Day: 09/05/2012

Researchers Use Gene Deletions to Find Cancer Treatment Targets.

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Chromosomal damage that can transform healthy cells into cancer cells may also create weaknesses that can be exploited to kill the cancer cells, a new study suggests. The idea, called “collateral vulnerability,” could be used to identify new targets for drug therapy in multiple cancers, according to researchers from the Dana-Farber Cancer Institute and the University of Texas MD Anderson Cancer Center. The study was published August 16 in Nature.

Directly targeting genetic mutations that drive cancer with drugs is difficult, particularly in the case of mutations that delete tumor suppressor genes. Using data on the brain cancer glioblastoma multiforme (GBM) from The Cancer Genome Atlas (TCGA) initiative, the research team identified a number of “collateral” or “passenger” gene deletions that occurred during chromosomal damage that resulted in the loss of tumor suppressor genes.

The researchers next looked for passenger gene deletions that met two criteria: the deleted genes were involved in functions vital to cell survival, and the deleted genes were closely related to existing genes that perform similar functions. This loss of redundancy caused by passenger gene deletions can potentially be exploited to selectively kill tumor cells, the authors explained.

One gene that met these criteria is ENO1. ENO1 produces enolase 1, an enzyme that plays a central role in a process cells use to make energy. Human cells have a closely related gene (ENO2) that produces the enzyme enolase 2, which acts as a back-up for enolase 1 in brain tissue. Brain cells normally have a high level of enolase 1 activity and a small amount of enolase 2 activity. In some patients with GBM, however, the tumor cells lack enolase 1 activity because ENO1 was deleted when a tumor suppressor gene was deleted. This lack of enolase 1 activity could make these tumor cells more vulnerable to enolase inhibition.

This idea was tested using two targeting strategies. First, in GBM cell lines that lacked ENO1, the investigators showed that silencing ENO2 gene expression with a short hairpin RNA (a short RNA sequence that blocks the production of enolase 2 protein from ENO2 messenger RNA) sharply reduced cell growth, and tumors failed to form in mice injected with the treated cells.

The second approach involved a drug that targets the enolase 1 and enolase 2 proteins. Treatment of GBM cell lines lacking ENO1 with the drug caused the cancer cells to die because of the low overall enolase levels in these cells. But drug treatment had little effect on normal brain cells or GBM cells that had ENO1, since these cells have high levels of ENO1 gene expression and are, therefore, less sensitive to the drug.

The collateral vulnerability concept is similar in some respects to the idea of synthetic lethality, which uses genetic mutations in cancer-associated genes to identify other potential cellular vulnerabilities, explained the study’s co-lead author, Dr. Florian Muller of MD Anderson.

There are many more passenger gene deletions than tumor suppressor gene deletions, “and some of these passenger-deleted genes perform functions critical for cell survival,” Dr. Muller continued. “So, by expanding the concept to passenger genes, we vastly expand the possibility of finding these relationships, and, in the case of essential-redundant gene pairs like ENO1 and ENO2, we also provide a rational, knowledge-based method of drug-target discovery.”

The researchers are extending their work to other passenger gene deletions in GBM, Dr. Muller said.

This research was supported in part by the National Institutes of Health (CA95616-10 and CA009361).

Also in the Journals: Youth Tobacco Use Dropped between 2000 and 2011

Tobacco use and cigarette smoking fell among middle and high school students between 2000 and 2011, according to data from the National Youth Tobacco Survey, a school-based, self-administered questionnaire given to students in grades 6 through 12. Researchers from the Centers for Disease Control and Prevention published the findings last month in Morbidity and Mortality Weekly Report.

Percentage of U.S. Middle and High School Students Using Tobacco

Middle School Students

High School Students

2000

2011

2000

2011

Current Tobacco Use

14.9

7.1

34.4

23.2

Current Smoked Tobacco Use

14.0

6.3

33.1

21.0

Current Cigarette Use

10.7

4.3

27.9

15.8

Source: NCI

 

 

 

 

 

Sequencing “Outlier” Genome Suggests Some Patients May Benefit from Cancer Drug.

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Clinical trials that fail to identify drugs that benefit most patients may still yield valuable information by identifying subsets of patients who would benefit from the drugs. That is the conclusion of a study in which researchers used whole-genome sequencing to salvage a potentially beneficial drug that might have been discarded.

In a report published August 23 in Science, researchers at Memorial Sloan-Kettering Cancer Center describe how they sequenced the tumor genome of a 73-year-old woman with advanced bladder cancer who had a complete response to the drug everolimus (Afinitor) that has lasted for more than 2.5 years. The patient was part of a 45-patient, early-phase clinical trial in which treatment with everolimus failed to improve progression-free survival, the trial’s primary endpoint, among the patient population enrolled in the trial as a whole.

“The patient was a dramatic outlier in terms of her clinical response,” said the study’s senior author, Dr. David Solit.

After targeted sequencing of a few specific genes in the woman’s tumor “didn’t turn up anything revealing,” Dr. Solit continued, the researchers decided to sequence the woman’s entire tumor genome to see if they could discover a molecular basis for her strong response.

Among the many genomic alterations the researchers identified, inactivating mutations in two genes, TSC1 and NF2, stood out. Evidence from laboratory studies had suggested that loss-of-function mutations in TSC1 and NF2 might increase sensitivity to everolimus.

The researchers then analyzed the tumor DNA from 13 other patients enrolled in the trial and found TSC1-inactivating mutations in the tumors of three more patients, two of whom had measurable tumor shrinkage and lived longer without their cancer progressing than patients whose tumors lacked a TSC1 mutation. None of the 13 patients’ tumors had an NF2 mutation.

Sequencing the TSC1 and NF2 genes in tumor samples from 96 other patients with advanced bladder cancer revealed five more patients with TSC1 mutations, but no NF2 mutations.

