30. December 2009 by admin.

If you are a supplement follower, you may have already read a newspaper article today on the major study on Ginkgo and cognition just reported in JAMA.  Here is a firsthand copy of the abstract of the original article Ginkgo biloba for Preventing Cognitive Decline in Older Adults - A Randomized Trial:

“Context  The herbal product Ginkgo biloba is taken frequently with the intention of improving cognitive health in aging. However, evidence from adequately powered clinical trials is lacking regarding its effect on long-term cognitive functioning.  

Objective  To determine whether G biloba slows the rates of global or domain-specific cognitive decline in older adults.

Design, Setting, and Participants  The Ginkgo Evaluation of Memory (GEM) study, a randomized, double-blind, placebo-controlled clinical trial of 3069 community-dwelling participants aged 72 to 96 years, conducted in 6 academic medical centers in the United States between 2000 and 2008, with a median follow-up of 6.1 years.

Intervention  Twice-daily dose of 120-mg extract of G biloba (n = 1545) or identical-appearing placebo (n = 1524).

Main Outcome Measures  Rates of change over time in the Modified Mini-Mental State Examination (3MSE), in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and in neuropsychological domains of memory, attention, visual-spatial construction, language, and executive functions, based on sums of z scores of individual tests.

Results  Annual rates of decline in z scores did not differ between G biloba and placebo groups in any domains, including memory (0.043; 95% confidence interval [CI], 0.034-0.051 vs 0.041; 95% CI, 0.032-0.050), attention (0.043; 95% CI, 0.037-0.050 vs 0.048; 95% CI, 0.041-0.054), visuospatial abilities (0.107; 95% CI, 0.097-0.117 vs 0.118; 95% CI, 0.108-0.128), language (0.045; 95% CI, 0.037-0.054 vs 0.041; 95% CI, 0.033-0.048), and executive functions (0.092; 95% CI, 0.086-0.099 vs 0.089; 95% CI, 0.082-0.096). For the 3MSE and ADAS-Cog, rates of change varied by baseline cognitive status (mild cognitive impairment), but there were no differences in rates of change between treatment groups (for 3MSE, P = .71; for ADAS-Cog, P = .97). There was no significant effect modification of treatment on rate of decline by age, sex, race, education, APOE*E4 allele, or baseline mild cognitive impairment (P > .05).

Conclusion  Compared with placebo, the use of G biloba, 120 mg twice daily, did not result in less cognitive decline in older adults with normal cognition or with mild cognitive impairment.”

Because of the size and controlled nature of the study, I can find no reason to challenge its conclusions.  In fact the conclusions are compatible with those of a January 2007 review study Ginkgo biloba for cognitive impairment and dementia. “AUTHORS’ CONCLUSIONS: Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo. Many of the early trials used unsatisfactory methods, were small, and we cannot exclude publication bias. The evidence that Ginkgo has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unconvincing.”

The completely negative results are somewhat puzzling to me however, given a number of earlier research studies indicating that ginkgo biloba extract EGb 761, the same one used in the latest study,  has a capacity to promote neurogenesis in the hippocampus and improves cognitive functioning in small-animal models of Alzheimer’s disease.  For example:

·          The 2008 article Ginkgo Extract Has Multiple Actions on Alzheimer Symptoms, for example, states:  “In ongoing studies, a research team led by Luo found that giving mice with the human Alzheimer’s gene the ginkgo extract called EGb 761 improved the process of making new nerve cells in part of the brain much affected by the disease. The team found evidence that the protective effect of the extract also could be due to decreasing senile plaques or the clumping of beta-amyloid in the brain tissues.”  

·         Another relevant research report is the 2007 publication EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer’s disease. “The present findings suggest that 1) enhanced neurogenesis by EGb 761 may be mediated by activation of CREB, 2) stimulation of neurogenesis by EGb 761 may contribute to its beneficial effects in AD patients and improved cognitive functions in the mouse model of AD, and 3) EGb 761 has therapeutic potential for the prevention and improved treatment of AD.” 

