Wright had some fundamental disagreements about the relative roles of selection and drift.[6]

In Great Britain E.B. Ford, the pioneer of ecological genetics, continued throughout the 1930s and 1940s to demonstrate the power of selection due to ecological factors including the ability to maintain genetic diversity through genetic polymorphisms such as human blood types. Ford's work, in collaboration with Fisher, contributed to a shift in emphasis during the course of the modern synthesis towards natural selection over genetic drift.[1][2][7][8]

Recent studies of eukaryotic transposable elements, and of their impact on speciation, point again to a major role of nonadaptive processes such as mutation and genetic drift.[9] Mutation and genetic drift are also viewed as major factors in the evolution of genome complexity.[10]

Biston betularia f. carbonaria is the black-bodied form of the peppered moth.

Population genetics is the study of the frequency and interaction of alleles and genes in populations.[11] A sexual population is a set of organisms in which any pair of members can breed freely together. This implies that all members belong to the same species and are located near each other.[12]

For example, all of the moths of the same species living in an isolated forest are a population. A gene in this population may have several alternate forms, which account for variations between the phenotypes of the organisms. An example might be a gene for coloration in moths that has two alleles: black and white. A gene pool is the complete set of alleles for a gene in a single population; the allele frequency for an allele is the fraction of the genes in the pool that is composed of that allele (for example, what fraction of moth coloration genes are the black allele). Evolution occurs when there are changes in the frequencies of alleles within a population; for example, the allele for black color in a population of moths becoming more common.

Natural selection, which includes sexual selection, is the fact that some traits make it more likely for an organism to survive and reproduce. Population genetics describes natural selection by defining fitness as a propensity or probability of survival and reproduction in a particular environment. The fitness is normally given by the symbol w=1-s where s is the selection coefficient. Natural selection acts on phenotypes, or the observable characteristics of organisms, but the genetically heritable basis of any phenotype which gives a reproductive advantage will become more common in a population (see allele frequency). In this way, natural selection converts differences in fitness into changes in allele frequency in a population over successive generations.

Before the advent of population genetics, many biologists doubted that small differences in fitness were sufficient to make a large difference to evolution.[5] Population geneticists addressed this concern in part by comparing selection to genetic drift. Selection can overcome genetic drift when s is greater than 1 divided by the effective population size. When this criterion is met, the probability that a new advantageous mutant becomes fixed is approximately equal to 2s.[13][14] The time until fixation of such an allele depends little on genetic drift, and is approximately proportional to log(sN)/s.[15]

Natural selection will only cause evolution if there is enough genetic variation in a population. Before the discovery of Mendelian genetics, one common hypothesis was blending inheritance. But with blending inheritance, genetic variance would be rapidly lost, making evolution by natural or sexual selection implausible. The HardyWeinberg principle provides the solution to how variation is maintained in a population with Mendelian inheritance. According to this principle, the frequencies of alleles (variations in a gene) will remain constant in the absence of selection, mutation, migration and genetic drift.[16] The HardyWeinberg "equilibrium" refers to this stability of allele frequencies over time.

A second component of the HardyWeinberg principle concerns the effects of a single generation of random mating. In this case, the genotype frequencies can be predicted from the allele frequencies. For example, in the simplest case of a single locus with two alleles: the dominant allele is denoted A and the recessive a and their frequencies are denoted by p and q; freq(A)=p; freq(a)=q; p+q=1. If the genotype frequencies are in HardyWeinberg proportions resulting from random mating, then we will have freq(AA)=p2 for the AA homozygotes in the population, freq(aa)=q2 for the aa homozygotes, and freq(Aa)=2pq for the heterozygotes.

Genetic drift is a change in allele frequencies caused by random sampling.[17] That is, the alleles in the offspring are a random sample of those in the parents.[18] Genetic drift may cause gene variants to disappear completely, and thereby reduce genetic variability. In contrast to natural selection, which makes gene variants more common or less common depending on their reproductive success,[19] the changes due to genetic drift are not driven by environmental or adaptive pressures, and may be beneficial, neutral, or detrimental to reproductive success.

The effect of genetic drift is larger for alleles present in few copies than when an allele is present in many copies. Scientists wage vigorous debates over the relative importance of genetic drift compared with natural selection. Ronald Fisher held the view that genetic drift plays at the most a minor role in evolution, and this remained the dominant view for several decades. In 1968 Motoo Kimura rekindled the debate with his neutral theory of molecular evolution which claims that most of the changes in the genetic material are caused by neutral mutations and genetic drift.[20] The role of genetic drift by means of sampling error in evolution has been criticized by John H Gillespie[21] and Will Provine,[22] who argue that selection on linked sites is a more important stochastic force.

The population genetics of genetic drift are described using either branching processes or a diffusion equation describing changes in allele frequency.[23] These approaches are usually applied to the Wright-Fisher and John Moran models of population genetics. Assuming genetic drift is the only evolutionary force acting on an allele, after t generations in many replicated populations, starting with allele frequencies of p and q, the variance in allele frequency across those populations is

Mutation is the ultimate source of genetic variation in the form of new alleles. Mutation can result in several different types of change in DNA sequences; these can either have no effect, alter the product of a gene, or prevent the gene from functioning. Studies in the fly Drosophila melanogaster suggest that if a mutation changes a protein produced by a gene, this will probably be harmful, with about 70 percent of these mutations having damaging effects, and the remainder being either neutral or weakly beneficial.[25]

Mutations can involve large sections of DNA becoming duplicated, usually through genetic recombination.[26] These duplications are a major source of raw material for evolving new genes, with tens to hundreds of genes duplicated in animal genomes every million years.[27] Most genes belong to larger families of homologous shared ancestry.[28] Novel genes are produced by several methods, commonly through the duplication and mutation of an ancestral gene, or by recombining parts of different genes to form new combinations with new functions.[29][30] Here, protein domains act as modules, each with a particular and independent function, that can be mixed together to produce genes encoding new proteins with novel properties.[31] For example, the human eye uses four genes to make structures that sense light: three for the cone cell which produce color vision and one for the rod cell which produces night vision; all four arose from a single ancestral gene.[32] Another advantage of duplicating a gene (or even an entire genome) is that this increases redundancy; this allows one gene in the pair to acquire a new function while the other copy performs the original function.[33][34] Other types of mutation occasionally create new genes from previously noncoding DNA.[35][36]

In addition to being a major source of variation, mutation may also function as a mechanism of evolution when there are different probabilities at the molecular level for different mutations to occur, a process known as mutation bias.[37] If two genotypes, for example one with the nucleotide G and another with the nucleotide A in the same position, have the same fitness, but mutation from G to A happens more often than mutation from A to G, then genotypes with A will tend to evolve.[38] Different insertion vs. deletion mutation biases in different taxa can lead to the evolution of different genome sizes.[39][40] Developmental or mutational biases have also been observed in morphological evolution.[41][42] For example, according to the phenotype-first theory of evolution, mutations can eventually cause the genetic assimilation of traits that were previously induced by the environment.[43][44]

Mutation bias effects are superimposed on other processes. If selection would favor either one out of two mutations, but there is no extra advantage to having both, then the mutation that occurs the most frequently is the one that is most likely to become fixed in a population.[45][46] Mutations leading to the loss of function of a gene are much more common than mutations that produce a new, fully functional gene. Most loss of function mutations are selected against. But when selection is weak, mutation bias towards loss of function can affect evolution.[47] For example, pigments are no longer useful when animals live in the darkness of caves, and tend to be lost.[48] This kind of loss of function can occur because of mutation bias, and/or because the function had a cost, and once the benefit of the function disappeared, natural selection leads to the loss. Loss of sporulation ability in a bacterium during laboratory evolution appears to have been caused by mutation bias, rather than natural selection against the cost of maintaining sporulation ability.[49] When there is no selection for loss of function, the speed at which loss evolves depends more on the mutation rate than it does on the effective population size,[50] indicating that it is driven more by mutation bias than by genetic drift.

Due to the damaging effects that mutations can have on cells, organisms have evolved mechanisms such as DNA repair to remove mutations.[51] Therefore, the optimal mutation rate for a species may be trade-off between costs of a high mutation rate, such as deleterious mutations, and the metabolic costs of maintaining systems to reduce the mutation rate, such as DNA repair enzymes.[52] Viruses that use RNA as their genetic material have rapid mutation rates,[53] which can be an advantage since these viruses will evolve constantly and rapidly, and thus evade the defensive responses of e.g. the human immune system.[54]

Gene flow is the exchange of genes between populations, which are usually of the same species.[55] Examples of gene flow within a species include the migration and then breeding of organisms, or the exchange of pollen. Gene transfer between species includes the formation of hybrid organisms and horizontal gene transfer.

Migration into or out of a population can change allele frequencies, as well as introducing genetic variation into a population. Immigration may add new genetic material to the established gene pool of a population. Conversely, emigration may remove genetic material. Population genetic models can be used to reconstruct the history of gene flow between populations.[56]

As barriers to reproduction between two diverging populations are required for the populations to become new species, gene flow may slow this process by spreading genetic differences between the populations. Gene flow is hindered by mountain ranges, oceans and deserts or even man-made structures such as the Great Wall of China, which has hindered the flow of plant genes.[57]

Depending on how far two species have diverged since their most recent common ancestor, it may still be possible for them to produce offspring, as with horses and donkeys mating to produce mules.[58] Such hybrids are generally infertile, due to the two different sets of chromosomes being unable to pair up during meiosis. In this case, closely related species may regularly interbreed, but hybrids will be selected against and the species will remain distinct. However, viable hybrids are occasionally formed and these new species can either have properties intermediate between their parent species, or possess a totally new phenotype.[59] The importance of hybridization in creating new species of animals is unclear, although cases have been seen in many types of animals,[60] with the gray tree frog being a particularly well-studied example.[61]

Hybridization is, however, an important means of speciation in plants, since polyploidy (having more than two copies of each chromosome) is tolerated in plants more readily than in animals.[62][63] Polyploidy is important in hybrids as it allows reproduction, with the two different sets of chromosomes each being able to pair with an identical partner during meiosis.[64] Polyploids also have more genetic diversity, which allows them to avoid inbreeding depression in small populations.[65]

Because of physical barriers to migration, along with limited tendency for individuals to move or spread (vagility), and tendency to remain or come back to natal place (philopatry), natural populations rarely all interbreed as convenient in theoretical random models (panmixy) (Buston et al., 2007). There is usually a geographic range within which individuals are more closely related to one another than those randomly selected from the general population. This is described as the extent to which a population is genetically structured (Repaci et al., 2007). Genetic structuring can be caused by migration due to historical climate change, species range expansion or current availability of habitat.

Horizontal gene transfer is the transfer of genetic material from one organism to another organism that is not its offspring; this is most common among bacteria.[66] In medicine, this contributes to the spread of antibiotic resistance, as when one bacteria acquires resistance genes it can rapidly transfer them to other species.[67] Horizontal transfer of genes from bacteria to eukaryotes such as the yeast Saccharomyces cerevisiae and the adzuki bean beetle Callosobruchus chinensis may also have occurred.[68][69] An example of larger-scale transfers are the eukaryotic bdelloid rotifers, which appear to have received a range of genes from bacteria, fungi, and plants.[70]Viruses can also carry DNA between organisms, allowing transfer of genes even across biological domains.[71] Large-scale gene transfer has also occurred between the ancestors of eukaryotic cells and prokaryotes, during the acquisition of chloroplasts and mitochondria.[72]

Basic models of population genetics consider only one gene locus at a time. In practice, epistatic and linkage relationships between loci may also be important.

Because of epistasis, the phenotypic effect of an allele at one locus may depend on which alleles are present at many other loci. Selection does not act on a single locus, but on a phenotype that arises through development from a complete genotype.

According to Lewontin (1974), the theoretical task for population genetics is a process in two spaces: a "genotypic space" and a "phenotypic space". The challenge of a complete theory of population genetics is to provide a set of laws that predictably map a population of genotypes (G1) to a phenotype space (P1), where selection takes place, and another set of laws that map the resulting population (P2) back to genotype space (G2) where Mendelian genetics can predict the next generation of genotypes, thus completing the cycle. Even leaving aside for the moment the non-Mendelian aspects of molecular genetics, this is clearly a gargantuan task. Visualizing this transformation schematically:

(adapted from Lewontin 1974, p.12). XD

T1 represents the genetic and epigenetic laws, the aspects of functional biology, or development, that transform a genotype into phenotype. We will refer to this as the "genotype-phenotype map". T2 is the transformation due to natural selection, T3 are epigenetic relations that predict genotypes based on the selected phenotypes and finally T4 the rules of Mendelian genetics.

In practice, there are two bodies of evolutionary theory that exist in parallel, traditional population genetics operating in the genotype space and the biometric theory used in plant and animal breeding, operating in phenotype space. The missing part is the mapping between the genotype and phenotype space. This leads to a "sleight of hand" (as Lewontin terms it) whereby variables in the equations of one domain, are considered parameters or constants, where, in a full-treatment they would be transformed themselves by the evolutionary process and are in reality functions of the state variables in the other domain. The "sleight of hand" is assuming that we know this mapping. Proceeding as if we do understand it is enough to analyze many cases of interest. For example, if the phenotype is almost one-to-one with genotype (sickle-cell disease) or the time-scale is sufficiently short, the "constants" can be treated as such; however, there are many situations where it is inaccurate.

If all genes are in linkage equilibrium, the effect of an allele at one locus can be averaged across the gene pool at other loci. In reality, one allele is frequently found in linkage disequilibrium with genes at other loci, especially with genes located nearby on the same chromosome. Recombination breaks up this linkage disequilibrium too slowly to avoid genetic hitchhiking, where an allele at one locus rises to high frequency because it is linked to an allele under selection at a nearby locus. This is a problem for population genetic models that treat one gene locus at a time. It can, however, be exploited as a method for detecting the action of natural selection via selective sweeps.

In the extreme case of primarily asexual populations, linkage is complete, and different population genetic equations can be derived and solved, which behave quite differently from the sexual case.[73] Most microbes, such as bacteria, are asexual. The population genetics of microorganisms lays the foundations for tracking the origin and evolution of antibiotic resistance and deadly infectious pathogens. Population genetics of microorganisms is also an essential factor for devising strategies for the conservation and better utilization of beneficial microbes (Xu, 2010).

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Population genetics - Wikipedia, the free encyclopedia

Arthritis can arise in many forms and can affect everyone including children and adolescents. While the most commonly known form, osteoarthritis, is a degenerative disease that progresses as we age, many forms of inflammatory arthritis can affect people at any age.

Osteoarthritis, also known as degenerative joint disease (DJD), happens when cartilage is worn down over time, usually from a lifetime of use or as the result of an injury to the joint. As the normally smooth surface of the cartilage is destroyed, exposing the underlying bone, the joint becomes more painful to move and the range of motion may diminish. This type of arthritis usually involves one or more large weight-bearing joints such as a hip or a knee. With this type of arthritis, pain is usually made worse with activity and is better with rest. It is common for symptoms to be at their worst at the end of the day.