Dr. Solit and his colleagues hope to launch a small clinical trial testing everolimus in patients with bladder cancer tumors that have mutations in TSC1 or a related gene, TSC2.

“We often see cases where just a few patients in an otherwise negative trial have significant benefit,” Dr. Solit said. “With the in-depth analysis provided by novel technologies like whole-genome sequencing, we can possibly salvage potentially beneficial drugs that were otherwise going to fail.”

Source: NCI

 

Gene in Stem Cell Donors May Decrease Relapse Risk in Leukemia Patients.

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An analysis of patients who had undergone blood stem cell transplants for acute myelogenous leukemia (AML) suggests that certain genetic features of the donors are related to risk of AML relapse. The findings of this retrospective study show that stem cell transplants from genetically similar donors who carry a gene known as KIR2DS1, which can activate cancer-fighting natural killer (NK) cells, appear to be associated with a reduced risk of relapse in AML patients.

The study, by Drs. Katharine Hsu and Bo Dupont of Memorial Sloan-Kettering Cancer Center and their colleagues, appeared August 30 in the New England Journal of Medicine.

KIR genes code for members of a group of proteins called killer-cell immunoglobulin-like receptors, which are found on the surface of NK cells—white blood cells that can kill tumor cells.

Researchers also found that the reduced relapse rate associated with KIR2DS1 was restricted to stem cell donors with specific variants of the gene HLA-C. HLA genes code for cell-surface HLA proteins, which make up a person’s tissue type.

Hematopoietic stem cell transplants (HSCT) are given to patients who have AML to replace the diseased cells in the bone marrow with healthy stem cells that can develop into all types of blood and immune system cells to fight the leukemia. When selecting donors for HSCT, physicians match the HLA tissue type of donor and recipient to reduce the chances that the recipient’s new immune system will damage his or her other tissues and organs.

“Studies over the last 15 to 20 years have pointed to the fact that the NK cells that emerge after transplant are quite potent in destroying any remaining leukemia cells, particularly in AML,” Dr. Hsu said.

“We know that NK cells are inhibited or activated by the various KIR receptors and their interactions with HLA molecules,” she continued. “The real goal is to figure out which KIR-HLA combinations are going to allow the donor-derived NK cell to have its maximal effects in terms of leukemia control.”

The researchers examined the outcomes of HSCT in 1,277 patients with AML and 427 patients with acute lymphoblastic leukemia (ALL) who had received transplants between 1989 and 2008 from unrelated donors. The donors and recipients were matched for at least 9 of 10 possible versions of the five HLA genes. The researchers used stored blood and DNA samples to test for various types of KIR genes in stem cell donors and for HLA genes in donors and recipients.

They found that patients with AML (but not those with ALL) who received transplants from donors carrying the KIR2DS1 gene had a significantly lower risk of relapse than patients with transplants from donors without KIR2DS1. But KIR2DS1 did not improve outcomes when the donor had two copies, or alleles, of the HLA-C2 gene. This last finding is consistent with studies showing that high levels of HLA-C2 protein reduce the activity of NK cells bearing KIR2DS1 receptors.

Dr. Hsu commented that future studies should examine the effects of other KIR-HLA interactions or combinations in HSCT. “As we do this, we can become more and more refined in our donor selection criteria, with the goal of selecting a donor who is going to give the greatest benefit in terms of reducing leukemic relapse and increasing survival.”

Source: NCI

Flavored Cigar Use Common among Young Adult Cigar Smokers.

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Flavored cigar use is common among adults who smoke cigars, and particularly high among young adult cigar smokers, according to the first nationwide survey to assess adult use of these products. Flavored cigar smoking also varies by geographic region, the study found.

Also in the News: CDC Updates Hepatitis C Testing Recommendations

Adults born from 1945 through 1965 should be tested for the hepatitis C virus (HCV), according to updated recommendations from the Centers for Disease Control and Prevention (CDC). The CDC estimates that people born during these years account for three-quarters of all HCV infections and nearly three-quarters of HCV-associated deaths in the United States. As a result, these individuals are at greatest risk for liver cancer and other HCV-related liver diseases.

This update adds a target population for testing, but does not replace previous guidelines.

Dr. Brian King and colleagues from the Centers for Disease Control and Prevention (CDC) reported the findings online August 27 in Nicotine & Tobacco Research.

Using data from the 2009–2010 National Adult Tobacco Survey, which included about 119,000 landline and cell phone users, the researchers estimated that 6.6 percent of adults in the United States smoke cigars. Cigar smoking was especially high (15.5 percent) among 18 to 24 year olds. Approximately 43 percent of adults who smoke cigars use flavored cigars, they found. Among 18- to 24-year-old cigar smokers, 57 percent use flavored cigars.

Flavored cigar use was also more common among certain groups, including women and Hispanic cigar smokers, as well as cigar smokers with less education and lower incomes. The highest rates of flavored cigar use among cigar smokers were in North Dakota (71.6 percent) and New Mexico (69.0 percent), and the lowest rates were in New Hampshire (11.1 percent) and New Jersey (23.7 percent).

In 2009, the U.S. Food and Drug Administration (FDA) prohibited the use of certain flavors in cigarettes—such as vanilla, chocolate, cherry, and others that have a distinguishable taste or aroma—under authority granted by the Family Smoking Prevention and Tobacco Control Act. However, the FDA does not currently regulate cigars, and flavored cigars may still be manufactured and sold.

Flavorings, the study authors said, “mask the natural harshness and taste of tobacco.” Cigars contain many of the same toxic substances as cigarettes and smokeless tobacco and raise the risk of several cancers, heart disease, and chronic obstructive pulmonary disease.

Given the high rate of use among cigar smokers, the authors concluded, “efforts to curb flavored cigar smoking have the potential to reduce the prevalence of overall cigar smoking among U.S. adults.”

Source: NCI

 

High Breast Density Does Not Predict Death among Breast Cancer Patients.