·         The 2003 report Prenatal exposure of rats to Ginkgo biloba extract (EGb 761) increases neuronal survival/growth and alters gene expression in the developing fetal hippocampus states “These findings, which have provided the first genetic profile of the effects of EGb 761 on the developing rat hippocampus, increase our understanding of the molecular and genetic programs that are activated by the extract. These effects of EGb 761 may underlie its neuroprotective properties.” 

·         Studies of the neuroprotective effects of EGb 761 relating to Alzheimer’s Disease go back some time.  For example the 2000 publication The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid reported test-tube findings.  “We have investigated here the potential effectiveness of EGb 761 against toxicity induced by (Abeta)-derived peptides (Abeta25-35, Abeta1-40 and Abeta1-42) on hippocampal primary cultured cells, this area being severely affected in AD. A co-treatment with EGb 761 concentration-dependently (10-100 microg/mL) protected hippocampal neurons against toxicity induced by Abeta fragments, with a maximal and complete protection at the highest concentration tested.” 

·          The 2009 report Stimulation of Neurogenesis and Synaptogenesis by Bilobalide and Quercetin via Common Final Pathway in Hippocampal Neurons “Among the constituents tested, bilobalide and quercetin significantly increased cell proliferation in the hippocampal neurons in a dose-dependent manner. Bilobalide and quercetin also enhanced phosphorylation of cyclic-AMP Response Element Binding Protein (CREB) in these cells, and elevated the levels of pCREB and, brain-derived neurotrophic factor in mice brain. Immunofluorescence staining of synaptic markers shows remarkable dendritic processes in hippocampal neurons treated with either quercetin or bilobalide. Furthermore, both constituents restored amyloid-β oligomers (also known as ADDL)-induced synaptic loss and phosphorylation of CREB. The present findings suggest that enhanced neurogenesis and synaptogenesis by bilobalide and quercetin may share a common final signaling pathway mediated by phosphorylation of CREB. Despite a recent report showing that EGb 761 was insufficient in prevent dementia, its constituents still warrant future investigation.”

This all leaves me is thinking:

·        Despite the negative clinical studies related to cognition and dementia, there is much more to ginkgo biloba extract EGb 761 than vitamin-marketing smoke-and-mirrors.

·        I find the results of the large-scale human clinical study hard to understand given the results of the earlier animal studies but, hey, we are not rats and science is science.

·        For the present, I want to avoid any further claim that ginkgo biloba extract supplementation can prevent dementia or enhance cognition.

·        Until I can review the issue in more detail, I am leaving ginkgo biloba extract  as part of my Anti-aging firewalls supplement regimen because of possible health-giving actions the substance may have above and beyond cognition enhancement or dementia prevention.  For example, see Studies on the effect of Ginkgo biloba extracts on NF-kappaB pathway,  Ginkgo biloba Extract Inhibits Tumor Necrosis Factor- –Induced Reactive Oxygen Species Generation, Transcription Factor Activation, and Cell Adhesion Molecule Expression in Human Aortic Endothelial Cells and Ginkgo biloba extract reduces endothelial progenitor-cell senescence through augmentation of telomerase activity.

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29. December 2009 by admin.

A number of interesting studies related to calorie restriction (CR) have shown up recently.   I will discuss a few of these studies here, particularly ones relating CR to cancers.   I will discuss additional studies relating CR to gene activation in a Part II post and speculate there on what I think these studies mean. 