This form of arthritis is usually treated with anti-inflammatory medications taken orally as a pill or as an injected form, and can also be relieved with physical therapy, exercise, and proper nutrition. Joint replacement surgery is considered when conservative, non-surgical methods have failed to provide adequate benefit. Hip replacement surgery and knee replacement surgery have become trusted treatments for restoring mobility and easing pain.

Thomas P. Sculco, MDexplains what arthritis is, what causes it, and how it can be avoided, diagnosed, andtreated. This is Part 1 of a series on total hip replacement surgery. The rest of this video series can be found here.

Less frequent but often more serious are the inflammatory forms of arthritis, which include conditions such as rheumatoid arthritis and lupus. These forms usually involve many joints throughout the body at the same time andare caused by a problem with the immune system becoming over-active, resulting in joint inflammation. Arthritis caused by inflammation often results in pain and stiffness after periods of rest or inactivity, particularly in the morning. Swelling, redness and warmth may be present in the affected joints. Other areas in the body can be affected by the inflammation as well, including the skin and internal organs such as the lungs and heart.

Inflammatory arthritis is usually treated with a combination of medications to relieve swelling and pain while regulating the immune system. As with osteoarthritis, joint replacement surgery should also be considered when these non-surgical methods have failed to provide lasting benefit.

When detected and treated early, arthritis can be halted in its tracks. The HSS Inflammatory Arthritis Center connects patients quickly and efficiently with a rheumatologist who can evaluate their joint pain and get each patient started on an appropriate course of treatment. Hospital for Special Surgery also offers specialized patient education and support programs for conditions such as lupus and rheumatoid arthritis.

This webinarpresents an overview of the clinical research process, the phases of a clinical trial, and insight into the importance of medical research in patient care. Presenter: Jessica Gordon, MD, MSc Date Recorded: Thursday, March 14, 2013 Watch Now

To learn more about arthritis, access the articles, audio clips, and video programs in the categories listed below.

see also Osteoarthritis see also Rheumatoid Arthritis

see also Arthritis - Elbow see also Arthritis - Foot & Ankle see also Arthritis - Hand & Wrist see also Arthritis - Hip see also Arthritis - Knee see also Arthritis - Shoulder see also Arthritis - Thumb

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Arthritis Treatment at New York's Hospital for Special ...

Stem cell therapy is a type of cell therapy wherein cells are introduced into the damaged tissue so as to treat the disorder or the injury. There are a number of medical researchers who believes that the stem cell therapy has the potential to change the treatment of human diseases and reduce the suffering people face when they have a disease. They believe that there are a lot of potential to replace the damaged and diseased tissues in the body without getting the risk of rejections.

The stem cells have the ability to self-renew and also give rise to further generation of cells that can multiply. There are a number of stem cell therapies that do exist but most of them are still in the experimental stages. The treatments are very costly with an exception of bone marrow transplant. However, researchers believe that one day they will be able to develop technologies from embryonic stem cells and also adult stem cells to cure type I diabetes, cancer, Parkinsons disease, cardiac failure, neurological disorders and many more such ailments.

The stem cell therapy however carries its own pros and cons and like any other therapy it cannot be said that the stem cell therapy is an advantageous package. Here are some of the pros and cons of the therapy.

Pros of the stem cell therapy include:

It offers a lot of medical benefits in the therapeutic sectors of regenerative medicine and cloning.

It shows great potential in the treatment of a number of conditions like Parkinsons disease, spinal cord injuries, Alzheimers disease, schizophrenia, cancer, diabetes and many others.

It helps the researchers know more about the growth of human cells and their development.

In future, the stem cell research can allow the scientists to test a number of potential medicines and drugs without carrying out any test on animals and humans. The drug can be tested on a population of cells directly.

The stem cell therapy also allows researchers to study the developmental stages that cannot be known directly through the human embryo and can be used in the treatment of a number of birth defects, infertility problems and also pregnancy loss. A higher understanding will allow the treatment of the abnormal development in the human body.

The stem cell therapy puts into use the cells of the patients own body and hence the risk of rejection can be reduced because the cells belong to the same human body.

The cons of the stem cell therapy include the following:

The use of the stem cells for research involves the destruction of the blastocytes that are formed from the laboratory fertilization of the human egg.

The long term side effects of the therapy are still unknown.

The disadvantage of adult stem cells is that the cells of a particular origin would generate cells only of that type, like brain cells would generate only brain cells and so on.

If the cells used in the therapy are embryonic then the disadvantage is that the cells will not be from the same human body and there are chances of rejection.

The stem cell therapy is still under the process of research and there are a number of things that needs to be established before it used as a treatment line.

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Pros and Cons of Stem Cell Therapy - Health Guidance

The immune system also produces proteins called antibodies that can help neutralise infection or the toxins that some germs produce.

Some infections, like influenza and the common cold, have to be fought many times, because so many different viruses can cause these illnesses. Catching a cold from one virus does not give you immunity against the others.

The immunisations you may need are decided by your health, age, lifestyle and occupation. Together, these factors are referred to as HALO.

HALO is defined as:

This page has been produced in consultation with and approved by: Australasian Society of Clinical Immunology and Allergy (ASCIA)

Last updated: March 2015

Content on this website is provided for education and information purposes only. Information about a therapy, service, product or treatment does not imply endorsement and is not intended to replace advice from your doctor or other registered health professional. Content has been prepared for Victorian residents and wider Australian audiences, and was accurate at the time of publication. Readers should note that, over time, currency and completeness of the information may change. All users are urged to always seek advice from a registered health care professional for diagnosis and answers to their medical questions.

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Immune system | Better Health Channel

immunesystem.com is dedicated as an information resource about the immune system.

With stress increasing steadily in our lives, our immune systems can become overwhelmed and unable to cope with so many diseases, staff infections, viruses, and bacteria. This can leads us to using more pharmaceutical products, which can save your life and/or further deteriorate your immune system.

How does one best boost the immune system naturally? What pharmaceuticals are best against which specific diseases?

At the moment, there is an ebola crisis that is threatening Africa. How does we protect ourselves from these oncoming epidemics and outbreaks?

Our goal here is to share information about the immune system and increasing the strength of the organism, and thus staying healthy in the face of an onslaught of pathogens.

An immune system is a synthesis of biological processes within any kind of organism that defends against disease by recognizing and killing pathogens and tumour cells. It detects a wide variety of pathogens, from bacteria to viruses, and distinguishes these pathogens from the organism's own healthy cells and tissues in order to function properly. Identification is not easily done, as pathogens can evolve quickly, producing mutations that avoid the immune system and allow the pathogens to successfully infect their hosts.

Malfunctions of the immune system can cause autoimmune and inflammatory diseases and cancer.[ Deficiency of the immune system occurs when the immune system is lethargic, with the potentional of serious infections spreading throughout the body. Immunodeficiency in humans can occur because of genetic diseases, such as severe combined immunodeficiency, environmentally acquired conditions like HIV/AIDS, or the overuse of certain immunosuppressive medications. Conversely, autoimmunity can be caused from a hyperactive immune system destroying normal tissues as if they were foreign pathogens organisms.

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Immune System

Your immune system is responsible for helping to eliminate invaders (antigens) such as infectious organisms. The key cells in your immune system are lymphocytes known as B cells and T cells, which originate in your bone marrow. After T cells further develop in your thymus, all of your immune system cells gather in your lymph nodes and spleen. Antigens (triangular shapes above) are ingested (1), partially digested (2) and then presented to helper T cells by special cells called macrophages (3). This process activates the helper T cell to release hormones (lymphokines) that help B cells develop (4). These hormones, along with recognition of further antigens (5), change the B cell into an antibody-producing plasma cell (6). The antibodies (Y shapes above) produced can be one of several types (IgG, IgM, IgA, IgE and IgD) (7). The antibody "fits" the antigen much like a lock fits a key. The antigen is thus rendered harmless. The helper T cells also aid in development of cytotoxic T cells (8), which can kill antigens directly; memory T cells are produced (9) so that re-exposure to the same antigen will provide a more rapid and effective response (10).

.

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Your immune system - Mayo Clinic

Scanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor. Source: National Institute of Allergy and Infectious Diseases (NIAID).

The immune systems natural capacity to detect and destroy abnormal cells may prevent the development of many cancers. However, cancer cells are sometimes able to avoid detection and destruction by the immune system. Cancer cells may:

In the past few years, the rapidly advancing field of cancer immunology has produced several new methods of treating cancer, called immunotherapies, that increase the strength of immune responses against tumors. Immunotherapies either stimulate the activities of specific components of the immune system or counteract signals produced by cancer cells that suppress immune responses.

These advances in cancer immunotherapy are the result of long-term investments in basic research on the immune systemresearch that continues today. Additional research is currently under way to:

Why is immunotherapy such a hot area of cancer research today? In this short excerpt from the documentary, Cancer: The Emperor of All Maladies, PBS, Dr. Steven A. Rosenberg of the National Cancer Institutes Center for Cancer Research discusses his work in immunotherapy and its promise for cancer patients.

One immunotherapy approach is to block the ability of certain proteins, called immune checkpoint proteins, to limit the strength and duration of immune responses. These proteins normally keep immune responses in check by preventing overly intense responses that might damage normal cells as well as abnormal cells. But, researchers have learned that tumors can commandeer these proteins and use them to suppress immune responses.

Blocking the activity of immune checkpoint proteins releases the "brakes" on the immune system, increasing its ability to destroy cancer cells. Several immune checkpoint inhibitors have been approved by the Food and Drug Administration (FDA). The first such drug to receive approval, ipilimumab (Yervoy), for the treatment of advanced melanoma, blocks the activity of a checkpoint protein known as CTLA4, which is expressed on the surface of activated immune cells called cytotoxic T lymphocytes. CTLA4 acts as a "switch" to inactivate these T cells, thereby reducing the strength of immune responses; ipilimumab binds to CTLA4 and prevents it from sending its inhibitory signal.

Two other FDA-approved checkpoint inhibitors, nivolumab (Opdivo) and pembrolizumab (Keytruda), work in a similar way, but they target a different checkpoint protein on activated T cells known as PD-1. Nivolumab is approved to treat some patients with advanced melanoma or advanced lung cancer, and pembrolizumab is approved to treat some patients with advanced melanoma.

Researchers have also developed checkpoint inhibitors that disrupt the interaction of PD-1 and proteins on the surface of tumor cells known as PD-L1 and PD-L2. Agents that target other checkpoint proteins are also being developed, and additional research is aimed at understanding why checkpoint inhibitors are effective in some patients but not in others and identifying ways to expand the use of checkpoint inhibitors to other cancer types.

Progress is also being made with an experimental form of immunotherapy called adoptive cell transfer (ACT). In several small clinical trials testing ACT, some patients with very advanced cancerprimarily blood cancershave had their disease completely eradicated. In some cases, these treatment responses have lasted for years.

In one form of ACT, T cells that have infiltrated a patients tumor, called tumor-infiltrating lymphocytes (TILs), are collected from samples of the tumor. TILs that show the greatest recognition of the patient's tumor cells in laboratory tests are selected, and large populations of these cells are grown in the laboratory. The cells are then activated by treatment with immune system signaling proteins called cytokines and infused into the patients bloodstream.

The idea behind this approach is that the TILs have already shown the ability to target tumor cells, but there may not be enough of them within the tumor microenvironment to eradicate the tumor or overcome the immune suppressive signals that are being released there. Introducing massive amounts of activated TILs can help to overcome these barriers and shrink or destroy tumors.

Another form of ACT that is being actively studied is CAR T-cell therapy. In this treatment approach, a patients T cells are collected from the blood and genetically modified to express a protein known as a chimeric antigen receptor, or CAR. Next, the modified cells are grown in the laboratory to produce large populations of the cells, which are then infused into the patient.

CARs are modified forms of a protein called a T-cell receptor, which is expressed on the surface of T cells. These receptors allow the modified T cells to attach to specific proteins on the surface of cancer cells. Once bound to the cancer cells, the modified T cells become activated and attack the cancer cells.

Therapeutic antibodies are antibodies made in the laboratory that are designed to cause the destruction of cancer cells.

One class of therapeutic antibodies, called antibodydrug conjugates (ADCs), has proven to be particularly effective, with several ADCs having been approved by the FDA for the treatment of different cancers.

ADCs are created by chemically linking antibodies, or fragments of antibodies, to a toxic substance. The antibody portion of the ADC allows it to bind to a target molecule that is expressed on the surface of cancer cells. The toxic substance can be a poison, such as a bacterial toxin; a small-molecule drug; or a radioactive compound. Once an ADC binds to a cancer cell, it is taken up by the cell and the toxic substance kills the cell.

The FDA has approved several ADCs for the treatment of patients with cancer, including:

Other therapeutic antibodies do not carry toxic payloads. Some of these antibodies cause cancer cells to commit suicide (apoptosis) when they bind to them. In other cases, antibody binding to cancer cells is recognized by certain immune cells or proteins known collectively as "complement," which are produced by immune cells, and these cells and proteins mediate cancer cell death (via antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity, respectively). Sometimes all three mechanisms of inducing cancer cell death can be involved.

One example of this type of therapeutic antibody is rituximab (Rituxan), which targets a protein on the surface of B lymphocytes called CD20. Rituximab has become a mainstay in the treatment of some B-cell lymphomas and B-cell chronic lymphocytic leukemia. When CD20-expressing cells become coated with rituximab, the drug kills the cells by inducing apoptosis, as well as by antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.

Other therapies combine non-antibody immune system molecules and cancer-killing agents. For example, denileukin diftitox (ONTAK), which is approved for the treatment of cutaneous T-cell lymphoma, consists of the cytokine interleukin-2 (IL-2) attached to a toxin produced by the bacterium Corynebacterium diphtheria, which causes diphtheria. Some leukemia and lymphoma cells express receptors for IL-2 on their surface. Denileukin diftitox uses its IL-2 portion to target these cancer cells and the diphtheria toxin to kill them.

The use of cancer treatment (or therapeutic) vaccines is another approach to immunotherapy. These vaccines are usually made from a patients own tumor cells or from substances produced by tumor cells. They are designed to treat cancers that have already developed by strengthening the bodys natural defenses against the cancer.

In 2010, the FDA approved the first cancer treatment vaccine, sipuleucel-T (Provenge), for use in some men with metastatic prostate cancer. Other therapeutic vaccines are being tested in clinical trials to treat a range of cancers, including brain, breast, and lung cancer.

Yet another type of immunotherapy uses proteins that normally help regulate, or modulate, immune system activity to enhance the bodys immune response against cancer. These proteins include cytokines and certain growth factors. Two types of cytokines are used to treat patients with cancer: interleukins and interferons.