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High breast density is a strong risk factor for developing breast cancer, but it does not affect a breast cancer patient’s risk of death, according to a study recently published in the Journal of the National Cancer Institute.

Denser breasts have more glandular tissue (cells that produce milk during lactation) and supportive connective tissue than fatty tissue. Doctors use a scale called the Breast Imaging Reporting and Data System (BI-RADS) to classify breast density as observed on mammograms on a scale from 1 to 4, with 1 being the least dense and 4 the most dense.

To examine the relationship between breast density and risk of death from breast cancer, Dr. Gretchen Gierach and her colleagues from NCI’s Division of Cancer Epidemiology and ­­­Genetics and the NCI-sponsored Breast Cancer Surveillance Consortium (BCSC) examined medical records from more than 9,000 breast cancer patients collected by the BCSC.

After accounting for age, body mass, treatment, and other factors that could influence the risk of death, the researchers found that among women diagnosed with breast cancer, women with dense breasts were not more likely to die of the disease or of other causes than women with less-dense breasts during nearly 7 years of follow-up, on average.

Unexpectedly, the researchers observed that breast cancer patients with the least-dense breasts had an increased risk of death from breast cancer if they had large tumors or were obese. However, given that this result was based on relatively small numbers of women and has not been previously suggested by other studies, “these findings need to be replicated in larger studies,” said Dr. Gierach.

Obesity is a risk factor for death from breast cancer and is also inversely related to breast density. (That is, obese women are less likely to have dense breasts.) Therefore, obesity could affect associations between breast density and breast cancer death.

“We already know that obesity is a poor prognostic factor for breast cancer in general, but this particular analysis showed that the subgroup of women who were obese and had less-dense, fatty breasts were at greatest risk,” she explained. “Our hypothesis is that the fat content in the breast might be enhancing obesity-related mechanisms that heighten tumor aggressiveness in breast cancer. We are conducting studies to better understand the biology of breast density.”

Source: NCI

Genome Study Points to Treatments for High-Risk Form of Childhood Leukemia.

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Using genomic tools, researchers have uncovered genetic changes associated with a form of leukemia that recurs in some children. The findings, reported last month in Cancer Cell, suggest that some of these young patients may benefit from targeted drugs that are available but currently not used to treat this particular form of the disease.

The study focused on a subtype of acute lymphoblastic leukemia (ALL) known as Philadelphia chromosome-like ALL. Children with this subtype have a higher risk of a recurrence after standard chemotherapy and lower rates of long-term survival than other children with high-risk ALL.

Since the subtype was first described in 2009 (here and here), researchers have identified genetic changes that could explain about half of these cases. Building on this work, a team led by Dr. Charles Mullighan of the St. Jude Children’s Research Hospital analyzed RNA from 15 patients with the subtype and sequenced the genomes of two of these patients.

The results, Dr. Mullighan said, were “striking.” His team found a diverse set of genetic abnormalities linked to cancer, including DNA mutations and chromosomal rearrangements. The biological effects of these changes, however, appeared to be concentrated primarily on two signaling pathways involved in cell growth and proliferation.

Making Use of Available Drugs 

“We found a wide range of gene fusions, but they converged on a limited number of pathways,” said Dr. Kathryn Roberts of St. Jude, a study author. These pathways included the proteins ABL1, PDGFRB, and JAK2, which all play a role in cell growth.

In the lab, several drugs that inhibit growth-promoting signals through these pathways—including imatinib (Gleevec), dasatinib (Sprycel), and ruxolitinib (Jakafi)—showed anticancer effects against models of Philadelphia chromosome-like ALL.

“These findings are important because these children frequently have very poor outcomes,” Dr. Mullighan said. Future studies could test whether patients with mutations affecting these pathways could be candidates to receive targeted drugs along with chemotherapy, he added.

Overall, children with high-risk ALL have a greater than 80 percent chance of being cured by standard treatments, but only about 60 percent of children with Philadelphia chromosome-like ALL are alive and free of cancer after 5 years. This subtype, which accounts for about 15 percent of childhood ALL cases, shows similar patterns of gene activity as Philadelphia chromosome-positive ALL, but the BCR-ABL1 fusion gene is absent.

Better Diagnostic Tests Needed

The new results are from the TARGET initiative, an NCI-supported project that brings together experts on childhood cancers and genome analysis to identify genetic alterations that could be targeted by new or existing therapies.

“These are exactly the kind of results this initiative was created to generate,” said Dr. Malcolm Smith of NCI’s Cancer Therapy Evaluation Program and an NCI leader of the TARGET initiative.

“At this point there are anecdotal examples of how these findings could be translated for broader application,” Dr. Smith continued. Future challenges include improving diagnostic tests to detect the specific molecular alterations and developing treatments appropriate for each alteration, he noted.

At St. Jude, Dr. Roberts is investigating two approaches for detecting this subtype of ALL at the time of diagnosis. One strategy is to profile the active pathways in the leukemia cells, and the other is to look for signature patterns of gene activity.

These tests could serve as an initial screen for Philadelphia chromosome-like ALL, followed by testing for specific genetic alterations associated with the disease, according to Dr. Christine Harrison of Newcastle University in the United Kingdom, who wrote an accompanying editorial.

She praised the study for providing “a comprehensive genomic definition” of Philadelphia chromosome-like ALL, showing it to be a disease with distinctive genetic alterations that affect a range of proteins involved in cell growth.

The work also illustrates one way that cancer researchers are increasingly using genomic tools, noted co-author Dr. Stephen Hunger of the University of Colorado, who is also chair of the Children’s Oncology Group ALL Disease Committee.

“The first step is to identify the abnormalities driving the development of a particular cancer,” he explained. “Then, you use therapies directed against those abnormalities—either alone or with chemotherapy—to improve the outcomes of patients with the least possible side effects.”

Dr. Smith added, “Targeted agents are already known for some of the molecular alterations in Philadelphia chromosome-like ALL, but for others they will need to be identified.”