Calorie restriction  involves systematic dietary restriction of calorie intake.  It has long been known to work as an effective longevity-enhancing intervention.  “CR when not associated with malnutrition,^[1] improves age related health and slows the aging process in some animals and fungi. CR is one of the few dietary interventions that has been documented to increase both the median and maximum lifespan in a variety of species, among them yeast, fish, rodents and dogs. There are currently ongoing studies on primates to show if CR works on primates, and even though they are showing positive indications^[2][3] it is still not certain that CR has a positive effect on longevity for primates and humans, due to the very lengthy time required for the completion of such lifespan studies(ref).^[2][3] “ 

The news this week in interesting since it describes effects of limiting glucose on the cellular level on both normal and precancerous cells.  The online pre-publication is entitled Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression.  “We analyzed normal WI-38 and immortalized (precancerous) WI-38/S fetal lung fibroblasts and found that glucose restriction resulted in growth inhibition and apoptosis in WI-38/S cells, whereas it induced lifespan extension in WI-38 cells.” (Both sets of cells were exposed to either normal or reduced levels of glucose (sugar) while being grown in the laboratory.)  “Moreover, in WI-38/S (precancerous) cells glucose restriction decreased expression of hTERT (human telomerase reverse transcriptase) and increased expression of p16INK4a. Opposite effects were found in the gene expression of hTERT and p16 in WI-38 cells in response to glucose restriction.”   

Said differently, reducing glucose decreased telomerase expression and increased apoptosis in precancerous cells leading them to die off, and produced the opposite effect in normal cells. 

The observed effects were epigenetic.  “The altered gene expression was partly due to glucose restriction-induced DNA methylation changes and chromatin remodeling of the hTERT and p16 promoters in normal and immortalized WI-38 cells. Furthermore, glucose restriction resulted in altered hTERT and p16 expression in response to epigenetic regulators in WI-38 rather than WI-38/S cells, suggesting that energy stress-induced differential epigenetic regulation may lead to different cellular fates in normal and precancerous cells. Collectively, these results provide new insights into the epigenetic mechanisms of a nutrient control strategy that may contribute to cancer therapy as well as anti-aging approaches(ref).”  

A 2008 report in Science Daily Calorie Restriction Limits — And Obesity Fuels — Development Of Epithelial Cancers  further examines the CR-cancer connection.  “A restricted-calorie diet inhibited the development of precancerous growths in a two-step model of skin cancer, reducing the activation of two signaling pathways known to contribute to cancer growth and development,–“ –“ This study employed four diets, two representing calorie reductions of 30 percent and 15 percent, a control diet including 10 percent kilocalories from fat, and an obesity-inducing diet consisting of 60 percent kilocalories from fat.  Agents were then given to the mice to induce premalignant lesions called papillomas, which are precursors to cancer. — Those on the calorie restricted diets had statistically significant inhibition of papilloma formation compared with the other two diets. — In a separate experiment the development of carcinomas and the effect of dietary energy balance on conversion of papillomas to carcinomas was evaluated. This study demonstrated that dietary energy balance determines the number of carcinomas found through its effects on the number of premalignant lesions but does not affect the rate of malignant conversion.” 

The molecular signaling pathways involved in the CR-cancer link appear to be ones discussed several times previously in this blog, namely IGF-1, Akt and mTOR(ref)(ref)(ref).  “Epithelial cancers arise in the epithelium - the tissue that lines the surfaces and cavities of the body’s organs. They comprise 80 percent of all cancers.  “Calorie restriction and obesity directly affect activation of the cell surface receptors epidermal growth factor (EGFR) and insulin-like growth factor (IGF-1R),” Moore said. “These receptors then affect signaling in downstream molecular pathways such as Akt and mTOR.” – “increased Akt and mTOR signaling are linked to the growth, proliferation and survival of many human cancers.”  These findings provide the basis for future translational studies targeting Akt/mTOR pathways through combinations of lifestyle and pharmacologic approaches to prevent and control obesity-related epithelial cancers in humans,” DiGiovanni said(ref).” 

It is interesting that CR inhibiting the Akt-mTOR pathways as mentioned in this study and glucose limitation inhibiting expression of hTERT and promoting P16 in cancer cells as mentioned in the other study seem on the surface to be independent effects.  No doubt, on a deeper level these effects are linked.   