Immune-modulating agents may work through different mechanisms. One type of interferon, for example, enhances a patients immune response to cancer cells by activating certain white blood cells, such as natural killer cells and dendritic cells. Recent advances in understanding how cytokines stimulate immune cells could enable the development of more effective immunotherapies and combinations of these agents.

Immunotherapy research at NCI is done across the institute and spans the continuum from basic scientific research to clinical research applications.

The Center of Excellence in Immunology (CEI) brings together researchers from across NCI and other NIH institutes to foster the discovery, development, and delivery of immunotherapy approaches to prevent and treat cancer and cancer-associated viral diseases.

Go here to see the original:
Immunotherapy: Using the Immune System to Treat Cancer ...

Posted by Mark Crislip on September 25, 2009

My right bicep. Oily, a little sticky, and otherwise completely unlike your immune system.

This post is a wee bit of a cheat in that it is a rewrite of a Quackcast, but I have three lectures and board certification in the near future, so sometimes you have to cook the wolf.

What does that mean: boost the immune system? Most people apparently think that the immune system is like a muscle, and by working it, giving it supplements and vitamins, the immune system will become stronger. Bigger. More impressive, bulging like Mr. Universes bicep. Thats the body part I am thinking about. What they are boosting is vague, on par with chi/qi or innate intelligence. They never really say what is being boosted.

The other popular phrase is support. A product supports prostate health, or breast health or supports the immune system. It sounds like the immune system is sagging against gravity due to age and needs a lift.

The immune system, if you are otherwise healthy, cannot be boosted, and doing those things you learned in kindergarten health (reasonable diet, exercise and sleep), will provide the immune system all the boosting or support it needs.

Someone is going to write in and say Americans have a lousy diet and dont exercise and can benefit from better food and exercise. And thats true. If you are not taking care of yourself, your immune function can be improved to function better. But if you are at your optimal baseline, you cannot make your immune function better.

What is the immune system? The immune system is a mind boggling complex set of coordinated cells and proteins.

There are antibodies: IgG, IgA, IgM, IgE and IgM, further divided into 5 subtypes of IgG and 2 of IgA, each with a different affinity for different parts of pathogens.

There is complement, a series of proteins that can be activated by two separate pathways and are important in killing some kinds of bacteria and attracting white cells to infection.

There are blood components: Polymorphonuclear leukocytes, also known as white cells. And monocytes. And eosinophils and macrophages. And the lymphocytes oh my, of which there are multiple types and with different functions. Each cell line can have either a specific task or a general task in the attempt to prevent you from dying from infection. If you are infected by a virus, there is one response, a bacterium produces a different response, a parasite, yet another response, and within each response there are subsets of types of response depending on the pathogen and whether or not you have been exposed to the infectious agent in the past.

There are all the proteins and their receptors that regulate the response to infection: chemokines and interferons and interleukins, a hodgepodge of letters and numbers: IL6 and TNF and CCR5 and on and on and on.

There is the Toll system, a wing of the immune system so ancient it is found in plants.

And there all the nonspecific parts of immunity that help prevent infection: platelets and cilia that sweep potential pathogens out and iron metabolism that keeps iron away from bacteria and the list goes on and on and on. The above is the briefest of overviews of the constituents of the immune system. It is almost like saying you have described the works of Shakespeare by noting it contains the words the, and, of, verily, and forsooth. But the purpose of this post is not to describe the immune system in detail as I would soon embarrass myself.

So when something allegedly boosts the immune system, I have to ask what part. How? What is it strengthening/boosting/supporting? Antibodies? Complement? White cells? Are the results from test tubes (often meaningless), animal studies, or human studies? And if in human studies, what was the study population? Are the results even meaningful? Or small, barely statistically significant, outcomes in poorly-done studies?

The answer, as we shall see, is usually nothing. It is the usual making a Mt. Everest out of a molehill, and a small molehill at that. If you google the phrase boost the immune system you will find over 288,000 pages that give advice on how to give that old immune system a lift. Curiously, a Pubmed search with the same phase yields 1,100 references, most concerning vaccination. If you Pubmed enhanced immune system you get 41,000 references mostly concerning immunology. None of the references concern taking a normal person and making the immune system work better than its baseline to prevent or treat infection. I have yet to see a quality clinical study that demonstrates that, in normal, not nutritionally- or otherwise-compromised people, that some intervention can lead to a meaningful increase in immune function and as a result have fewer infections. Maybe such a study exists. I cant find it. Send me the reference. I suppose the comment section will soon flood me with examples.

If you are normal and in good health, there is nothing you can do to make your baseline better.

Randomly reading some of the advice on boosting the immune system yields Dr. Phil-level inanities that are trivial yet true. Get a good nights sleep. Duh. Exercise regularly. Double duh. Avoid being a fat ass couch potato American whose idea of exercise is driving to Burger King for a triple Whopper with extra-large fries. What a concept. Dont smoke or drink. These sites often intermix common, well-known beneficial lifestyle changes with all sorts of nonsense.

By the way, I need a lifestyle. Best as I can tell, I just have a life. I live it, and someday I wont. But I need style. That is the problem of being from Portland: no style. Its the old joke: whats the difference between yogurt and Portland, Oregon? Yogurt has culture. Sigh.

There are numerous quack nostrums that allegedly boost your immune system. Exactly what is boosted and how is a mystery. Perhaps you are filled with toxins, then any number of detoxification regimens can improve your immune function. How precisely? Another mystery.

All the classic quack interventions: chiropractic, homeopathy, acupuncture, can also boost your immune system by, you know, changing some energy vibration or unblocking something or other. In fact one of the amazing things is that as best I can tell, there is no quack practice that someone, somewhere, will not say boosts your immune system.

People who receive regular chiropractic adjustments have immune system competency that is 200% greater than those who dont.

Homeopathic remedies stimulate the immune system to assist the body in repairing any imbalances that may have occurred.

The following acupressure points are effective for dealing with a condition that may be caused by a weak immune system. Elegant Mansion (K 27) reinforces immune system functioning by strengthening the respiratory system. Steady, firm pressure on the Sea Of Vitality points (B 23 and B 47) fortifies the immune system, rejuvenates the internal organs, and relieves pain associated with lower back problems. The Sea of Energy (CV 6) tones the abdominal muscles and intestines, and helps fortify the immune, urinary, and reproductive systems. Firm pressure on the Three Mile Point (St 36) immediately boosts the immune system with renewed energy. It helps tone and strengthen the major muscle groups, providing greater endurance. Bigger Stream (K 3) on the inside of the ankle helps balance the kidney meridian and strengthen the immune system. Bigger Rushing (Lv 3) and Crooked Pond (LI 11),ire important points for relieving pain and strengthening the immune system. The Outer Gate point (TW 5) helps to balance the immune system and strengthen the whole body. Hoku (LI 4) is a famous decongestant and anti-inflammatory point; it relieves arthritic pain and strengthens the immune system Last, and most important of all, the Sea of Tranquility (CV 17) governs the bodys resistance to illness and decreases anxiety by regulating the thymus gland. Each of these important points benefits the immune system by enabling the internal organs to function at optimal levels.

I suspect that if one were to do all these interventions as once, your immune system would be raised to such a high level of activation that you would probably spontaneously combust. You heard it here first: the reason for spontaneous combustion is multiple, simultaneous boostings of the immune system.

This kind of nonsense is successful in part because that we all are aware that chance of illness increases with the number of stressors in your life, and the worse your life or lifestyle, the worse you are likely to feel and the more likely you are to have an illness. This phenomenon is real for groups of people. The more stressors, the higher the likelihood something will bad will happen with your life. This effect is harder to quantify for an individual. If you dont sleep well, eat poorly, dont exercise, get a divorce and a parent dies, in the next year you are more likely to have a medical problem. I remember toting up my stress score in medical school and based on my number I should have been dead three months earlier.

I would bet that when people turn to these quack nostrums, they do feel better, but not because of the nostrums, but because, for however short a period of time, they are no longer participating in the less than optimal habits that define standard American diet and activity. What they are probably doing is getting back towards a baseline of optimal health, not improving their health past what it is capable of.

I would bet 6 million years of evolution have more or less tuned our immune system to be running optimally, as long as we do the basics of eating well, exercising etc. All the stuff we failed to learn in kindergarten. You can be deficient in vitamins or sleep, etc., which will make you prone to illness, but if you are at baseline, you cant improve your immune system in any meaningful way.

When reading the literature on the immune boosting properties of various products you find there are several kinds of results that they use to justify their claims, all with a thick coating of exaggeration and hyperbole.

The first is just made up. Somebody somewhere decided that this product enhanced immune function. Often the claim is based on ancient wisdom. You know, ancient wisdom, the same ancient wisdom that gave us the flat Earth and slavery and women as inferior, that ancient wisdom. Always a reliable indicator. Most of the time there is no data to support the claims of immune boosting.

Then there are test tube tests for boosting immune system,

The immune system is always looking to distinguish between self and not self. All the cells of your body are labeled with proteins, the major histocompatabilty complex for those of you keeping score, that are, in part, signals to the immune system. This protein on my cell surface identifies me as me to me. And no I am not preparing to sing opera. It tells the immune system, dont shoot, Im one of you. Other peoples tissue dont have the same labels. Bacteria and other pathogens not only lack these signals, they have constituents in their cells that the body has evolved very specific responses against.

For example, E. coli has a toxin, called lipopolysaccaride in its cell walls that the body very specifically recognizes with a wing of the immune system, called the Toll-like receptor. If you incubate immune cells in a test tube with chemicals or non-self life (bacteria, virus, etc.) the cells react. That is what they are supposed to do. In medicine we call it the inflammatory response.

Oh look: Virus. Fungus. New chemical. Is it part of us? Nope. Respond. Kill kill kill. Here is a point I have made in the past. If you take a cell from the immune system and expose it to some chemicals or bacteria, you activate it, you get an inflammatory response. Its primed. And if you then challenge that activated cell with another pathogen, it will kill that pathogen better than if the cell was not primed. It only works with some pathogens, usually those that are killed by nonspecific cell-medicated immunity.

Listeria and Candida are always popular pathogens that the immune system responds with a nonspecific (i.e. cellular) rather than a specific (i.e. humoral or antibody) response, probably because they are unusual enough pathogens that it made no sense evolutionarily to develop a specific response like we see to more common pathogens.

Some organisms, often unusual ones, are killed with a nonspecific response of the immune system, whereas others, such as viruss, which are killed by very specific antibody, or meningococcus, which really needs complement for optimal killing. This response is used to suggest that the immune system is being boosted and they imply that this boosting is to your benefit. Other test tube studies may show that mediators of inflammation, such as TNF or Il-1 are increased, which is what one would expect if you expose the immune system to a pathogen or a probiotic organism.

Those who say that that their product, for example probiotics, boost the immune system, point to studies such as these that show that in response to bacteria, cells of the immune system are activated, they are exhibiting the expected inflammatory response to a foreign invader. They call it boosting. I call it the inflammatory response. What could be better than priming your immune system so that it is better able to respond to a pathogen? This preamble leads us to the meat of this post: Is it good to have the immune system activated? Is it good to have your immune system primed? Or boosted? Maybe not. It does explain why taking a probiotic helps increase the antibody response to influenza vaccine in the elderly and decreases the duration of respiratory infections. A short term inflammatory response may be of benefit, but it may not be an effect you want to have persist.

But here is some recent, interesting literature, about the effects of having an inflammatory response to acute and chronic infections. Chronic inflammation of all types is associated with atherosclerosis i.e. hardening of the arteries, nicely reviewed in Libby et al.s Circulation article, Inflammation and Atherosclerosis from 2002. An inflammatory state can occur from many things, not just infections.

First up: the NEJM, Treatment of periodontitis and endothelial function from 2007.

Periodontitis is gum infection and endothelial cells are them what line the arteries of the body. So they took a 120 people in England with bad periodontal disease (insert your own English dentition joke here, I dont stoop to those kind of cheap shots) to either aggressive treatment of their disease or standard treatment. Aggressive treatment consisted of scenes from the movie Marathon Man:

Patients in the intensive-treatment group underwent the adjunctive full-mouth intensive removal of subgingival dental plaque biofilms with the use of scaling and root planing after the administration of local anesthesia; teeth that could not be saved were extracted, and microspheres of minocycline were delivered locally into the periodontal pocket.

What they looked at in this study, however, were markers of inflammation and endothelial function. Initially, when they were really reefing and scraping the teeth, which is going to cause bacteremia and bleeding, the aggressively treated group had a big spike in signs of inflammation, but long term, as their gums healed, they had a decrease markers of inflammation and better measured arterial flow. Those in the standard group did not get the same long term response; they continued to have signs of inflammation and endothelial cell activation. And this means?

Chronic exposure to bacteria leads to an inflammatory state and has detrimental effects on arteries. Taking lots of probiotics, or other substances that cause an inflammatory response, or boosting the immune system in the parlance of the quacks, should act like chronic periodontitis with chronic sustained signs of inflammation.

Who cares?

Maybe you, if you are taking immune boosters that could really activate the immune system; that should lead to chronic inflammation, which is associated with hardening of the arteries.

But wait. Theres more. The inflammatory state is a prothombotic state. Infected people make blood clots, and they can make these clots for a long time. Clots can manifest in several common ways: heart attacks, strokes, and pulmonary emboli (i.e. blood clot to the lung). There are now several studies out there demonstrate an epidemiological link between a recent infection and a thrombotic event. For example, from Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting, Lancet, 2006:

7278 deep vein thrombosis patients and 3755 pulmonary embolism patients who were registered in a UK general practice database from 1987 to 2004. In the 2 weeks after a urinary tract infection, the risks of deep vein thrombosis and pulmonary embolism increased by 2.1-fold each, the report indicates. It took longer than 1 year for these elevated risks to return to baseline values.

Urinary tract infections increase your risk of blood clots and pulmonary embolism for up to a year.

How about heart attacks? Well, in Clinical Infectious Diseases 2007; 45:158-65 they looked at acute myocardial infarction and acute pneumococcal pneumonia and found an association, which had been noted since early last century. Acute pneumonia leads to heart attack.

Stroke? In European Heart Journal they looked at a database of strokes and heart attacks and found that:

There was strong evidence of an increased risk of both events in the seven days following infection for MI, the adjusted odds ratio (OR) was 2.10, and for stroke, the OR was 1.92. The risk was highest in the three days following infection (OR 3.75 for MI and 4.07 for stroke). The risk of events was reduced over time, so there was little excess risk beyond one month after infection.

And a simple community-acquired pneumonia decreases 5 year life expectancy in a VA population from 84 months to 34 months:

Although the cause of the decreased long-term survival is not yet clear, it may be that the systemic inflammatory response produced by CAP accelerates the natural course of medical comorbidities such as atherosclerosis, Dr. Peyrani suggested. This hypothesis, she said, is bolstered by a recent study that showed reduced long-term survival in CAP+ patients who were clinically cured but had increased interleukin 6 and interleukin 10 levels at the time of hospital discharge.