Dr. Mullighan agreed that a more complete understanding of the Philadelphia chromosome-like ALL subtype is needed. When his team expanded their analysis to include samples from more than 400 patients, the critical lesions in about 20 percent of the cases were unknown.

“We need to know what the changes are, and no single method of analysis is going to pick up every genetic alteration,” he said.

Knowledge gained from studying Philadelphia chromosome-like ALL in children could prove useful for adolescents and young adults as well. This subtype is thought to be more common with advancing age, and the prognosis may also worsen with age.

Since the study was published, Dr. Mullighan has received inquiries from doctors who want to know whether their patients with ALL might be candidates for the new approach. For the study authors, this has underscored the importance of developing clinically accredited tests.

“We really need to develop the diagnostic tests so that we can identify these patients at the time of diagnosis and direct them to the most appropriate targeted therapy,” Dr. Roberts said.

Source: NCI.

 

Gut microflora and probiotics.

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There are 100 trillion cells in your body, but 90% of the genetic material is not yours. It is from the bacteria, fungi, viruses and other microorganisms, i.e. your microflora. Gut microbes are big in the news lately, as researchers continue to discover the important roles these tiny organisms play in your overall health and well-being. We now know that your microflora influence your:

  • Genetic expression
  • Immune system
  • Weight, and
  • Risk of numerous chronic and acute diseases, from diabetes to cancer

Most recently, research has shown that a certain set of these microbes may actually influence the activity of genes in your brain – and the parts they play are not small parts. They may work to manipulate your behavior, and your memory as well.

Microbes Manipulate Your Mind

According to a recent article in The Guardian1, certain species of gut bacteria have been found to influence gene activity in your brain. Some of this research was published in 2011.2 Mice lacking gut bacteria were found to engage in “high-risk behavior,” and this altered behavior was accompanied by neurochemical changes in the mouse brain.

According to the authors, microbiota (your gut flora) may play a role in the communication between your gut and your brain, and:

“Acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of the gastrointestinal, immune, neuroendocrine and metabolic systems. For example, the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity.”

But they also discovered other differences between the mice with normal gut flora and those lacking gut bacteria. When examining the animals’ brains, they discovered a number of genetic alterations in the germ-free mice. According to The Guardian:

“Brain-derived neurotrophic factor (BDNF) was significantly up-regulated, and the 5HT1A serotonin receptor sub-type down-regulated, in the dentate gyrus of the hippocampus. The gene encoding the NR2B subunit of the NMDA receptor was also down-regulated in the amygdala.

All three genes have previously been implicated in emotion and anxiety-like behaviors.

BDNF is a growth factor that is essential for proper brain development, and a recent study showed that deleting the BDNF receptor TrkB alters the way in which newborn neurons integrate into hippocampal circuitry and increases anxiety-like behaviors in mice. Serotonin receptors, which are distributed widely throughout the brain, are well known to be involved in mood, and compounds that activate the 5HT1A subtype also produce anxiety-like behaviors.

The finding that the NR2B subunit of the NMDA receptor down-regulated in the amygdala is particularly interesting. NMDA receptors are composed of multiple subunits, but those made up of only NR2B subunits are known to be critical for the development and function of the amygdala, which has a well established role in fear and other emotions, and in learning and memory. Drugs that block these receptors have been shown to block the formation of fearful memories and to reduce the anxiety associated with alcohol withdrawal in rodents.”

Your Gut Bacteria Are Under Constant Assault

Your lifestyle can and does influence your gut flora on a daily basis. For example, your gut bacteria are extremely sensitive to:

All of these common exposures can wreak havoc on the makeup of bacteria in your gut, but researchers are now increasingly looking at the cascading ill effects of antibiotics in particular.

Not only are antibiotics overused in medicine, the vast majority of these drugs enter you via livestock – you consume antibiotics every time you eat meat from an animal raised in a confined animal feeding operation (CAFO). In fact, about 80 percent of all the antibiotics produced are used in agriculture3 – not only to fight infection, but to promote unhealthy (though profitable) weight gain in the animals.

Early Use of Antibiotics Also Linked to Obesity

With that in mind, is it any wonder that researchers are now finding that antibiotics are associated with weight gain in humans as well?

“For many years now, farmers have known that antibiotics are great at producing heavier cows for market,” Dr. Jan Blustein, MD, PhD, professor of population health and medicine told PreventDisease.com in a recent article.4 “While we need more research to confirm our findings, this carefully conducted study suggests that antibiotics influence weight gain in humans, and especially children…”

According to The Washington Post:5

“The use of antibiotics in young children might lead to a higher risk of obesity, and two new studies, one on mice and one on humans, conclude that changes of the intestinal bacteria caused by antibiotics could be responsible. Taken together, the New York University researchers conclude that it might be necessary to broaden our concept of the causes of obesity and urge more caution in using antibiotics.”

The first study, published in the journal Nature6, found that young mice treated with low doses of common antibiotics gained 10-15 percent more fat than the untreated controls. After surveying the gut bacteria in the mice, they found that mice treated with antibiotics had a different composition of gut bacteria compared to the untreated mice. Specifically, certain species of bacteria previously shown to be associated with obesity were found in higher concentrations in the treated mice. Furthermore, after genetic analysis of the bacteria’s metabolism, they discovered that genes responsible for fat synthesis had greater levels of activity in the treated mice.

According to lead author Martin Blaser:7

“The rise of obesity around the world is coincident with widespread antibiotic use, and our studies provide an experimental linkage. It is possible that early exposure to antibiotics primes children for obesity later in life.”

The co-author Dr Ilseung Cho added:8

“By using antibiotics, we found we can actually manipulate the population of bacteria and alter how they metabolize certain nutrients. Ultimately, we were able to affect body composition and development in young mice by changing their gut microbiome through this exposure.”