Several other research reports highlight the association between CR and lower levels of cancer.  One research study  reported in 2008 “sheds light on the connection between obesity, calorie intake and pancreatic cancer by comparing a calorie restricted diet, an overweight diet and an obesity-inducing diet in a strain of mice that spontaneously develops pancreatic lesions that lead to cancer. – “Our findings indicate that calorie restriction hinders development of pancreatic cancer, which could have implications for prevention and treatment of pancreatic tumors caused by chronic inflammation and obesity.”–  The group’s analysis points to a connection between calorie intake and a protein called Insulin-like Growth Factor (IGF) -1, with obesity increasing and calorie restriction decreasing levels of IGF-1. IGF-1 is an important growth factor known to stimulate the growth of many types of cancer cells. Inflammatory signaling proteins also were found to be reduced in the blood of the calorie-restricted mice.”

“Mice on the heavier diets had significantly more lesions and larger lesions than those on the restricted calorie diet, — These lesions develop into pancreatic cancer and virtually all of these mice die within six to eight months.   The researchers fed the calorie restricted group a diet that was 30 percent lower in calories than that consumed by the overweight group and 50 percent lower than the obese group. Only 7.5 percent of mice on the calorie-restricted diet developed pancreatic lesions at the end of the experiment, and these lesions were so small that none exhibited symptoms of illness. For mice on the overweight diet, 45 percent developed lesions, as did 57.5 percent of those on the obesity-inducing diet. Lesions were also much larger in the overweight and obese mice than the calorie restricted mice. –. Pancreatic cancer is the fourth leading cause of cancer death and remains mostly intractable to existing treatments(ref). 

Sex differences and hormonal factors may also impact on the results of CR.  Regarding a 2008 study (ref) done by Spanish and Italian researchers, “Using lab rats as stand-ins for humans, the researchers found that the livers of both female rats and calorie-restricted rats produced different levels of 27 proteins than male rats or those on a normal diet. — The findings suggest that a previously unrecognized set of cellular pathways may be involved in the longevity boost from being female and eating a sparse diet, the study says, suggesting that these insights could lead to new ways of boosting human longevity(ref).” 

I will continue this discussion in the follow-up post, Calorie restriction research roundup – Part I.

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26. December 2009 by admin.

A news item appeared this week citing mortality and morbidity statistics for patients who undergo abdominal surgery.  This led me to probe a bit into how surgery risks increase with age and even to speculate on why. 

First of all, to be clear on terminology, morbidity relates to ongoing disease, sickness or poor health and mortality describes the probability of death, usually measured in numbers of death per thousand individuals.  Both are cause-independent, that is, if mortality connected with  cancer surgery is counted in terms of deaths in the year following the operation, deaths due to pneumonia, stroke or other causes would be counted along with deaths due to cancer.  Comorbidity refers to the presence of one or more additional diseases or disorders, such as pneumonia and hypertension going along with lung cancer. 

In the latest study Impact of advancing age on abdominal surgical outcomes “Nader N. Massarweh, M.D., and colleagues at University of Washington School of Medicine, Seattle, examined complication and death rates of 101,318 adults age 65 or older who underwent common abdominal procedures such as cholecystectomy (gall bladder removal), hysterectomy and colectomy from 1987 to 2004. Complications were recorded within 90 days of discharge and deaths were recorded within 90 days of hospital admission(ref).” 

A review of the publication states:  “Older adults have a higher risk of complications and early death after common abdominal surgeries than doctors thought, a new study found.”

“Among patients 65 and older, the 90-day complication rate after abdominal surgery was 17.3% and the 90-day death rate was 5.4%, according to an online report in the Dec. 21 Archives of Surgery.”