So chronic inflammation and acute inflammation both increase your risk of thrombosis and vascular events. What would probiotics and immune boosters do if they really worked? They would cause acute and chronic inflammation. For those who may think I am talking about vaccines, not here. Vaccines cause the development of a specific antibody against whatever you are immunizing against, but it does not cause a generalized inflammatory response.

Now I am well aware that association is not causality, and I am also well aware of the issues with epidemiological data to prove causality. But I submit for your consideration that if some product is really boosting your immune system, it is really activating your inflammatory response, and perhaps it may not be such a good idea.

Whenever I listen to skeptics talk about ID, they always complain how ID cannot make any predictions. Now I have been practicing ID for 23 years, and it is a science and I can make predictions. To suggest that ID is somehow inferior is. Huh? What? ID is intelligent design? Not infectious diseases? Oh. Thats different. Never mind.

But I will make a prediction: people who use probiotics or other substances that can measurably lead to an inflammatory response, or, have their immune system boosted, will have more strokes, heart attacks and pulmonary embolisms. So when you read that some product or other boosts the immune system, ask:

If the answer to number three is a big yes, perhaps you should avoid the product. When it comes to your immune system, if you are normal, leaving good enough alone is probably the way to go.

Read the original here:
Boost Your Immune System? Science-Based Medicine

The immune system is the set of tissues which work together to resist infections. The immune mechanisms help an organism identify a pathogen, and neutralize its threat.[1]

The immune system can detect and identify many different kinds of disease agents. Examples are viruses, bacteria and parasites. The immune system can detect a difference between the body's own healthy cells or tissues, and 'foreign' cells. Detecting an unhealthy intruder is complicated, because intruders can evolve and adapt so that the immune system will no longer detect them.

Once a foreign cell or protein is detected, the immune system creates antibodies to fight the intruders, and sends special cells ('phagocytes') to eat them up.

Even simple unicellular organisms such as bacteria possess enzyme systems that protect against viral infections. Other basic immune mechanisms appeared in ancient life forms and remain in their modern descendants, such as plants and insects. These mechanisms include antimicrobial peptides (called defensins), phagocytosis, and the complement system. These are the innate immune system, which defends the host from infections in a non-specific way.[2] The simplest innate system is the cell wall or barrier on the outside to stop intruders getting in. For example, skin stops most outside bacteria getting in.

Vertebrates, including humans, have much more sophisticated defense mechanisms. Whereas the innate immune system is found in all metazoa, the adaptive immune system is only found in vertebrates. It is thought to have arisen in the first jawed vertebrates.[3]

The adaptive immune response gives the vertebrate immune system the ability to recognize and remember specific pathogens. The system mounts stronger attacks each time the pathogen is encountered. It is adaptive immunity because the body's immune system prepares itself for future challenges.

The typical vertebrate immune system consists of many types of proteins, cells, organs, and tissues that interact in a complex and ever-changing network. This acquired immunity creates a kind of "immunological memory".

The process of acquired immunity is the basis of vaccination. Primary response can take 2 days to 2 weeks to develop. After the body gains immunity towards a certain pathogen, if infection by that pathogen occurs again, the immune response is called the secondary response.

In some organisms, the immune system has its own problems within itself, called disorders. These result in other diseases, including autoimmune diseases, inflammatory diseases and possibly even cancer.[4][5]Immunodeficiency diseases occur when the immune system is less active than normal. Immunodeficiency can either be the result of a genetic (inherited) disease, or an infection, such as the acquired immune deficiency syndrome (AIDS), that is caused by the retrovirus HIV, or other causes.

In contrast, autoimmune diseases result from an immune system that attacks normal tissues as if they were foreign organisms. Common autoimmune diseases include Hashimoto's thyroiditis, rheumatoid arthritis, Type 1 diabetes, and Lupus erythematosus.

Immunology is the study of all aspects of the immune system. It is very important to health and diseases.

Immunology is scientific part of medicine that studies the causes of immunity to disease. For many centuries people have noticed that those who recover from some infectious diseases do not get that illness a second time.[6]

In the 18th century, Pierre Louis Maupertuis made experiments with scorpion venom and saw that certain dogs and mice were immune to this venom.[7] This and other observations of acquired immunity led to Louis Pasteur (18221895) developing vaccination and the germ theory of disease.[8] Pasteur's theory was in direct opposition to contemporary theories of disease, such as the miasma theory. It was not until the proofs Robert Koch (18431910) published in 1891 (for which he was awarded a Nobel Prize in 1905) that microorganisms were confirmed as the cause of infectious disease.[9] Viruses were confirmed as human pathogens in 1901, when the yellow fever virus was discovered by Walter Reed (18511902).[10]

Immunology made a great advance towards the end of the 19th century, through rapid developments, in the study of humoral immunity[11] and cellular immunity.[12] Particularly important was the work of Paul Ehrlich (18541915), who proposed the side-chain theory to explain the specificity of the antigen-antibody reaction. The Nobel Prize for 1908 was jointly awarded to Ehrlich and the founder of cellular immunology, Ilya Mechnikov (18451916).[13]

The immune system is extremely ancient, and may go back to single-celled eukaryotes which needed to distinguish between what was food and what was part of themselves.[14]

Excerpt from:
Immune system - Simple English Wikipedia, the free ...

[Below is my transcript of my video about winning the battle with your immune system, along with supplemental information on immune system boosters.]

Today, Im going to share with you how to win the battle for your immune system and really create a strong immune system and boost your immune system naturally with probiotics.

One of the biggest keys in doing so is getting more probiotics benefits and foods in your diet and improving your digestive health. In fact, theres new research showing that a condition called leaky gut is a major cause of food sensitivities, autoimmune disease, and immune imbalance or a weakened immune system in the body, and again, the key is really increasing probiotics. There are really two main steps here in the immune system boosters probiotics offer.

Stay away from the toxicity of tap water that contains fluoride and chlorine. Be careful of taking prescription antibiotic medications. Thats the leading cause of probiotics getting wipe out today.

Then also be careful about not consuming too much sugar. Consuming too much sugar can cause bad bacteria to feed, which actually imbalances the good and bad bacteria in your body. Sugar can even cause cancer.

Probiotics are good bacteria that help you digest nutrients that help detoxify your colon and that help balance out and support your immune system within your body. So the next step is consuming more probiotic foods and taking a quality probiotic supplement.

The probiotic foods you should look to consume are things like:

Getting some of those probiotic foods will absolutely help your immune system and then so will taking a quality probiotic supplement that contains live or living probiotics. Getting a better brand will help you with those.

Again, if you want to take your immune system to the next level, start staying away from the things that kill probiotics. Load up your diet with probiotics. If you do so, youre going to take your immune system and function to the next level.

There are numerous different recipes that are great immune system boosters and theyre delicious, too! Check out some of my favorite immune-boosting recipes.

Immune-Boosting Juice Recipe

Total Time: 5 minutes Serves: 2

INGREDIENTS:

DIRECTIONS:

Immune-Boosting Smoothie Recipe

Total Time: 5 minutes

Serves: 1

INGREDIENTS:

DIRECTIONS:

Link:
Immune System Boosters: Winning the Battle with Your ...

There are physical, chemical, and cellular defenses against invasion by viruses, bacteria, and other agents of disease.

During the early stages of an infection, there is an inflammatory response

During later stages, leucocytes produce immune responses

The first two lines of defense are called Innate Immunity

The last line of defense is called Acquired Immunity

Animation - the First Two Lines of Defense

Types of cells involved in the immune system:

Each type of virus, bacteria, or other foreign body has molecular markers which make it unique

Thus, immunological specificity and memory involve three events:

(1) Recognition of a specific invader

(2) Repeated cell divisions that form huge lymphocyte populations

(3) Differentiation into subpopulations of effector and memory cells

Antigen-presenting cell - a macrophage which digests a foreign cell, but leaves the antigens intact. It then binds these antigens to MHC molecules on its cell membrane. The antigen-MHC complexes are noticed by certain lymphocytes (recognition) which promotes cell division (repeated cell divisions)

T cells (Helper T cells and Cytotoxic T cells)

Cell-mediated immune response

B cells, Plasma Cells, and Antibodies

Antibody-mediated immune response

Summary of the Immune Response

The Clonal-Selection Theory

Scientific evidence showed early researchers:

To explain these patterns, researched developed the clonal-selection theory, whihc made several key claims about how the adaptive immune system works:

Edward Jenner (1749-1823)

Read more from the original source:
The Immune System - University of Illinois at Chicago

The immune system is composed of specialized cells, various proteins, tissue and organs. The immune system works to defend us against hordes of microorganisms and germs that we are exposed to every day. In majority of the cases, the immune system performs and excellent job of preventing diseases and infections and keep us healthy. However, in some cases, problems can occur in the immune system, which can lead to occurrence of numerous illnesses and diseases.

The bodys defense against various microorganisms that cause disease and illness is the immune system. The immune system attacks these disease causing organisms through a sequence of steps referred to as the immune response.

The immune system is composed of a number of cells, tissues and organs that work in association and attacks the disease causing microorganisms and protect the human body. The cells of the immune system are the leukocytes or the white blood cells. They are of two main types that work in combination and destroy organisms and substances that invade the body.

Leukocytes are manufactured and stored in multiple organs of the body such as the spleen, bone marrow and the thymus gland. Hence, these organs are referred to as the lymphoid organs. Clumps of lymphoid tissues are also present throughout the body in the form of lymph nodes that contain the leukocytes.

The circulation of the leukocytes in the body takes place between the lymph nodes and the various organs through the blood vessels and lymphatic vessels. Hence, the functioning of the immune system occurs in a coordinated manner, thereby, monitoring the body against disease causing germs and microorganisms.

Leukocytes are divided into two main types as: phagocytes and lymphocytes.

When foreign particles or antigens invade the body, the various types of immune system cells work in combination to recognize and destroy them. The B lymphocytes are triggered in the process producing antibodies, which are specialized proteins that block specific antigens.

Once these antibodies are produced, they remain in the body and if the same antigen invades the body again, they are already present to block the antigen. Hence, if a person gets a specific disease, that person will not get sick with that disease again. This is the principle used behind immunizations used to prevent diseases.

After an antigen is locked by an antibody, the T cells come into action and destroy the antigens tagged by a particular antibody. T cells are therefore, sometimes referred to as killer cells.

Antibodies can also help in neutralizing toxins secreted by the microorganisms. They also help in activating a specialized group of proteins referred to as complement that helps in destroying viruses, bacteria and other infected cells.

The body is thus protected against diseases by these specialized cells of the immune system and this protection is referred to as immunity.

Read this article:
What Is the Function of the Immune System? | Med-Health.net

Nanomedicine Overview

What if doctors had tiny tools that could search out and destroy the very first cancer cells of a tumor developing in the body? What if a cell's broken part could be removed and replaced with a functioning miniature biological machine? Or what if molecule-sized pumps could be implanted in sick people to deliver life-saving medicines precisely where they are needed? These scenarios may sound unbelievable, but they are the ultimate goals of nanomedicine, a cutting-edge area of biomedical research that seeks to use nanotechnology tools to improve human health.

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A lot of things are small in today's high-tech world of biomedical tools and therapies. But when it comes to nanomedicine, researchers are talking very, very small. A nanometer is one-billionth of a meter, too small even to be seen with a conventional lab microscope.

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Nanotechnology is the broad scientific field that encompasses nanomedicine. It involves the creation and use of materials and devices at the level of molecules and atoms, which are the parts of matter that combine to make molecules. Non-medical applications of nanotechnology now under development include tiny semiconductor chips made out of strings of single molecules and miniature computers made out of DNA, the material of our genes. Federally supported research in this area, conducted under the rubric of the National Nanotechnology Initiative, is ongoing with coordinated support from several agencies.

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For hundreds of years, microscopes have offered scientists a window inside cells. Researchers have used ever more powerful visualization tools to extensively categorize the parts and sub-parts of cells in vivid detail. Yet, what scientists have not been able to do is to exhaustively inventory cells, cell parts, and molecules within cell parts to answer questions such as, "How many?" "How big?" and "How fast?" Obtaining thorough, reliable measures of quantity is the vital first step of nanomedicine.

As part of the National Institutes of Health (NIH) Common Fund [nihroadmap.nih.gov], the NIH [nih.gov] has established a handful of nanomedicine centers. These centers are staffed by a highly interdisciplinary scientific crew, including biologists, physicians, mathematicians, engineers and computer scientists. Research conducted over the first few years was spent gathering extensive information about how molecular machines are built.

Once researchers had catalogued the interactions between and within molecules, they turned toward using that information to manipulate those molecular machines to treat specific diseases. For example, one center is trying to return at least limited vision to people who have lost their sight. Others are trying to develop treatments for severe neurological disorders, cancer, and a serious blood disorder.

The availability of innovative, body-friendly nanotools that depend on precise knowledge of how the body's molecular machines work, will help scientists figure out how to build synthetic biological and biochemical devices that can help the cells in our bodies work the way they were meant to, returning the body to a healthier state.

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Last Updated: January 22, 2014

Original post:
NIH National Human Genome Research Institute

by Ben Best CONTENTS: LINKS TO SECTIONS BY TOPIC

Often we see people who smoke, don't exercise and eat all the wrong foods living to be a ripe old age. People tell us that it doesn't matter whether you smoke or are overweight, what matters is having good genes. Is this true?

The simple answer is that for every elderly person who is overweight, smokes, doesn't exercise, eats the wrong foods and doesn't take supplements there are many more who lived the same lifestyle and are in the cemetery (and who are therefore less visible). There are also many more people the same age who are living a more healthy lifestyle (emphasis on "living") and who are more healthy. Good heredity can protect you from bad living somewhat, but you are better off to live well.

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The longest, largest and most authoritative study on the effects of smoking upon health and longevity has followed the lives of nearly 35,000 British physicians since 1951[BRITISH MEDICAL JOURNAL; Doll,R; 328(7455):1519-1528 (2004)]. Although physicians may not seem representative of the population in general, their health histories and causes of death are very well documented.

Claims have been made that smokers die earlier than nonsmokers due to more risk-taking personalities, rather than because of the effects of tobacco. True enough, heavy smokers (over 25 cigarettes per day) in the study died of accidents, injury and poisoning more than twice as often as nonsmokers (in a couple of cases from fires started while smoking in bed). But these deaths accounted for less than 3% of total mortality.

According to the study, a heavy smoker is about 25 times more likely to die of lung cancer than a nonsmoker. And a light smoker (1 to 14 cigarettes per day) is about 8 times more likely to die of lung cancer. Similarly, a heavy smoker is about 24 times more likely to die of chronic obstructive pulmonary disease than a nonsmoker and a light smoker is about 9 times more likely. A similar relationship is seen for death rates from other forms of cancer and respiratory disease. This close relationship between fatal lung disease and smoking makes it difficult to deny that the smoke is directly damaging to the lungs.