The second study, published in the International Journal of Obesity9, aimed to corroborate these findings in human subjects. The study, which included more than 10,000 children, found that treating babies with antibiotics before the age of six months old appears to predispose them to being overweight in childhood. Children exposed to antibiotics between the ages of six to 14 months did not have significantly higher body mass than unexposed children.

While this study does not prove causation between antibiotic use in infancy and later obesity, it does show a correlation, and the mechanism appears to be related to the way antibiotics alter your child’s gut flora. However, excess weight is not the only, or the worst problem that such imbalance can create. As previously explained by Dr. Natasha Campbell-McBride, children with imbalanced gut flora are more prone to develop neurological disorders, such as ADD/ADHD and various learning disorders. These children are also more prone to vaccine damage.

Prebiotics Research Highlighted at American Chemical Society Meeting

Increasingly, researchers are finding that proper nutrition is not just about getting the right kind and amount of nutrients needed for biological processes. You also need to nourish these non-human cells in your body, i.e. your gut microflora. This issue was recently raised at the 244th National Meeting & Exposition of the American Chemical Society. According to a recent article in NewHope360:10

“‘Just as people need food to thrive, so do the billions of healthful bacteria that live in our guts, our gastrointestinal tract,’ [Robert] Rastall [Phd] explained. ‘There’s a large and expanding body of scientific evidence that bacteria in the gut play a role in health and disease. Prebiotics are foods that contain nutrients that support the growth and activity of these friendly bacteria.’

Rastall contrasted prebiotics to the more familiar probiotics, already being promoted on the labels of food like yogurt and some dietary supplements.

Probiotic foods actually contain friendly bacteria like Lactobacillus acidophilus believed to release healthful substances as they grow in the GI tract. Prebiotics are indigestible food ingredients that provide no nutrition to people. Their purpose is to nourish the friendly bacteria among the estimated 100 trillion microbes living inside the human GI tract.”

While raised awareness about the importance of prebiotics and probiotics is good news, it comes with the territory that researchers are also working on ways to produce prebiotics that can easily be added to processed foods. Pre- and probiotics are very sensitive to heat, and excessive heat-treatment is a hallmark of most processed foods. It therefore stands to reason that any prebiotic inventions they come up with for the processed foods market will inevitably be of inferior quality, and I strongly recommend avoiding any and all processed foods that proclaim to contain prebiotics or probiotics, and stick with the real thing, i.e. traditionally fermented foods for healthful probiotics, and unprocessed whole foods for prebiotics, such as onions and garlic.

Study Finds “Clear Link” Between Inflammation, Bacterial Communities and Cancer

Demonstrating just how far-reaching the health impact of the bacterial balance in your gut can be, another recent study claims the key factor behind cancer appears to be ecological rather than genetic.11

Published in the journal Science12, the study suggests cancer may be due to a chain reaction that starts with inflammation that disrupts your gut ecosystems, allowing pathogens, such as E.coli, to invade your gut and cause cellular damage. The presence of E.coli was increased by a factor of 100 by inflammation, and 80 percent of germ-free mice infected with E.coli developed colorectal cancer, while germ-free mice inoculated with another common gut bacterium remained cancer-free, although these mice, like the others, did develop severe colitis (gut inflammation).

According to a press release by the University of North Carolina:13

“In a series of experiments conducted with mice prone to intestinal inflammation, the researchers found that inflammation itself causes significant simplification in diverse communities of gut microbes and allows new bacterial populations to establish major footholds. Among the bacterial taxa invading the disturbed intestinal ecosystem, the research team found a greatly increased presence of E. coli and related bacteria.

By putting E. coli bacteria into mice that were raised under sterile conditions, the team also found that the presence of E. coli promoted tumor formation. When regions of the E. coli genome known to be involved in DNA damage were removed, the ability of the E. coli to cause tumors was substantially decreased.

The researchers noted that the mouse results may have implications for human health as well, as they also found an E. coli variant with the suspect genes in high percentages of human patients with colorectal cancer and irritable bowel disease.

…’As is usual in human studies, we didn’t have cause and effect,’ Fodor noted. ‘We don’t know if microbes are somehow causing conditions to shift in the gut that would cause cancer or if there are conditions that are associated with cancer that would increase the openness of the gut to particular microbes. A shift in the microbial community is associated with inflammation… It is interesting that the microbial community is actually changing with the disease state, which indicates that it is either responding to or contributing to the disease state.'”

Like Bacteria, Cancer Cells Rely on Communication and Cooperation

In related news, an article published in Trends in Microbiology14 examines the shared traits of cancer cells and bacteria. Bacteria and cancer cells both use sophisticated communication to gain supremacy within the host. As reported by Medical News Today:15

“Inspired by the social and survival tactics of bacteria, the team presents a new picture of cancer as a meta-community of smart communicating cells possessing special traits for cooperative behavior. Using intricate communication, cancer cells can distribute tasks, share resources, differentiate, and make decisions. Before sending cells to colonize organs and tissues throughout the body (metastasis), ‘spying cells’ explore the body and return the cancer’s origin. Only then do metastatic cells leave the primary tumor and navigate to new posts.

Also like bacteria, cancer cells change their own environment. They induce genetic changes and enslave surrounding normal cells, forcing them to do the disease’s bidding – providing physical support, protecting them from the immune system, and more.”

Three years ago, I posted a TED video featuring Bonnie Bassler, in which she discusses how bacteria “talk” to each other using a chemical language that lets them coordinate defense and mount attacks. Cancer cells, as it turns out, employ similar forms of communication, and as discussed by Bassler, these discoveries pave the way for the development of drugs aimed at shutting down or altering cell-to-cell communication.

According to Medical News Today:

“The team also suggests further research into cancer ‘cannibalism,’ when cancer cells may consume their peers when they run out of resources. The idea is to send signals which trigger cancer cells to kill each other, which can be done with bacteria. Other researchers have demonstrated that injected bacteria can ‘outsmart cancer.’ Bacteria can be used to induce gap junctions between the cancer cells and immune cells, ‘teaching’ the immune system to recognize and kill the tumor cells.”