“The likelihood of complications increased as patients aged beyond 65 years, with the researchers finding the following associations between age and complication frequency (trend test, P<0.001):

• 65 to 69 years, 14.6%
• 70 to 74 years, 16.1%
• 75 to 79 years, 18.8%
• 80 to 84 years, 19.9%
• 85 to 89 years, 22.6%
• 90 and older, 22.7%

Similarly, older patients were at higher risk of mortality. Death rates by age group were (trend test, P<0.001):

• 65 to 69 years, 2.5%
• 70 to 74 years, 3.8%
• 75 to 79 years, 6.0%
• 80 to 84 years, 8.1%
• 85 to 89 years, 12.6%
• 90 and older, 16.7%”

“Among older adults, the risk of complications and early death after commonly performed abdominal procedures is greater than previously reported,” Nader N. Massarweh, MD, of University of Washington School of Medicine, Seattle, and colleagues concluded(ref).”  What I find interesting is the rapid acceleration of death rates with age.  Comparing the 65-69 range with the 85-89 range, over a 20 year age interval the death rate associated with a surgery has gone up by a factor of five.

Reading this report led me to wonder if the reported  magnitudes of increase in risks with advancing age are typical or whether they are unique to the kinds of surgery studied.  So, I set out to look for other large scale studies of age-related morbidity and mortality associated with different surgical procedures.  One such study is reported in the 2005 paper Early mortality among Medicare beneficiaries undergoing bariatric surgical procedures.  “Results:  A total of 16,155 patients underwent bariatric procedures (mean age, 47.7 years [SD, 11.3 years]; 75.8% women). The rates of 30-day, 90-day, and 1-year mortality were 2.0%, 2.8%, and 4.6%, respectively. Men had higher rates of early death than women (3.7% vs 1.5%, 4.8% vs 2.1%, and 7.5% vs 3.7% at 30 days, 90 days, and 1 year, respectively; P<.001). Mortality rates were greater for those aged 65 years or older compared with younger patients (4.8% vs 1.7% at 30 days, 6.9% vs 2.3% at 90 days, and 11.1% vs 3.9% at 1 year; P<.001).   After adjustment for sex and comorbidity index, the odds of death within 90 days were 5-fold greater for older Medicare beneficiaries (aged 75 years; n = 136) than for those aged 65 to 74 years (n = 1381; odds ratio, 5.0; 95% confidence interval, 3.1-8.0).”  Normally, the risk of death associated with bariatric surgery is low (0.5%), but apparently the risk rises very steeply with advanced age, much as observed in the first-mentioned study.

Both of the above studies were concerned with surgeries of the GI track.  Turning to a different kind of operative procedure the report Coronary arteriography and coronary artery bypass surgery: morbidity and mortality in patients ages 65 years or older. A report from the Coronary Artery Surgery Study, ‘Of 2144 patients age 65 years or older entered into the registry of the Coronary Artery Surgery Study (CASS) who had coronary arteriography, 1086 underwent isolated coronary artery bypass grafting. Complications of angiography included death in four patients and nonfatal myocardial infarction in 17. Eight patients suffered neurologic complications, which were transient in five. The perioperative mortality was 5.2% (57 of 1086), which is significantly greater than the perioperative mortality of 1.9% (151 of 7827) in patients younger than 65 years entered in CASS (p less than 0.001). There was a trend toward an increased mortality rate with age; it was 4.6% (37 of 803) in patients age 65-69 years, 6.6% (16 of 241) in those 70-74 years and 9.5% (four of 42) in those 75 years or older. The duration of hospital stay after operation was significantly longer for the patients 65 years or older than for the patients younger than 65 (13.3 vs 11.4 days; p less than 0.001).”  Again, the observed increase of mortality with age was drastic and consistent with that reported in the other studies.

I checked out one more study Effect of patient age on increasing morbidity and mortality following urogynecologic surgery.  “There were 264,340 women in our study population. Increasing age was associated with higher mortality risks per 1000 women (<60 years, 0.1; 60-69 years, 0.5; 70-79 years, 0.9; ≥80 years, 2.8; P < .01) and higher complication risks per 1000 women (<60 years, 140; 60-69 years, 130; 70-79 years, 160; ≥80 years, 200; P < .01). Using multivariable logistic regression, increasing age was associated with an increased risk of death (60-69 years, odds ratio [OR] 3.4 [95% CI 1.7-6.9]; 70-79 years, OR 4.9 [95% CI 2.2-10.9]; ≥80 years, OR 13.6 [95% CI 5.9-31.4]), compared with women <60 years. The risk of peri-operative complications was also higher in elderly women 80 years of age and older (OR 1.4 [95% CI 1.3-1.5]) compared with younger women.”  Again, a similar pattern was observed, 5.6 times he mortality risk in the oldest group compared to that that in the younger group.  Amazing how similar these rates are to those observed in the first-mentioned study above, and amazing the difference that 20 years makes at the end of life! 