On average, the nonsmokers lived about 10 more years than the smokers. For those born between 1920 and 1929 the death rate between the ages of 35 and 69 for nonsmokers was 15% and for smokers was 43% nearly three times greater. Of course, the smokers who survived beyond age 69 probably had better genes than those who did not, but they undoubtedly suffered more from respiratory disease and other forms of illness than the surviving nonsmokers.

The British physician study results are very similar to a survey of nearly a million American men and women by the American Cancer Society[AMERICAN JOURNAL OF PUBLIC HEALTH; Taylor,DH; 92(6):990-996 (2002)].

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(For more detail, see Health Benefits of Exercise)

Many studies have shown an association between exercise and reduced incidence of heart disease, adult onset diabetes and even cancer. A study of nearly 45,000 male health professionals showed that those who exercised in the highest 25% of intensity had a risk of coronary heart disease that was 70% that seen among the lowest 25%[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Tanasescu,M; 288(16):1994-2000 (2002)]. A study of nearly 22,000 male physicians showed that men who exercised 2 to 4 times weekly had 80% the stroke rate of those who exercised less than once per week[STROKE; Lee,IM; 30(1):1-6 (1999)]. A study of over 72,000 nurses showed that the fifth of women who exercised the most had 66% the stroke risk of the fifth who exercised the least. The middle fifth had 82% of the stroke risk of the fifth who exercised the least25%[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Hu,FB; 283(22):2961-2967 (2000)].

Diabetes increases the incidence of a variety of health conditions, including heart disease, neuropathy, kidney failure, etc. increasing the likelihood of an early death. In many ways diabetes exhibits the features of accelerated aging. "Type2 diabetes" also called "non-insulin-dependent diabetes" was formerly called "adult onset diabetes". But adolescents have increasingly been developing the disease. A Cincinnati study showed a ten-fold increase in adolescent type2 diabetes in the period between 1982 and 1994[THE JOURNAL OF PEDIATRICS; Pinhas-Hamiel,O; 128(5Pt1):608-615 (1996)]. There was not a ten-fold change in genetic makeup of adolescents in that period, but there was a great increase in adolescent obesity. A study of nearly 85,000 nurses concluded that obesity is the single most important factor leading to type2 diabetes in women[NEW ENGLAND JOURNAL OF MEDICINE; Hu,FB; 345(11):790-797 (2001)] (a result which is probably valid for men as well).

A study of nearly 22,000 male physicians showed that those who exercised more than 5times weekly had only 58% the incidence of type2 diabetes as those who exercised less than once per week. Those who exercised two to four times weekly had 62% the diabetes incidence and those who exercised once weekly had 77% the incidence[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Manson,JE; 268(1):63-67 (1992)]. Someone could argue that those who chose to exercise were those who are less likely to get diabetes, but a study which randomly assigned 3,234 non-diabetic persons to exercise at least 150 minutes per week or to not exercise showed those who exercised were only 58% as likely to get type2 diabetes as those who did not[NEW ENGLAND JOURNAL OF MEDICINE; Knowler,WC; 346(6):393-403 (2002)].

Even cancer risk might be reduced by exercise. An extensive review of the literature found a high relationship for both colorectal cancer and breast cancer with lack of exercise[CANCER CAUSES AND CONTROL; McTiernan,A; 9(5):487-508 (1998)]. Breast cancer and colorectal cancer are significantly influenced by diet as well as by exercise. A study in Italy found a correlation between these forms of cancer and the intake of saturated (but not polyunsaturated) fat[ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY; Favero,A; 492:51-55 (1999)].

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(For more detail, see Macronutrients, Dieting and Health)

A study of nearly 40,000 women health professionals found that the fifth who consumed the most dietary fiber had 46% the risk of myocardial infarction and 65% the total cardiovascular disease risk of the fifth consuming the least dietary fiber[JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY; Liu,S; 39(1):49-56 (2002)].

A study of Seventh Day Adventists showed that those who observed a vegetarian diet were at least four times less likely to have high blood pressure than those who ate meat[JOURNAL OF HYPERTENSION; Rouse,IL; 1(1):65-71 (2002)]. About a third of California Seventh Day Adventists are vegetarians, and those vegetarians have been shown to live 9.5 years (men) or 6.1 years (women) longer than other Californians. High blood pressure can cost 4.2 years (men) or 3.2 years (women) and diabetes (which is usually very susceptible to influence by diet) can cost 4.6 years (men) or 8.6 years (women)[ARCHIVES OF INTERNAL MEDICINE; Fraser,GE; 161(13):1645-1652 (2001)]. A prospective study of over half-a-million people found elevated mortality, cancer mortality and cardiovascular disease mortality in those who at red meat and processed meat (sausage, hot dogs, etc.)[ARCHIVES OF INTERNAL MEDICINE; Sinha,R; 169(6):562-571 (2009)].

The literature abounds with evidence that diets rich in fruits and vegetables reduce the risk of cancer and cardiovascular disease[JOURNAL OF POSTGRADUATE MEDICINE; Heber,D; 50(2):145-149 (2004)]. Diet certainly has an influential effect on longevity which is separable from heredity.

Caloric Restriction with Adequate Nutrition (CRAN) dramatically extends the maximum lifespan of laboratory animals. Rats, mice and hamsters experience maximum lifespan extension from a diet which contains 4060% of the calories (but all of the required nutrients) which the animals consume when they can eat as much as they want. Mean lifespan is increased over 50% and maximum lifespan is increased over 30%. There is evidence that humans on CRAN experience similar benefits. The experimental animals in these studies are compared to genetically-matched controls which eat freely and experience no life extension benefits. The dramatic diffenece in lifespan is due to diet, not genes.

The composition of protein, carbohydrate and fat in the diet can also significantly affect health and longevity. For details on this subject, see my essay Macronutrients, Dieting and Health.

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(For more detail, see Nutraceuticals Topic Index )

What about nutritional supplements? Poor nutrition is common, especially in the elderly. Supplements consisting of recommended dietary allowances of nutrients (plus extra VitaminE & beta-carotene) significantly improved the immune status of elderly subjects[THE LANCET 340:1124-1127 (1992)]. In fact, a randomized, double-blind placebo-controlled study of 200IU supplementation with alpha-tocopherol in persons over 65 years of age showed a 20% reduction in incidence of the common cold[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Meydani,SN; 292(7):828-836 (2004)].

In 1996 the JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION published the results of a multi-center, double-blind, randomized, placebo-controlled cancer prevention trial based on 200g/day selenium or placebo to 1,312 patients over a mean period of 4.5years[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Clark,LC; 276(24):1957-1963 (1996)]. The study reported a 50% decrease in total cancer incidence as well as a 63% reduction in prostate cancer, a 58% reduction in colorectal cancer and a 48% reduction in lung cancer. Only 6 of the 1,312 subjects had selenium blood levels below that achievable by the RDA prior to supplementation. Not only was this study a powerful refutation of the claim that dietary supplements are of no benefit, but its results were so impactful that it would be unethical for anyone to repeat it. After extensive scrutiny of the data only the evidence for reduction of prostate cancer is now accepted as statistically significant (for a 42% reduction in prostate cancer). The data still shows a total cancer mortality reduction of 51%[CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION; Duffield-Lillico,AJ; 11(7):630-639 (2002)].

It is worth noting the recent efforts of Dr. Bruce Ames to promote the use of supplements. Bruce Ames is most famous for the "Ames Test" which has allowed researchers to use bacteria rather than lab animals to screen for potential cancer-causing agents thus expediting the screening process. Dr. Ames says that it is unreasonable to expect that everyone (particularly the poor) is going to eat the recommended five servings of fruits and vegetables every day. He not only advocates a general vitamin and mineral supplement as an "insurance policy" to ensure getting the recommended minimums, but advises that recommended minimums are not sufficient to provide maximum protection from disease. And he notes the regenerative potential of taking supplements that combine lipoic acid with acetyl-L-carnitine[EMBO REPORTS; Ames,BN; 6(SpecNo):S20-S24 (2005)].

AntiOxidants and other supplements are excessively disparaged by some biogerontologists on the grounds that they do not increase maximum lifespan. But significantly increasing average age of death can be a gain in both life and health. The Nutraceuticals section of this website provides a great deal of evidence that nutritional supplements can improve health and thereby increase average lifespan ("square the curve").

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In Western countries, females live about 10% longer than males. Males have 4times as much oxidative DNA damage as females, presumably because females have more MnSOD and glutathione peroxidase[FREE RADICAL BIOLOGY & MEDICINE; Borras,C; 34(5):546-552 (2003)]. A 2002 study of centenarians in the United States found that female siblings were 8times more likely to reach age100 than cohorts born the same year and male siblings were 17times for likely to become centenarians themselves[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Perls,TT; 99(12):8442-8447 (2002)]. Mothers of persons who lived to at least 110years ("supercentenarians") were nearly six times more likely to have lived to age90 than females in the general population[JOURNAL OF GERONTOLOGY; Perls,T; 62A(9):1028-1034 (2007)]. Studies of centenarian populations have found quite a number of longevity-associated genotypes[PLoS GENETICS; Martin,GM; 3(7):e125 (2007)].

Children of older fathers (within the age range 25 to 45) were found to have longer telomeres and greater resistance to mortality from aging-associated diseases[AGING CELL; Unryn,BM; 4(2):97-101 (2005)]. A ten-year study of Danish twins aged 73-94 found a positive correlation between leucocyte telomere length and expected lifespan[AMERICAN JOURNAL OF EPIDEMIOLOGY; Kimura,M; 167(7):799-806 (2008)]. Studies of sperm from young(<30years) and old(>50years) donors found that sperm telomerase length increases with age[PLOS GENETICS; Kimura,M; 4(2):e37 (2008)].

Male sperm are produced throughtout life, whereas a woman typically produces few, if any, new egg cells during her reproductive years. For this reason, a mother typically passes about 14mutations to her offspring, whereas a father will pass about 40mutations at age20 and 80mutations at age40. Mutations in the father increase exponentially with age, doubling about every 16.5years[NATURE;Kong,A; 488:471-475 (2012)]. Risk of diseases such as autism and schizophrenia in offspring rise with increasing age of the father[Ibid.].

The cause of death for a sample 143 people over the age of 60 with shorter telomeres was found to be several times greater for heart disease and infectious diseases, but not for cancer[THE LANCET; Cawthon,RM; 361:393-395 (2003)]. Another study showed a significant correlation between telomere shortening and cognative impairment in elderly subjects[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Canela,A; 104(12):5300-5305 (2007)]. Yet another study found an inverse relationship between telomere length and pulse pressure, indicating a possible direct relationship between vascular aging and telomere length[HYPERTENSION; Jeanclos,E; 36(2):195-200 (2000)]. In a cohort of coronary artery disease outpatients the rate of telomere shortening was inversely related to blood levels of omega-3 polyunsaturated fatty acids[JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Farzaneh-Far,R; 303(3):250-257 (2010)]. Higher levels of oxidative stress due to environmental factors increase the rate of telomere shortening[TRENDS IN BIOCHEMICAL SCIENCES 27(7):339-344 (2002)]. Psychological stress may be one of the environmental factors[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Epel,ES; 101(49):17312-17315 (2004)]. A study of 175 elderly Swedish twin-pairs found that the twins with the shortest telomeres (75% of the cohort) had 3times the risk of death compared to the 25% with the longest telomeres[AGING CELL; Bakaysa,SL; 6(6):769-774 (2007)].

Identical twins (monozygotic twins) have the same heredity (identical genes), so differences in the health and longevity of identical twins can only be due to environmental factors. Of course, identical twins typically have similar environments. Fraternal twins are also born together, are no closer genetically than other siblings, and have environments which are probably as similar as those shared by identical twins. Thus, comparing identical twins with fraternal twins can be a way of determining which effects are due to heredity and which are due to lifestyle (environment).

A study of Scandinavian twins found that if a female lived to be at least 92years, a fraternal twin had 1.57 the chance of doing so, and an identical twin was 2.5times more likely to do so than other females. For males, a fraternal twin was 1.76times as likely to reach 92 and an identical twin was 4.83times as likely[HUMAN GENETICS; Hjelmborg,J; 119(3):312-321 (2006)].

Both fraternal and identical twins show correlated levels of the inflammatory cytokines Tumor Necrosis Factor-alpha(TNF) and IL6 which play a role in diabetes and metabolic syndrome indicative of the influence of a common environment, including the intrauterine environment. Nonetheless, elderly twins show a strong genetic component to their plasma TNF levels[DIABETOLOGIA; Grunnet,L; 49(2):343-350 (2006)]. A study of 80-year-olds found that serum IL6 levels predicted mortality for both males & females, but TNF only predicted mortality for males[CLINICAL &; EXPERIMENTAL IMMUNOLOGY; Bruunsgaard,H; 132(1):24-31 (2003)]. But another study found serum TNF to predict mortality in centenarians, whereas IL6, IL8 and CRP did not[AMERICAN JOURNAL OF MEDICINE; Bruunsgaard,H; 115(4):278-283 (2003)].

Female centenarians are significantly more likely to have a gene that reduces IGF1 receptor signalling[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Suh,Y; 105(9):3438-3442 (2008)]. Two copies of a FOXO3A allele tripled the odds of becoming a centenarian in a Japanese-American cohort[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Willcox,BJ; 105(37):13987-13992 (2008)].

A long-term study of twins in Denmark showed that when one fraternal twin had a fatal stroke, there was a 10% chance that the other fraternal twin would die of stroke. But for identical twins there was an 18% chance that the second twin would also die of a stroke[STROKE; Bak,S; 33(3):769-774 (2002)]. The fact that identical twins (who have exactly the same genes) would be nearly twice as likely to have a stroke as fraternal twins (who are no closer genetically than any brother or sister) indicates that heredity does play a role in the likelihood of having a stroke. Nonetheless, the fact that when one of two genetically identical twins has a stoke that there is a less than 20% chance that the second genetically identical twin will have a stroke indicates that at least 80% of the chance of having a stroke is due to environmental (lifestyle) factors.

The Framingham Longevity Study showed that age at death can be predicted much better by Coronary Heart Disease (CHD) risk factors than risk factors for stroke or cancer[JOURNAL OF CLINICAL EPIDEMIOLOGY; Brand,FN; 45(2):169-174 (1992)]. A study of nearly 21,000 Swedish twins[JOURNAL OF INTERNAL MEDICINE; 252(3):247-254 (2002)] showed that when one male twin died of CHD there was a 57% likelihood that the other male twin would also die of CHD. Insofar as only about 20% of males normally die of CHD (roughly half of all male deaths due to cardiovascular disease are due to CHD), 57% represents nearly 3 times the frequency that would be expected between randomly selected pairs of men. Although this represents a significant role for heredity in CHD death for men, the fact that 43% of male twins die of causes different from the CHD that killed the first twin indicates a significant role for lifestyle in causing CHD death.