The Phenomenal Health Benefits of Fermented Vegetables

Cultured or fermented foods have a very long history in virtually all native diets, and have always been highly prized for their health benefits. The advent of processed foods dramatically altered the human diet, and we’re now reaping the results in the form of rapidly rising chronic health problems. I believe the shunning of traditionally fermented foods has a lot to do with this.

The culturing process produces beneficial microbes that are extremely important for your health as they help balance your intestinal flora. If you do not regularly consume the traditionally fermented foods below, a high-quality probiotic supplement will provide similar benefits:

  • Fermented vegetables
  • Lassi (an Indian yoghurt drink, traditionally enjoyed before dinner)
  • Fermented milk, such as kefir (a quart of unpasteurized kefir has far more active bacteria than you can possibly purchase in any probiotics supplement)
  • Natto (fermented soy)

When choosing fermented foods, steer clear of pasteurized versions, as pasteurization will destroy many of the naturally occurring probiotics. This includes most of the “probiotic” yogurts you find in every grocery store these days; since they’re pasteurized, they will be associated with all of the problems of pasteurized milk products and they typically contain added sugars, high fructose corn syrup, artificial coloring, or artificial sweeteners, all of which will only worsen your health.

Fermented foods are also some of the best chelators and detox agents available, meaning they can help rid your body of a wide variety of toxins, including heavy metals.

When you first start out, you’ll want to start small, adding as little as half a tablespoon of fermented vegetables to each meal, and gradually working your way up to about a quarter to half a cup (2 oz to 4 oz) of fermented vegetables or other cultured food with one to three meals per day. Since cultured foods are efficient detoxifiers, you may experience detox symptoms, or a “healing crisis,” if you introduce too many at once.

Learn to Make Your Own Fermented Vegetables

Fermented vegetables are easy to make on your own. It’s also the most cost-effective way to get high amounts of healthful probiotics in your diet. To learn how, review the following interview with Caroline Barringer, a Nutritional Therapy Practitioner (NTP) and an expert in the preparation of the foods prescribed in Dr. Natasha Campbell-McBride’s Gut and Psychology Syndrome (GAPS) Nutritional Program. In addition to the wealth of information shared in this interview, I highly recommend getting the book Gut and Psychology Syndrome, which provides all the necessary details for Dr. McBride’s GAPS protocol.

Although you can use the native bacteria on cabbage and other vegetables, it is typically easier to get consistent results by using a starter culture. Caroline prepares hundreds of quarts of fermented vegetables a week and has found that she gets great results by using three to four high quality probiotic capsules to jump start the fermentation process.

Caroline prepares the vegetables commercially and I used hers for a month before I started making my own. So, if you just want to put your toe in the water and see if you like them, you can order a jar or two and try them out. You can find her products on www.CulturedVegetables.net or www.CulturedNutrition.com.

AVOID This to Optimize Your Gut Flora!

Along with eating naturally fermented foods and/or taking a high-quality supplement, it’s essential that you avoid sugar, including fructose. Sugar nourishes pathogenic bacteria, yeast, and fungi in your gut, which may actually harm you more than its impact on insulin resistance. One of the major results of eating a healthy diet like the one described in my nutrition plan is that you cause your beneficial gut bacteria to flourish, and they secondarily perform the real “magic” of restoring your health.

Remember, an estimated 80 percent of your immune system is located in your gut, which is just one more reason why “tending to” your gut microflora is an essential element of good health. A robust immune system, supported by your flourishing inner ecosystem, is your number one defense against ALL disease, from the common cold to cancer.

I feel very strongly that if we can catalyze a movement to get more people to implement this ancient dietary wisdom to their normal eating patterns, then we’ll start seeing a radical change in health.

Sources and References

Source: Dr. Mercola

New Charges of Fraud on Heels of Abbott’s $1.5 Billion Plea Agreement .

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Only weeks after pleading guilty to criminal charges that it promoted its anti-seizure drug Depakote for uses not approved by the U.S. Food and Drug Administration (FDA), Abbott Labs is being sued again for similar charges with a different drug.

The new lawsuit alleges similar practices with Abbott’s cholesterol drug, TriCor. A former employee filed the whistleblower lawsuit.

Illegal Marketing Practices Mean More Trouble for Abbott

Earlier this year, Abbott settled for $1.6 billion for aggressively promoting their seizure drug Depakote to physicians for off-label use in elderly dementia patients, despite lacking evidence of safety or effectiveness.

In most cases, a billion-dollar (or more) fraud settlement would be a death-sentence for a business, but for the drug industry, it’s just another cost of doing business.

Now, just weeks later, Abbott is in the hot seat again after Amy Bergman, a former Abbott saleswoman, filed a federal lawsuit against them, alleging the company illegally promoted the drug TriCor for uses not approved by the FDA, such as reducing cardiac health risks in patients with diabetes.

The suit, which was filed under the False Claims Act in September 2009, was previously kept confidential in order to protect the whistleblower, but it was recently unsealed after federal and state governments declined to intervene.

Doctors are well within their legal rights to prescribe a drug for off-label use; it’s actually a common, albeit sometimes dangerous, practice. However, drug companies may not promote them for uses other than those that are FDA-approved.

According to a report in the Chicago Tribune:1

“Bergman, who says she was an Abbott saleswoman from 1999 through 2008, alleges in the suit that she was ‘trained, directed, incentivized, and encouraged’ by Abbott to promote TriCor for so-called off-label and medically unnecessary uses. She also claims the company directed her to give illegal kickbacks to doctors to encourage them to prescribe the drug.

In doing so, she alleges, the company defrauded federal health programs, including Medicaid, for an eight-year period between 2000 and 2008.”