These results are not surprising given what we know about aging.  Vulnerability to multiple causes of illness and death starts to accelerate around 50, picks up in the 60s, accelerates further in the 70s and goes into warp overdrive in the 80s – resulting in everybody in known history being dead by age 123.  There are many ways to explain this effect, the 14 theories of aging and seven candidate theories in my treatise being the main ones from a scientific viewpoint.  The darkest view is that given in my blog entry Homicide by DNA methylation.   According to that view, lifelong progression of DNA methylation causes accumulation of irreversible DNA mutational damage.  Even if you could reverse the methylation at old age you could not undo the mutations so its soon curtains for us old folk, no matter what.  End of discussion.  The other theories of aging to some extent allow more hope for the prospect of extending life.  Discovering where the best realistic hope lies is an ultimate objective I have in following and understanding the research described in this blog.

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21. December 2009 by admin.

Genetics, genomics, epigenetics and epigenomics are important recurrent topics in the writing of this blog.  The discussions have included many examples of longevity-related  genes, “shortivity” genes, cancer and inflammation-related genes, gene silencing and gene mutations.  For reference purposes I list the genes I have discussed or mentioned with pointers to the corresponding blog entries.

Telomerase genes

·        “Genetic mutations in the components of telomerase (the RNA template sequence hTERC, reverse transcriptase hTERT, and Syskerin DKC1) have recently been implicated in a variety of bone marrow failure syndromes, idiopathic pulmonary fibrosis, and more recently, acute myeloid leukemia (AML)(ref).”

·        “The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Short telomeres in such patients are implicated in a variety of disorders including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer(ref).”

·        See also the blog entry Hoyeraal-Hreidarsson Syndrome and telomere dysfunction

VHL-1 gene:  See the blog entry Another longevity-related biochemical pathway.

P-53 gene:  See the blog entry P53 gene, normal and mutant, in the news.  Also see the blog entry: Senesco and the Factor 5A1 gene.

P-50/65 and NF-kappaB: See the blog entry Autoimmune diseases and lymphoma – Part II: focus on inflammation

P16 and P19 genes: See the blog entries Linking up the theories of aging and Revisiting the naked mole rat – two factors we can emulate for longevity 

WFS1, CISD2, WRN and LMNA genes: See the blog entry Another rare genetic disease, and shortevity genes   

LMNA gene: See the blog entry Progerin, HGPS and a possible new theory of aging. 

AOX gene:  This is a possibly-protective gene missing in humans.  See the blog entry Gene therapy for fruit flies with Parkinson’s Disease 

FRAP1 gene and mTOR:  See the blog entry Longevity genes, mTOR and lifespan. 

FA gene:  See the blog entry A simple treatment for human genetic diseases. 

CFTR, GSTZ1_02 ,pG42R), AKR1C3_35), TYR_02, SCARB1_03, SLC23A1_05. CD80_04, BCL2L1_03, CASP9, EPHX1_15, and ERCC4_01 genes:  See the blog entry Gene variations and diseases – far from simple. 

PINK1 gene:  See the blog entry Mitochondria and Parkinson’s Disease. 

RAS2 and SCH9 genes: See the blog entry Life extension by a factor of 10.

APOE4 and TOMM40  genes: See the blog entry APOE4 gene variant, memory loss and Alzheimer’s Disease risk  

Fas and FasL genes: See the blog entry: Fascinating dance of death and life – Fas, FasL and diseases.  See also : Autoimmune diseases and lymphoma: Part I: focus on Lupus.