For female twins only in 38% of cases did the second twin die of CHD when the first twin had died of CHD. This would seem to indicate that for women, lifestyle rather than heredity more strongly influences the chance of dying from CHD than is the case for men. However, the study noted that the older twins were when they died, the less likely it would be for both twins to die of the same cause. In other words, the longer you live, the more your cause of death will be determined by your lifestyle rather than by your heredity. Women normally live longer than men, so by dying at a greater age their causes of death are more influenced by lifestyle and less influenced by heredity than is the case for men. If men had lived longer, we would expect greater differences in cause of death between the male twins.

Divergence of twins with age is not only evident in lifestyle factors such as smoking, exercise, diet and environment, but in gene expression. A study which compared 3-year-old identical twins with 50-year-old identical twins found that the younger twins were very epigenetically similar, whereas the older twins were very distinct in epigenetic expression[PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Fraga,MF; 102(30):10604-10809 (2005)]. A study on mice showed that alterations in epigenetic expression with age may be up to two orders of magnitude greater than somatic mutations[GENETICS; Bennett-Baker,PE; 165(4):2055-2062 (2003)].

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Good genes do make a difference in being healthy and living long, but lifestyle choices usually make a bigger difference. And the longer we life, the more our remaining longevity depends upon our lifestyle rather than on our genes. The choice is not between quantity (long life) and quality (good health), because good health is usually a requirement for living long. Whether your genes are good or bad, you will probably be more healthy as well as live longer by not smoking, by exercising and by eating a good diet (which can be augmented by supplements).

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Is Longevity Entirely Hereditary? - BEN BEST

Stem Cell Research & Therapy20145:116

DOI: 10.1186/scrt506

Mukherjee et al.; licensee BioMed Central Ltd.2014

Received: 12April2014

Accepted: 6October2014

Published: 14October2014

The existence of cancer stem cells (CSCs) has been associated with tumor initiation, therapy resistance, tumor relapse, angiogenesis, and metastasis. Curcumin, a plant ployphenol, has several anti-tumor effects and has been shown to target CSCs. Here, we aimed at evaluating (i) the mechanisms underlying the aggravated migration potential of breast CSCs (bCSCs) and (ii) the effects of curcumin in modulating the same.

The migratory behavior of MCF-7 bCSCs was assessed by using cell adhesion, spreading, transwell migration, and three-dimensional invasion assays. Stem cell characteristics were studied by using flow cytometry. The effects of curcumin on bCSCs were deciphered by cell viability assay, Western blotting, confocal microscopy, and small interfering RNA (siRNA)-mediated gene silencing. Evaluations of samples of patients with breast cancer were performed by using immunohistochemistry and flow cytometry.

Here, we report that bCSCs are endowed with aggravated migration property due to the inherent suppression of the tumor suppressor, E-cadherin, which is restored by curcumin. A search for the underlying mechanism revealed that, in bCSCs, higher nuclear translocation of beta-catenin (i) decreases E-cadherin/beta-catenin complex formation and membrane retention of beta-catenin, (ii) upregulates the expression of its epithelial-mesenchymal transition (EMT)-promoting target genes (including Slug), and thereby (iii) downregulates E-cadherin transcription to subsequently promote EMT and migration of these bCSCs. In contrast, curcumin inhibits beta-catenin nuclear translocation, thus impeding trans-activation of Slug. As a consequence, E-cadherin expression is restored, thereby increasing E-cadherin/beta-catenin complex formation and cytosolic retention of more beta-catenin to finally suppress EMT and migration of bCSCs.

Cumulatively, our findings disclose that curcumin inhibits bCSC migration by amplifying E-cadherin/beta-catenin negative feedback loop.

The online version of this article (doi:10.1186/scrt506) contains supplementary material, which is available to authorized users.

Breast cancer is the most common form of cancer diagnosed in women. In 2013, breast cancer accounted for 29% of all new cancer cases and 14% of all cancer deaths among women worldwide[1]. Breast cancer-related mortality is associated with the development of metastatic potential of the primary tumor[2]. Given this high rate of incidence and mortality, it is critical to understand the mechanisms behind metastasis and identify new targets for therapy. For the last few decades, various modalities of cancer therapy were being investigated. But the disease has remained unconquered, largely because of its invasive nature.

Amidst the research efforts to better understand cancer progression, there has been increasing evidence that hints at a role for a subpopulation of tumorigenic cancer cells, termed cancer stem cells (CSCs), in metastasis formation[3]. CSCs are characterized by their preferential ability to initiate and propagate tumor growth and their selective capacity for self-renewal and differentiation into less tumorigenic cancer cells[4]. There are reports which demonstrate that CSCs are enriched among circulating tumor cells in the peripheral blood of patients with breast cancer[5]. Moreover, recent studies show that epithelial-mesenchymal transition (EMT), an early step of tumor cell migration, can induce differentiated cancer cells into a CSC-like state[6]. These observations have established a functional link between CSCs and EMT and suggest that CSCs may underlie local and distant metastases by acquiring mesenchymal features which would greatly facilitate systemic dissemination from the primary tumor mass[7]. Taken together, these studies suggest that CSCs may be a critical factor in the metastatic cascade. Now, the incurability of the malignancy of the disease raises the question of whether conventional anti-cancer therapies target the correct cells since the actual culprits appear to be evasive of current treatment modalities.

Studies focusing on the early steps in the metastatic cascade, such as EMT and altered cell adhesion and motility, have demonstrated that aggressive cancer progression is correlated with the loss of epithelial characteristics and the gain of migratory and mesenchymal phenotype[8], for which downregulation of E-cadherin is a fundamental event[9]. A transcriptional consequence of the presence of E-cadherin in epithelial cells can be inferred from the normal association of E-cadherin with -catenin in adherens junctions. This association prevents -catenin transfer to the nucleus and impedes its role as a transcriptional activator, which occurs through its interaction mainly with the TCF (T-cell factor)-LEF (lymphoid enhancer factor) family of transcription factors but also with other DNA-binding proteins[10]. Accordingly, the involvement of -catenin signaling in EMTs during tumor invasion has been established[11]. Aberrant expression of -catenin has been reported to induce malignant pathways in normal cells[12]. In fact, -catenin acts as an oncogene and modulates transcription of genes to drive cancer initiation, progression, survival, and relapse[12]. All of the existing information regarding abnormal expression and function of -catenin in cancer makes it a putative drug target[12] since its targeting will negatively affect both tumor metastasis and stem cell maintenance. Transcriptional target genes of -catenin involve several EMT-promoting genes, including Slug. Expression of Slug has been shown to be associated with breast tumor recurrence and metastasis[1315]. Pro-migratory transcription factor Slug (EMT-TF), which can repress E-cadherin, triggers the steps of desmosomal disruption, cell spreading, and partial separation at cell-cell borders, which comprise the first and necessary phase of the EMT process[16].

Recently, the use of natural phytochemicals to impede tumor metastasis via multiple targets that regulate the migration potential of tumor cells has gained immense importance[17]. In this regard, curcumin, a dietary polyphenol, has been studied extensively as a chemopreventive agent in a variety of cancers, including those of the breast, liver, prostate, hematological, gastrointestinal, and colorectal cancers, and as an inhibitor of metastasis[18]. In a recent report, curcumin was shown to selectively inhibit the growth and self-renewal of breast CSCs (bCSCs)[19]. However, there are no reports regarding the contribution of curcumin in bCSC migration.

The present study describes (i) the mechanisms governing the augmented migration potential of bCSCs, which (ii) possibly associates with tumor aggressiveness and is largely attributable to the inherent downregulation of the anti-migratory tumor suppressor protein, E-cadherin, in bCSCs, and (iii) the role of curcumin in modulating the same. A search for the upstream mechanism revealed higher nuclear translocation and transcriptional activity of -catenin resulting from disruption of E-cadherin/-catenin complex formation in bCSCs in comparison with non-stem tumor cells. Upregulation of nuclear -catenin resulted in the augmentation of Slug gene expression that, in turn, repressed E-cadherin expression. In contrast, exposure to curcumin inhibited the nuclear translocation of -catenin, thereby hampering the activation of its EMT-promoting target genes, including Slug. Resultant upregulation of E-cadherin led to increase in E-cadherin/-catenin complex formation, which further inhibited nuclear translocation of -catenin. As a consequence, the E-cadherin/-catenin negative feedback loop was amplified upon curcumin exposure, which reportedly inhibits EMT on one hand and promotes cell-cell adherens junction formation on the other. These results suggest that curcumin-mediated inhibition of bCSC migration may be a possible way for achieving CSC-targeted therapy to better fight invasive breast cancers.

Primary human breast cancer tissue samples used in this study were obtained with informed consent from all patients from Department of Surgery, Bankura Sammilani Medical College, Bankura, India, in accordance with the Institutional Human Ethics Committee (approval letter CNMC/ETHI/162/P/2010), and the associated research and analyses were done at Bose Institute, Kolkata, India, in compliance with the Bose Institute Human Ethics Committee (approval letter BIHEC/2010-11/11). These tumors were exclusively primary-site cancers that had not been treated with either chemotherapy or radiation. The selected cases consisted of three primary breast cancer patients of each group. The specimens were washed with phosphate-buffered saline (PBS), cut into small pieces (5 5 mm in size), and immersed in a mixture of colloagenase (10%; Calbiochem, now part of EMD Biosciences, Inc., San Diego, CA, USA) and hyaluronidase (0.5 mg/mL; Calbiochem) for 12 to 16 hours at 37C on orbital shaker. The contents were centrifuged at 80 g for 30 seconds at room temperature. The supernatant, comprising mammary fibroblasts, was discarded, and to the pellet pre-warmed 0.125% trypsin-EDTA was added. The mixture was gently pipetted and kept for 30 minutes at 37C. Finally, the pellet obtained was washed with cold Hanks buffer saline with 2% fetal bovine serum and centrifuged at 450 g for 5 minutes at room temperature. The single cells were seeded on poly-L lysine-coated dishes and cultured in medium containing growth factors, 0.1 ng/mL human recombinant epidermal growth factor, 5 g/mL insulin, 0.5 g/mL hydrocortisone, 50 g/mL gentamycin, 50 ng/mL amphotericin-B, and 15 g/mL bovine pituitary extract at 37C. Medium was replaced every 4 days, and passages were done when the cells reached 80% confluence[20].

Human breast cancer cell lines MCF-7 and T47D were obtained from the National Centre for Cell Science (Pune, India). The cells were routinely maintained in complete Dulbeccos modified Eagles medium (DMEM) supplemented with 10% heat-inactivated fetal bovine serum (FBS), penicillin (100 units/mL), and streptomycin (100 l g/mL) at 37C in a humidified incubator containing 5% CO2. Cells were allowed to reach confluency before use. Cells were maintained in an exponential growth phase for all experiments. All cells were re-plated in fresh complete serum-free medium for 24 hours prior to the experiments. Viable cell numbers were determined by Trypan blue dye exclusion test[21]. Cells were treated with different doses (5, 10, 15, and 20 M) of curcumin (Sigma-Aldrich, St. Louis, MO, USA) for 24 hours to select the optimum non-apoptotic dose of curcumin (15 m) which significantly abrogates migration potential of bCSCs. An equivalent amount of carrier (dimethyl sulfoxide) was added to untreated/control cells. To rule out cell proliferation, all migration assays were performed in the presence of 10 g/mL mitomycin C.

For mammosphere culture, MCF-7/T47D cells were seeded at 2.5 104 cells per well in sixwell Ultralow Adherence plates (Corning Inc., Corning, NY, USA) in DMEM/F12 with 5 g/mL bovine insulin (Sigma-Aldrich), 20 ng/mL recombinant epidermal growth factor, 20 ng/mL basic fibroblast growth factor, B27 supplement (BD Biosciences, San Jose, CA, USA), and 0.4% bovine serum albumin (BSA) as previously described[22]. Primary/1 and secondary/2 mammosphere formation was achieved by using weekly trypsinization and dissociation followed by reseeding in mammosphere media at 2.5 104 cells per well into Ultralow Adherence sixwell plates.

Cell viability assay was performed by using Trypan blue dye exclusion assay. Mammospheres were treated with different doses of curcumin for 24 hours. Thereafter, the numbers of viable cells were counted by Trypan blue dye exclusion by using a hemocytometer. The results were expressed as percentage relative to the control cells.

Expression of human bCSC markers CD44 and CD24 were analyzed by flow cytometric study in different stages of breast cancer tissue as well as in MCF-7/T47D cells and primary and secondary mammospheres by using CD44-FITC and CD24-PE antibodies (BD Biosciences). bCSCs were flow-cytometrically sorted from primary breast tumors on the basis of the cell surface phenotype CD44+/CD24-/low. De-differentiation, drug resistance, and stemness phenomena were quantified flow-cytometrically by measuring mean fluorescence intensities of de-differentiation markers Oct-4-PerCP-Cy5.5, Nanog-PE, and Sox-2-Alexa Fluor-647; drug-resistance markers MRP1-FITC, ABCG2-PE, and ALDH1-FITC (BD Biosciences); and epithelial markers cytokeratin-18-PE and cytokeratin-19-PE (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA). Expression levels of E-cadherin, -catenin, and Slug (Santa Cruz Biotechnology, Inc.) were determined with respective primary antibodies conjugated with PE as previously described[23].

For immunofluorescence, cells were grown on sterile glass coverslips at 37C for 24 hours. Cells after treatment were washed briefly with PBS and fixed with 4% formaldehyde for 20 minutes at 37C and permeabilized with Triton X100 (for intracellular protein expression analysis). Thereafter, cells were blocked for 2 hours in a blocking buffer (10% BSA in PBS) and incubated for another hour in PBS with 1.5% BSA containing anti-CD44/CD24/E-cadherin/-catenin/phospho-FAK antibody (Santa Cruz Biotechnology, Inc.). After washing in PBS, cells were incubated with FITC/PE-conjugated secondary antibodies in PBS with 1.5% BSA for 45 minutes at 37C in the dark. 4-6-diamidino-2-phenylindole (DAPI) was used for nuclear staining. Coverslips were washed with PBS and mounted on microscopy glass slides with 90% glycerol in PBS. Images were acquired by using a confocal microscope (Carl Zeiss, Jena, Germany)[21].

To determine the expression of bCSC markers in the migrating versus non-migrating fraction of MCF-7 cells, bi-directional wound-healing assay was performed. Briefly, cells were grown to confluency on sterile glass coverslips, after which a sterile 10-L tip was used to scratch the monolayer of cells to form a bi-directional wound. Cells were allowed to migrate for 24 hours and then the coverslips were used for immunofluorescence staining.