Even Billion-Dollar Settlements are Not Enough to Ensure Public Safety

The idea behind Big Pharma lawsuits, especially those that settle in the hundreds of millions or billions, is that the punishment will make these criminal corporations start to straighten out, abandon their fraud and deception, their kickbacks, price-setting, bribery and all other illegal sales activities in favor of looking out for public health, which to date has been clearly ineffective.

It would appear that a far better strategy would be to file criminal charges against the responsible individuals and put them in prison. This would make them think hard and long about trying to get away with these types of illegal behaviors in the future.

In the pharmaceutical world, there seem to be few crimes that don’t pay off – as long as you don’t get caught (and even then, all you’re bound to receive is a fine (a mere slap on the wrist) as long as you’re large and important enough). So make no mistake – the leading pharmaceutical companies are also among the largest corporate criminals in the world, behaving as if they are little more than white-collar drug dealers.

Two years ago, I set out to investigate some of the criminal activities that some of the largest pharmaceutical companies had been convicted of lately, and the amount of gross misconduct, fraud and deceit I found was so insidious, so massive, and so overwhelming that it shocked even me. In all, no less than 19 drug companies made AllBusiness.com’s Top 100 Corporate Criminals List! And if it seems like the number of lawsuits that Big Pharma is settling – many of them out of court without going to trial – are rising, it’s because they are.

To get a picture of what’s been going on, FiercePharma compiled a list of top marketing settlements that the industry has made in the past 10 years. In total, drug makers have agreed to pay more than $11 billion so far for their misdoings. But the worst may yet be ahead: more than 900 whistleblower lawsuits were filed in the last year alone. Some of the most not able in history include:2

  1. 2012: GlaxoSmithKline to pay $3 billion for illegal marketing of Paxil, Welbutrin and downplaying safety risks of Avandia.
  2. 2009: Pfizer pays $2.3 billion for marketing fraud related to Bextra, Lyrica and other drugs.
  3. 2012: Johnson & Johnson will pay anywhere from $1.5 to $2.2 billion for illegal marketing of Risperdal.
  4. 2012: Abbott Laboratories settles for $1.6 billion for aggressively promoting their seizure drug Depakote for off-label use in elderly dementia patients, despite lacking evidence of safety or effectiveness.
  5. 2009: Eli Lilly pays $1.4 billion for promoting Zyprexa for off-label uses, often to children and the elderly.
  6. 2011: Merck settles for $950 million to resolve fraudulent marketing allegations related to Vioxx.
  7. 2005: Serono (now Merck Serono) paid $704 million after pleading guilty to two felony charges for fraudulent marketing related to a growth hormone to treat wasting in HIV patients.
  8. 2007: Purdue Pharma paid $634.5 million for fraudulently misbranding Oxycontin, and suggesting it was less addictive and less abused than other painkillers.
  9. 2010: Allergan paid $600 million for aggressively pushing Botox for unapproved uses.
  10. 2010: AstraZeneca settled for $520 million for trying to persuade doctors to prescribe its psychotropic drug Seroquel for unapproved uses ranging from Alzheimer’s disease and ADHD to sleeplessness and post-traumatic stress disorder (PTSD).
  11. 2007: Bristol-Myers Squibb paid $515 million for illegally promoting its atypical antipsychotic drug Abilify to kids and seniors.

Drug Company Fines

Year Fine Drug Company
2012 $1.6 Billion Depakote Abbott
2011 $950 Million Vioxx Merck
2010 $600 Million Botox Allergan
2010 $520 Million Seroquel Astra Zeneca
2009 $2.3 Billion Bextra Pfizer
2007 $515 Million Abilify Bristol Meyers
2007 $635 Million Oxycontin Purdue
2006 $7-4 Million Serono  

Drug Companies Control the System

It is a well-documented fact that the drug companies have the largest political lobbying organizations. They are some of the most clever marketers on the planet, as they know how to leverage their resources by bribing politicians to give them an unfair advantage in the marketplace, often “buying” legislation that is devastating to their competition. This is typically implemented through federal regulatory agencies like the FDA and the U.S. Centers for Disease Control and Prevention (CDC).

The pharmaceutical industry spent $1.5 billion lobbying Congress in the last decade, and in so doing has manipulated the government’s involvement with the way medicine is being practiced and secondarily reinforced our dependence on pharmaceuticals, through government policies. So it should come as no surprise that the federal government has a long history of siding with, and protecting, the drug companies, such as:

  • Previous drug company funding – to the tune of $2 billion – in helping drug companies bring flu vaccines to the market faster3
  • Letting drug giants like Pfizer off the hook for fraudulent marketing charges so their products could continue to flow through Medicare and Medicaid
  • Including incentives in the “Affordable Health Care for America Act” for people to purchase more expensive prescription drugs in favor of their less expensive over-the-counter cousins4

So there should be no doubt about the power the drug industry wields in shaping the U.S. health care system. There are simply so many revolving doors between the pharmaceutical industry and the government that it makes your head spin. Here are just a few examples:

  • The American Cancer Society has close financial ties to both makers of mammography equipment and breast cancer drugs. Other conflicts of interest include ties to, and financial support from, the pesticide, petrochemical, biotech, cosmetics, and junk food industries – the very industries whose products are the primary contributors to cancer!
  • The second-highest funding source for drug studies is the National Institute of Health (NIH), which is not the group of neutral government experts you may have assumed them to be. In fact, NIH accepts a great deal of money from Big Pharma and is deeply enmeshed with the industry.
  • Drug companies pay seven-figure amounts into FDA coffers to gain approval of their drugs. FDA staff knows that the cash means higher salaries and more perks in the agency budget. (Incidentally, the FDA’s commissioner Margaret Hamburg came straight from the boardroom of America’s largest seller of dental amalgam, Henry Schein, Inc.)
  • Conflicts of interest are also rampant in a mass vaccination infrastructure that has the same people who are regulating and promoting vaccines also evaluating vaccine safety.
  • The vaccine industry gives millions for conferences, grants, and medical education classes sponsored by the American Academy of Pediatrics (AAP). The vaccine industry even helped build AAP’s headquarters.