Transwell migration assay was performed by using 8.0-m cell culture inserts (BD Biosciences) to test the migratory ability of primary breast cancer cells, MCF-7/T47D cells, and mammosphere-forming cells. Cells were seeded at 2.5 105 cells per well in serum-free DMEM in the upper chamber of 12-well plates and allowed to migrate for 8 hours toward DMEM containing 10% FBS in the lower chamber. After 8 hours, the cells in the upper chamber were removed with a cotton swab and the migrated cells in the lower surface of the membrane were fixed and stained with giemsa or the migrated fraction of 2 mammospheres were collected from the under-surface of the membranes after 24-hour migration assay for flow cytometry. Images were acquired with a brightfield microscope (Leica, Wetzlar, Germany) at 20 magnification. To quantify migratory cells, three independent fields were analyzed by using ImageJ software (National Institutes of Health, Bethesda, MD, USA). Migration was expressed as percentage of cells migrated. For the same, the percentage of cells that migrated in the control set of each relevant experiment was taken as 100%.

For evaluating cell adhesion property, cells were trypsinized by using trypsin-EDTA and resuspended in DMEM at a density of 0.8 106 cells per milliliter. These cell suspensions were allowed to recover from the trypsinization for 1 hour at 37C in a humidified incubator containing 5% CO2. They were mixed gently every 15 minutes during this hour of conditioning. After every 15 minutes of incubation, the dishes were removed from the incubator, and the medium containing unattached cells was removed. Images were acquired with an Olympus BX700 inverted microscope (Olympus, Tokyo, Japan) at 20 magnification. To quantify cell adhesion, the number of unattached cells at 1 hour was determined by counting three independent fields. Attachment (at 1 hour) was expressed as percentage of cells adhered, and the percentage of the control set of each relevant experiment was taken as 100%.

Spreading of the attached cells was monitored. At various time intervals (for every 30 minutes up to 3 hours), cells were imaged by using an Olympus BX700 inverted microscope (Olympus). Images of multiple fields were captured from each experimental set at 40 magnification. From the phase-contrast images, individual cell boundaries were marked with the free-hand tool of ImageJ, and the area within the closed boundary of each cell was quantified by using the analysis tool of ImageJ. Cell spreading (at 3 hours) was expressed as mean circularity of the cells. As confirmation assay for cell adhesion and spreading, MCF-7 cells and 2 mammosphere cells were plated on fibronectin (50 g/mL)-coated surface, and focal adhesions were stained and quantified by immunofluorescence staining for phospho-FAK. In fact, phospho-FAK-enriched clusters at lamellipodia were considered as focal adhesion complex. Focal adhesion segmentation and size measurement were done by using ImageJ software.

Three-dimensional (3D) invasion assay of mammospheres was performed in 96-well plates. Each well was first coated with 80 L matrigel (BD Biosciences) in 3:1 ratio with complete DMEM. Mammospheres with or without curcumin/small interfering RNA (siRNA)/short hairpin RNA (shRNA)/cDNA treatment were mixed with matrigel (6:1) and added to the previously coated wells. Thereafter, the mammospheres were allowed to invade for 48 hours. Images were photographed by using an Olympus BX700 inverted microscope (Olympus) at 20 magnification. Data were analyzed by using ImageJ software as area invaded and were expressed as percentage relative to the control set, the value of which was taken as 100%.

To obtain whole cell lysates, cells were homogenized in buffer (20 mM Hepes, pH 7.5, 10 mM KCl, 1.5 mM MgCl2, 1 mM Na-EDTA, 1 mM Na-EGTA, and 1 mM DTT). All buffers were supplemented with protease and phosphatase inhibitor cocktail[24, 25]. Protein concentrations were estimated by using Lowrys method. An equal amount of protein (50 g) was loaded for Western blotting. For direct Western blot analysis, the cell lysates or the particular fractions were separated by SDS-PAGE, transferred to polyvinylidene difluoride membrane (Millipore, Darmstadt, Germany), and probed with specific antibodies like anti-E-cadherin, anti--catenin, anti-histone H1, anti-cyclin-D1, anti-c-myc, anti-slug, anti-vimentin, anti-MMP-2, anti-MMP-9, anti-twist, anti-Snail, and anti--Actin (Santa Cruz Biotechnology, Inc.). The protein of interest was visualized by chemiluminescence (GE Biosciences, Piscataway, NJ, USA). To study the interaction between E-cadherin and -catenin, -catenin immunocomplex from whole cell lysate was purified by using -catenin antibody and protein A-Sepharose beads (Invitrogen, Frederick, MD, USA). The immunopurified protein was immunoblotted with E-cadherin antibody. The protein of interest was visualized by chemi-luminescence. Equivalent protein loading was verified by using anti--actin/Histone H1 antibody (Santa Cruz Biotechnology, Inc.)[26].

Two micrograms of the total RNA, extracted from cells with TRIzol reagent (Invitrogen, Carlsbad, CA, USA), was reverse-transcribed and subjected to polymerase chain reaction (PCR) with enzymes and reagents of the RTplusPCR system (Eppendorf, Hamburg, Germany) by using GeneAmpPCR 2720 (Applied Biosystems, Foster City, CA, USA). The cDNAs were amplified with specific primers for E-cadherin (forward-CACCTGGAGAGAGGCCATGT, reverse-TGGGAAACAT-GAGCAGCTCT) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (forward-CGT-ATTGGGCGCCTGGTCAC, reverse-ATGATGACCCTTT-TGGCTCC).

Cells were transfected separately with 300 pmol of E-cadherin shRNA (Addgene, Cambridge, MA, USA) or Slug siRNA (Santa Cruz Biotechnology, Inc.) by using Lipofectamine 2000 (Invitrogen). The levels of respective proteins were estimated by Western blotting. The Slug cDNA (Addgene) plasmid was used for overexpression studies. The Slug cDNA clone was introduced in cells by using Lipofectamine 2000. Stably expressing clones were isolated by limiting dilution and selection with G418 sulphate (Cellgro, a brand of Mediatech, Inc., Manassas, VA, USA) at a concentration of 400 g/mL, and cells surviving this treatment were cloned and screened by Western blot analysis with specific antibodies.

Tissues were dissected out; fixed in Bouins fixative overnight; cryoprotected in 10% (2 hours), 20% (2 hours), and 30% (overnight) sucrose solution in PBS at 4C; and frozen with expanding CO2, and serial sections were cut on a cryostat (CM1850; Leica) at 15-m thickness. The tissue sections were washed in PBS (pH 7.45) for 15 minutes and treated with 1% BSA in PBS containing 0.1% Triton X-100. Sections were incubated overnight at 25C in a humid atmosphere with primary antibodies against E-cadherin (1:100; Santa Cruz Biotechnology, Inc.) diluted in PBS containing and 1% BSA. Sections were rinsed in PBS for 10 minutes and incubated with biotinylated anti-mouse IgG (Sigma-Aldrich; 1:100) for 1 hour, followed by ExtrAvidin-peroxidase conjugate (Sigma-Aldrich; 1:100) for 40 minutes. 3-Amino-9-ethyl carbazole was used as chromogen (Sigma-Aldrich; 1:100) to visualize the reaction product. Thereafter, sections were counterstained with hematoxylin (1:1; Himedia, Mumbai, India). Finally, sections were washed in distilled water and mounted in glycerol gelatin. Images were acquired with a brightfield microscope (Leica) at 10 magnification.

Values are shown as standard error of mean unless otherwise indicated. Comparison of multiple experimental groups was performed by two-way analysis-of-variance test. Data were analyzed; when appropriate, significance of the differences between mean values was determined by a Students t test. Results were considered significant at a P value of not more than 0.05.

To determine whether CSCs are linked with tumor aggressiveness or malignancy, we performed flow cytometric analyses of bCSC markers CD44

/CD24

in patient-derived tumor samples of different stages. We also tested the migratory potentials of these primary cells of different stages of cancer by performing transwell migration assay. Interestingly, along with the gradual increase in percentage cell migration, that is, 188.67% 9.33% (

A and B), indicating that the CSC population is proportionally related with breast cancer migration. In a parallel experimental set using the razor-wound migration assay method, human breast cancer cell line MCF-7 furnished higher expression of CSC-markers (that is, CD44

/CD24

) in the migrating population as compared with the non-migrating fraction of cells as evident from our confocal data (Figure

C). In line with an earlier report[

], these results revealed that the increase in expression of CSC markers selects for breast cancer cells with enhanced malignant and metastatic ability.

Breast cancer stem cells (CSCs) are highly migratory and are correlated with aggressiveness of the disease. (A) The percentage content of breast CSCs (CD44+/CD24-/low) in different stages of breast cancer was determined by flow cytometry and represented graphically (right panel). The left panel depicts representative flow cytometry data. (B) Migration of primary breast cancer cells of different stages was evaluated by using transwell migration assay. Cells that had migrated to the lower surface of the 8.0-m membrane were stained with Giemsa stain, counted, and represented graphically (right panel). The left panel shows brightfield images of migration assay of different breast cancer stages. (C) Expression of CSC markers (CD44+/CD24-/low) was visualized by immunofluorescence in the migrating front and non-migrating pool of MCF-7 cells after 24-hour wound-healing assay. Data are presented as mean standard error of mean or representative of three independent experiments.

Our next attempt was to evaluate the migratory properties of bCSCs as compared with the non-stem tumor population. For the same, the percentage CSC content of MCF-7 and T47D, as well as of primary/1 and secondary/2 mammospheres generated from these two cell lines, was elucidated by using flow cytometry for the bCSC phenotype, CD44

CD24

. Results of Figure

A depict the presence of 4.3% 0.70% CSCs in MCF-7, 26.72% 2.40% in its 1 mammosphere, and 52.17% 2.86% in 2 mammosphere (

B); de-differentiation and drug-resistance markers, ABCG2 and MRP1 (Figure

C); and ALDH1 (Figure

D). After the presence of higher stemness and CSC enrichment in the mammospheres of both the breast cancer cell lines MCF-7 and T47D was validated, all of our later experiments were performed with mammospheres of MCF-7 cells while re-confirming the key experiments in mammospheres of T47D cells. Next, we compared the migration efficiency of mammospheres with MCF-7 cells. Interestingly, these bCSC-enriched mammospheres were found to be highly migratory as compared with MCF-7 cells within the same time frame. Briefly, mammosphere-forming cells exhibited higher adhesion property than MCF-7 cells; that is, 316% 18.19% mammosphere-forming cells were adhered as compared with MCF-7 cells (100%) (

A). Similarly, mammosphere cells demonstrated lesser circularity (0.503 0.04 mean circularity) than MCF-7 cells (0.873 0.04 mean circularity), thereby depicting higher mesenchymal and migration properties of mammospheres (

B). At this juncture, for more robust assessment of adhesion, we quantified the size of phospho-FAK-enriched focal adhesion area from the lammellipodia of MCF-7 and its 2 mammosphere-forming cells. Our results showed that the mean focal adhesion area of mammosphere-forming cells was significantly higher (

C). Even in transwell migration assay, the percentage migration of mammosphere cells (293.67% 9.56%) was higher than that of MCF-7 cells (taken as 100%) (

D). Results of Figure

D validated the findings of transwell migration assay in the T47D cell line and its mammospheres.

Relative quantification of breast cancer stem cells in MCF-7 and T47D cell lines and their mammospheres along with their characterization for stemness properties. (A) The percentage content of breast cancer stem cells (CD44+/CD24-/low) in MCF-7 and T47D cells, MCF-7/T47D-derived primary/1 and secondary/2 mammospheres, were determined by flow cytometry and represented graphically (right panel). The left panel depicts representative flow cytometry data. (B-D) Graphical representation of relative mean fluorescence intensities (MFIs) in arbitrary units (AU) of de-differentiation markers Oct-4, Sox-2, and Nanog; drug-resistance markers ABCG2 and MRP1; and stemness-related enzyme ALDH1 in MCF-7 and T47D cell lines, along with their respective 2 mammospheres as determined by flow cytometry (right panels). The left panels depict representative flow cytometric histogram overlay data. Data are presented as mean standard error of mean or representative of three independent experiments.

Breast cancer stem cell (CSC)-enriched mammospheres exhibit highly aggravated migratory properties. (A, B) Representative phase-contrast images of cell adhesion and spreading assays of MCF-7 and 2 mammosphere-forming cells (left panels). The right panels demonstrate relative quantification of the data. (C) Confocal images showing focal adhesions in MCF-7 and 2 mammosphere-forming cells, stained with phospho-FAK (PE) (red) and nuclear stain 4-6-diamidino-2-phenylindole (DAPI) (left panel). The right panel illustrates relative quantification data of mean focal adhesion area. (D) Representative brightfield images of transwell migration assays of MCF-7 and T47D cells and their respective 2 mammosphere-forming cells (left and middle panels). The right panel demonstrates relative quantification of the data graphically. (E) The percentage content of breast CSCs (CD44+/CD24-/low) in the migrated fractions of 2 mammospheres of MCF-7 and T47D cell lines as compared with non-stem cancer cells (NSCCs) was determined by flow cytometry and represented graphically (right panel). The left panel depicts representative flow cytometry data. Data are presented as mean standard error of mean or representative of three independent experiments.

At this stage, we considered the possibility that, since the mammosphere is a heterogeneous population of cells consisting of both CSCs and non-stem cancer cells, the migrated population of the mammosphere might be a heterogeneous one. It therefore becomes debatable whether the aggravated migration property of mammospheres is the contribution of bCSCs or of non-stem cancer cells. To get the answer, the migrated cells of the mammospheres were collected from the under-surface of the membranes, and flow cytometric analyses were performed to characterize the migrated cells. Results of Figure3E demonstrated that the majority of the migrating cells of the mammospheres were bCSCs for both the cell lines, that is, 83.67% 2.90% bCSCs for mammospheres of MCF-7 (P <0.001) and 80.33% 3.48% (P <0.001) bCSCs for mammospheres of T47D. These results validate that bCSCs are endowed with aggravated migration potential as compared with the rest of the non-stem tumor population.

Our effort to delineate the mechanism underlying the enhanced migratory behavior of bCSCs revealed suppression of E-cadherin expression, loss of which (a hallmark of EMT) has been reported to promote tumor metastasis[

]. In fact, our immunohistochemical analyses revealed a gradual decrease in the expression levels of E-cadherin protein with increasing stages of breast cancer (Figure

A). Results of our Western blot and reverse transcription-PCR analyses also elucidated lower protein and mRNA levels of E-cadherin in mammospheres than in MCF-7 cells (Figure

B). The same results were obtained in our confocal analyses (Figure

C). In our previous findings, we have shown an increase in CSC percentage with an increase in the stage of breast cancer (Figure

A). Therefore, we postulated that probably bCSCs maintain their aggravated migration property through suppression of the E-cadherin protein expression. As a validation of this hypothesis, shRNA-mediated silencing of E-cadherin protein expression in mammospheres resulted in significant augmentation of the migratory phenotype of these mammospheres, as reflected in our cell-adhesion assay; that is, 316.67% 23.33% E-cadherin-silenced mammosphere cells adhered as compared with the control shRNA-transfected cells (100%) (

D,

). Similarly, E-cadherin-ablated mammospheres demonstrated augmented cell spreading as depicted by loss in mean circularity of cells: that is, 0.45 0.02 and 0.27 0.03 mean circularity of cells of control shRNA-transfected and E-cadherin-silenced mammospheres, respectively (

D,

). In addition, 3D invasion potential of E-cadherin-knocked-down mammospheres was also elevated (161.67% 7.31%) when compared with control shRNA-transfected set (100%) (

E,

). These results were finally confirmed in our transwell migration assay in which E-cadherin-shRNA-transfected mammosphere cells showed 340.67% 26.97% migration as compared with 100% migration of control shRNA-transfected cells (

E,

). Transwell migration assay of mammospheres of T47D cells also rendered similar results: that is, 291.67% 15.41% cell migration in E-cadherin-shRNA transfected mammospheres as compared with 100% cell migration in control shRNA set (

E,

). Taken together, these results validate that suppressed expression of E-cadherin is essential for maintaining accentuated migration potential of bCSCs.