Who Can You Trust With Your Life?

This is the question you need to ask yourself when deciding on a plan for your own health care, as your very life is at stake and depends on the options you choose.

Unfortunately, as the ever increasing slew of pharmaceutical company lawsuits and settlements reveal, when it comes to making money, many industries throw ethics and integrity out the window. You cannot blindly trust that the companies making your medications have your best interest at heart.

There’s a mountain of evidence supporting the use of drug alternatives, and there’s very strong evidence that some “alternative” treatments, such as diet and exercise, are FAR more effective than any of the drugs currently in use. But if your doctor is also under the spell of drug-industry influence, you also cannot trust that he or she will inform you of them (or even be aware of their benefit).

Sources and References

 

Source: Dr. Mercola

 

 

 

Zonisamide: A Good Option for Newly Diagnosed Epilepsy?

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A large practical monotherapy trial for the treatment of new-onset epilepsy in adults shows once-daily zonisamide to be generally as effective and safe as controlled-release, twice-daily carbamazepine.

Few new antiepileptic drugs (AEDs) are studied for efficacy as monotherapy, and most such studies involve medically intractable epilepsy. Therefore, despite numerous new-generation AEDs, little guidance is available for choice in newly diagnosed epilepsy patients. Now, researchers have designed a manufacturer-funded, randomized, double-blind, international trial to test the noninferiority of zonisamide (ZNS) to carbamazepine (CBZ) in adults with newly diagnosed epilepsy. The 583 patients enrolled had only generalized tonic–clonic seizures and no evidence of idiopathic generalized epilepsy, new-onset epilepsy (with at least two seizures in the previous year and at least one seizure in the preceding 3 months), and no prior treatment with an AED for >2 weeks. The study was powered such that it met strict noninferiority criteria. The primary endpoint was the proportion of patients achieving 6-month seizure freedom. Secondary endpoints were the proportion achieving 12-month seizure freedom and times to 6- and 12-month seizure freedom. Safety and tolerability were examined by measuring the incidence of treatment-related adverse events, withdrawal, and laboratory abnormalities.

Of the 456 patients who completed the protocol, 79% and 68% taking ZNS achieved 6-month and 12-month seizure freedom, compared with 84% and 75% taking CBZ — fulfilling the strict noninferiority criteria. Intention-to-treat results supported the results of the per-protocol analysis. The times to both 6- and 12-month endpoints were the same in both arms. Few patients in either group withdrew because of treatment-related adverse events — primarily rash, dizziness, fatigue, and memory impairment. Two cases of severe rash occurred in the CBZ arm. One case of mild purpura occurred in the ZNS arm. None of the other eight reported severe adverse events had a clear association with treatment. No clinically significant laboratory abnormalities occurred in either arm.

Comment: This remarkable clinical trial addresses an important clinical question: Whether a newer-generation AED may be used as first-line monotherapy in newly diagnosed epilepsy. Moreover, the trial was designed to reflect typical clinical practice, given the population involved and the use of flexible dosing regimens for a meaningful treatment duration. Both treatment arms were well balanced, including frequency of seizures pretreatment, a strong predictor of prognosis. Because ZNS has few drug interactions and is formulated for once-daily dosing, the finding that ZNS is generally as effective as CBZ may actually change clinical practice.

Source: Journal Watch Neurology

 

 

 

 

 

 

Does Obesity Attenuate Aromatase Inhibition?

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Estrogen suppression was less complete in obese women and was significantly greater with letrozole than with anastrozole across all weight groups.

Obesity is associated with elevated levels of circulating estrogen because steroid precursors are converted to estradiol by aromatase enzymes in adipose tissue. Estrogen exposure is a well-known risk factor for developing breast cancer, and obese women with early stage breast cancer (in particular, those with body-mass index 35 kg/m2) who receive the aromatase inhibitor anastrozole may have greater risk for disease recurrence than women who are of normal weight or who receive tamoxifen. These findings raise concerns that aromatase inhibition as a risk-reduction strategy might be less effective in obese women, and that use of less-potent aromatase inhibitors such as anastrozole might adversely affect clinical outcome. Evidence suggesting that one third-generation aromatase inhibitor is more effective than another has been sparse, although preclinical data have shown that letrozole is more potent than anastrozole at suppressing levels of estradiol and estrone sulfate.

The ALIQUOT (Anastrozole vs. Letrozole, an Investigation of Quality of Life and Tolerability) study was an open-label crossover study of 54 postmenopausal women with hormone receptor-positive breast cancer who were treated with adjuvant aromatase inhibition in the form of 3 months of anastrozole followed by 3 months of letrozole, or the opposite sequence. Plasma estradiol and estrone sulfate levels were measured before and after each course of therapy. Now, the authors have analyzed the data in the context of BMI.

Baseline levels of both forms of estrogen were significantly correlated with BMI; for example, obese women had >2-fold higher estradiol levels than did women with BMI <25. Additionally, suppression of both estrogens was less complete in obese women than in leaner women, and was significantly greater with letrozole than with anastrozole across all weight groups.

Comment: As intriguing as they are, these data fall short of showing that letrozole should be the preferred aromatase inhibitor in the adjuvant setting for all women (or even for any specific weight group). Whether the differences in estrogen suppression with anastrozole or letrozole actually translate into different clinical outcomes cannot be determined from these data. Furthermore, the association between obesity and breast cancer is certainly more complicated than would be indicated by suggesting that estradiol alone is the culprit. Increased levels of insulin, inflammatory mediators, and other proteins all have been implicated as risk factors for breast cancer incidence and recurrence in obese patients.

Source: Journal Watch Oncology and Hematology