The augmented migration potential of breast cancer stem cells (bCSCs) results from the suppression of the epithelial-mesenchymal transition (EMT) marker, E-cadherin. (A) Immunohistological staining for E-cadherin (brown color for antibody staining and counterstained with hematoxylin) of breast tumor samples. (B) Protein and mRNA expression profiles of E-cadherin in MCF-7 cells, 1 and 2 mammospheres, was determined by Western blotting (WB) (upper panel) and reverse transcription-polymerase chain reaction (RT-PCR) (lower panel). (C) Expression of E-cadherin in MCF-7 cells and 2 mammospheres was visualized by immunofluorescence. (D) Graphical representation of relative cell adhesion (left panel) and spreading (right panel) of MCF-7-derived 2 mammospheres with or without transfection with E-cadherin-short hairpin RNA (shRNA). The efficiency of transfection was assessed by evaluating the expression of E-cadherin through WB (inset). (E) A similar experimental setup was scored for three-dimensional (3D) invasion (left panel) and transwell migration (right panel) assays. Transwell migration assay was performed under similar experimental conditions in T47D-derived 2 mammospheres (right panel). -Actin/glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as an internal loading control. Data are presented as mean standard error of mean or representative of three independent experiments.

There are several reports delineating the pro-migratory role of -catenin protein[

,

]. Moreover, activation of -catenin pathway has been reported in CSCs[

]. Under normal conditions, -catenin exists in physical association with membrane-bound E-cadherin. However, if unbound with surface E-cadherin, -catenin becomes free to translocate to the nucleus and transcriptionally activates several pro-migratory genes necessary for EMT in association with the TCF/LEF transcription factors[

]. Results of our co-immunoprecipitation studies revealed a much lower association between E-cadherin and -catenin proteins in mammospheres as compared with MCF-7 cells (Figure

A). Moreover, although the total -catenin protein level remained unaltered, a significantly higher nuclear level of the protein was observed in mammospheres than MCF-7 cells (Figure

B). Higher nuclear localization of -catenin in mammospheres was confirmed by confocal microscopy (Figure

C). That the transcriptional activity of -catenin was augmented in mammospheres was confirmed in our Western blotting data, in which greater expression of cyclin-D1, c-myc, and Slug proteins (Figure

D), which are direct transcriptional targets of -catenin[

], was observed. However, the expression levels of another important -catenin transcriptional target, Snail, not only was very low in both MCF-7 cells and its mammospheres but also failed to show any significant difference between these two cell types (Figure

D). Cumulatively, these results validate that the higher pro-migratory milieu in bCSCs results from greater transcriptional activity of -catenin.

E-cadherin suppression in breast cancer stem cells (bCSCs) is associated with greater nuclear translocation of -catenin and subsequent trans-activation of Slug. (A) -catenin-associated E-cadherin was assayed by co-immunoprecipitation from cell lysates of MCF-7 and 2 mammospheres by using specific antibodies (left panel) or with normal human immunoglobulin G (IgG) as a negative control (right panel). To ensure comparable protein loading, 20% of supernatant from immunoprecipitation (IP) sample was subjected to determination of -actin by Western blotting (WB). (B) WB was conducted to study the levels of total -catenin and nuclear -catenin in MCF-7 and 2 mammospheres for determining the nuclear translocation of -catenin. (C) The relative nuclear expression of -catenin in MCF-7 and 2 mammospheres was visualized by immunofluorescence. (D) WB was performed to study the expression levels of -catenin target genes Cyclin-D1, c-Myc, Slug and Snail in MCF-7 cells and 2 mammospheres. (E) Protein and mRNA expression profiles of E-cadherin in 2 mammospheres of MCF-7 cells with or without transfection with Slug-short interfering RNA (siRNA) were determined by WB (right panel) and reverse transcription-polymerase chain reaction (RT-PCR) (left panel). The efficiency of transfection was assessed by evaluating the expression of Slug through WB (inset). (F, G) Graphical representation of relative cell adhesion, spreading, three-dimensional invasion, and transwell migration of MCF-7-derived 2 mammospheres with or without transfection with Slug siRNA. Transwell migration assay was also performed under similar experimental conditions in T47D-derived 2 mammospheres (G, right panel). -Actin/histone H1/glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as an internal loading control. Data are presented as mean standard error of mean or representative of three independent experiments.

It is reported that both the EMT-promoting transcription factors, Slug and Snail, the transcriptional target genes of -catenin, are potent transcriptional repressors of the E-cadherin gene[32]. Our results above, showing significantly greater Slug gene expression in mammospheres than in MCF-7 cells with very low expression levels of Snail in both of the cell types, tempted us to evaluate whether the repression of E-cadherin in bCSCs was mediated through the -catenin/Slug pathway. To that end, siRNA-mediated silencing of Slug in mammospheres resulted in restoration of E-cadherin expression at both protein and mRNA levels (Figure5E). Under such conditions, the migration potential of the mammospheres was simultaneously retarded as was assessed by monitoring (i) adhesion, that is, 52.67% 5.61% cells adhered in Slug-silenced mammospheres as compared with the control set (100%, P <0.01) (Figure5F); (ii) spreading, that is, 0.49 0.03 and 0.7 0.04 mean circularity in control and Slug-ablated mammospheres, respectively (P <0.05; Figure5G, left panel); (iii) invasion, that is, 46.67% 4.05% invasion in Slug-siRNA-transfected mammospheres as compared with control, that is, (100%, P <0.001) (Figure5G, middle panel); and (iv) transwell migration, that is, 37.33% 5.04% in Slug knocked-down mammospheres as compared with 100% migration of the control (P <0.001; Figure5G, right panel) of MCF-7 cells. The effect of Slug silencing in migration potential was further validated in mammospheres of T47D cells (28% 5.69% migration as compared with control, P <0.001, Figure5G, right panel). All of these results confirmed that E-cadherin repression in bCSCs results from the activation of the -catenin/Slug pathway.

The phytochemical curcumin is a known repressor of several tumor properties, including tumor cell migration[

]. Additionally, several recent studies suggest that CSCs could be targeted by using curcumin[

]. However, there are no detailed studies on the anti-migratory role of curcumin in CSCs. Results of our transwell migration assay revealed that 24-hour curcumin treatment inhibits migration of bCSC-enriched mammospheres of both MCF-7 and T47D cells in a dose-dependent manner (Figure

A). Our cell viability assay data showed that curcumin exerted apoptotic effects on mammospheres of both MCF-7 and T47D cells beyond a 15 M dose (Additional file

: Figure S1). Therefore, to avoid the possibility of curcumin-induced cell death in our experimental set-up, further experiments were restricted to the 15 M dose of this phytochemical. Additional validation of the effects of curcumin on adhesion, spreading, and 3D invasion properties of mammospheresthat is, 26% 3.46% cell adhesion,

B) and 44% 4.36% invasion,

D) as compared with 100% value of the respective control sets, and 0.46 0.02 and 0.80 0.05 mean circularity (Figure

C) in control and curcumin-treated mammospheres, respectively (

E). To find out whether curcumin exposure altered only E-cadherin expression or overall epithelial characteristics of these bCSCs, flow cytometric analyses of other epithelial markers cytokeratin-18 and -19 were performed. The results revealed that curcumin augmented the overall epithelial characteristics of these cells (Figure

F). On the other hand, silencing E-cadherin expression by using shRNA significantly nullified the effects of curcumin on the various migratory phenotypes of these CSCs, namely, cell adhesion (351.67% 10.14%), 3D invasion (174% 7.37%), and migration (304.67% 23.79%), as compared with the value of 100% of the respective control sets (

G). The results of mean circularity of control (0.463 0.03) and E-cadherin shRNA-transfected mammospheres (0.276 0.03) of MCF-7 cells (

G) were in line with these findings that silencing E-cadherin expression significantly nullified the effects of curcumin on various migratory phenotypes of these CSCs. These results were validated in T47D cells in which higher migration of E-cadherin shRNA-transfected cells of mammospheres (281.67% 14.81%) was observed in comparison with untransfected ones (100%,

H). These results together indicated that curcumin inhibited bCSC migration property by restoration of the EMT-suppressor, E-cadherin.

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Curcumin Inhibits Breast Cancer Stem Cell Migration by ...

Andrew Weil, MD

Founder & Program Director

Andrew Weil was born in Philadelphia in 1942, received an A.B. degree in biology (botany) from Harvard in 1964 and an M.D. from Harvard Medical School in 1968. After completing a medical internship at Mt. Zion Hospital in San Francisco, he worked a year with the National Institute of Mental Health, then wrote his first book, The Natural Mind. From 1971-75, as a Fellow of the Institute of Current World Affairs, Dr. Weil traveled widely in North and South America and Africa collecting information on drug use in other cultures, medicinal plants, and alternative methods of treating disease. From 1971-84 he was on the research staff of the Harvard Botanical Museum and conducted investigations of medicinal and psychoactive plants.

At present Dr. Weil is Director of the Center for Integrative Medicine of the College of Medicine, University of Arizona, where he also holds the Lovell-Jones Endowed Chair in Integrative Rheumatology and is Clinical Professor of Medicine and Professor of Public Health. The Center is the leading effort in the world to develop a comprehensive curriculum in integrative medicine. Graduates serve as directors of integrative medicine programs around the United States, and through its Fellowship, the Center is now training doctors and nurse practitioners around the world.

Under Dr. Weil's leadership, the Center has created two new programs for other health professionals including the Integrative Health and Lifestyle Program, and a certification program in Integrative Health Coaching.

Andrew Weil is the author of many scientific and popular articles and of 11 books, including: The Natural Mind; The Marriage of the Sun and Moon; From Chocolate to Morphine (with Winifred Rosen); Health and Healing; Natural Health, Natural Medicine; and the international bestsellers, Spontaneous Healing and Eight Weeks to Optimum Health. His most recent books are Eating Well for Optimum Health: The Essential Guide to Food, Diet, and Nutrition; The Healthy Kitchen: Recipes for a Better Body, Life, and Spirit (with Rosie Daley); Healthy Aging: A Lifelong Guide to Your Well-Being, and Why Our Health Matters: A Vision of Medicine that can Transform our Future, published in Sept. 2009. Oxford University Press is currently producing the Weil Integrative Medicine Library, a series of volumes for clinicians in various medical specialties; the first of these, Integrative Oncology (co-edited with Dr. Donald Abrams) appeared in 2009.

Dr. Weil also writes a monthly newsletter, Dr. Andrew Weil's Self Healing, maintains a popular website, Dr. Weil.com (www.drweil.com), and appears in video programs featured on PBS. He also writes a monthly column for Prevention magazine. Dr. Weil serves as the Director of Integrative Health at Miraval Life in Balance Resort in Catalina, Arizona. A frequent lecturer and guest on talk shows, Dr. Weil is an internationally recognized expert on medicinal plants, alternative medicine, and the reform of medical education. He lives near Tucson, Arizona, USA.

To contact Dr. Weil, please e-mail his assistant.

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Andrew Weil: Arizona Center for Integrative Medicine

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Floridians are increasingly feeling the effects of diabetes as thousands of people suffer from the disease, and many others may have diabetes and not know it! It is estimated that one out of every three children born after 2000 in the United States will be directly affected by diabetes.

That is why the American Diabetes Association's Jacksonville office is so committed to educating the public about how to stop diabetes and support those living with the disease.

We are here to help you.

We welcome your help.

Your involvement as an American Diabetes Association volunteer whether on a local or national level will help us expand our community outreach and impact, inspire healthy living, intensify our advocacy efforts, raise critical dollars to fund our mission, and uphold our reputation as the moving force and trusted leader in the diabetes community.

Find volunteer opportunities in our area through the Volunteer Center.

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Jacksonville Florida Office of the American Diabetes ...

Welcome to the future of Preventive Medicine

Princeton Longevity Center is a next-generation preventive medical facility providing one of the most advanced, integrated and individually tailored programs in the country. With focus on early disease detection and evaluating and modifying risk for future disease, Princeton Longevity Centers unique program gives you the ability to take control of your future health before the onset of symptoms or other indications of a problem.

Princeton Longevity Centers Comprehensive Preventive Exams combine the newest and most advanced technology with the most in-depth assessment available to detect potential health problems. Our preventive medicine experts will show you simple, easy adjustments you can make that wont dramatically impact your lifestyle but will give you the tools you need to maximize your future health and keep you looking and feeling years younger. Our individually tailored programs will improve your health and longevity, enabling you to make the most of your future years for you and the people who depend on you.

Named one of the countrys top centers for a Comprehensive or Executive Physical exam by the Wall Street Journal and Forbes Magazine, the Princeton Longevity Center provides you with an unparalleled level of personal care and attention.

When you visit Princeton Longevity Center, youll be met by a team of professionals that provides an extensive series of medical assessments, diagnostic tests and health screenings. On the same day well review all your results with you and give you as much time as you need to ask questions about them. Individualized attention from a team of Physicians, Exercise Physiologists, Registered Dietitians, Nurses and Patient Care Coordinators is a hallmark of our preventive medicine center, and sets us apart from other wellness centers. Patients come to Princeton Longevity Center because were not a hospital-based exam we are the specialist in prevention and early disease detection.

You will find that one day with Princeton Longevity Center will provide more insight into your health and future health than all your previous routine annual exams combined.

Follow this link:
Welcome to Princeton Longevity

Reference Terms

from Wikipedia, the free encyclopedia

The immune system is the system of specialized cells and organs that protect an organism from outside biological influences. (Though in a broad sense, almost every organ has a protective function - for example, the tight seal of the skin or the acidic environment of the stomach.) When the immune system is functioning properly, it protects the body against bacteria and viral infections, destroying cancer cells and foreign substances.

If the immune system weakens, its ability to defend the body also weakens, allowing pathogens, including viruses that cause common colds and flu, to grow and flourish in the body.

The immune system also performs surveillance of tumor cells, and immune suppression has been reported to increase the risk of certain types of cancer.

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