TREX1 gene: See the blog entry: Autoimmune diseases and lymphoma: Part I: focus on Lupus.

TNF superfamily of genes within chromosome 6p21.3 and Bcl-2 gene: See the blog entry: Autoimmune diseases and lymphoma – Part III: focus on lymphomas.

P13k gene: See the blog entry: Big pharma is targeting cancer stem cells.  Also see Nrf2 and cancer chemoprevention by phytochemicals, Rosmarinic acid, and Breakthrough telomere research finding.

FTO gene: See the blog entry: The “skinny” about the “fatso” gene FTO. 

FOXO genes:  See the blog entry: FOXO genes and protecting stem cells — What does resveratrol do?  

KLOTHO gene: See the blog entry: Klotho anti-aging gene in the news. 

NRG1 gene: See the blog entry: The NRG1 Gene – an important new tumor suppressor gene? And press sensationalism about it. 

BRCA1, BRCA2, APC, RB1. WIF1, MLH1, TIMP3, PTEN, APC, CD95, RASSF1A, E cadherin, RECK and GSTP1 genes:  See the blog entry: DNA demethylation – a new way of coming at cancers.

Factor 5A1 gene:  See the blog entry: Senesco and the Factor 5A1 gene. 

RPE65 gene: See the blog entry: A gene therapy home run. 

UCP1, PRDM16 genes: See the blog entry: Getting skinny from brown fat.

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19. December 2009 by admin.

A news item appeared this week saying that British researchers have succeeded in creating complete genome mappings for normal tissues, lung-cancer tissues and melanoma tissues in a single patient.  While the result is an exciting breakthrough in one sense, it also highlights the very long way there is still to go in decoding cancer genomes and using this information practically to identify cancer susceptibilities, to identify cancer preventative measures and to identify new anti-cancer therapies. I will say a few words about the background of this work, describe the new finding and mention a practical use of existing knowledge of cancer-related gene polymorphisms.

The website of the The Cancer Genome Project of the Wellcome Trust Sanger Institute in the UK provides an introduction:  “All cancers occur due to abnormalities in DNA sequence. Throughout life, the genome within cells of the human body is exposed to mutagens and suffers mistakes in replication. These corrosive influences result in progressive, subtle divergence of the DNA sequence in each cell from that originally constituted in the fertilised egg. Occasionally, one of these somatic mutations alters the function of a critical gene, providing growth advantage to the cell in which it has occurred and resulting in the emergence of an expanded clone derived from this cell. Acquisition of additional mutations, and consequent waves of clonal expansion result in the evolution of the mutinous cells that invade surrounding tissues and metastasise. One in three people in the Western world develop cancer and one in five die of the disease. Cancer is therefore the commonest genetic disease. — The identification of genes that are mutated and hence drive oncogenesis has been a central aim of cancer research since the advent of recombinant DNA technology. The Cancer Genome Project is using the human genome sequence and high throughput mutation detection techniques to identify somatically acquired sequence variants/mutations and hence identify genes critical in the development of human cancers. — –“.  “The census is not static but rather is updated regularly/as needed.  – Currently, more than 1% of all human genes are implicated via mutation in cancer. Of these, approximately 90% have somatic mutations in cancer, 20% bear germline mutations that predispose to cancer and 10% show both somatic and germline mutations.”

The site classifies known cancer genes as follows by type of genetic error:

Clicking on any of the error categories will show the oncogenes in the category. 

A discussion of genetic errors can be found in my blog entry Gene variations and diseases – far from simple.

The new findings

The 16 December advance online publication by members of the Wellcome Trust Sanger Institute is entitled A comprehensive catalogue of somatic mutations from a human cancer genome. By sequencing the entire genome of one patient with lung cancer and melanoma three times: once in healthy cells, once in lung cancer cells and once in melanoma cells, it was possible to identify the mutated genes associated with each of the two types of cancer. Amazing numbers of mutations were found:  33,000 in the melanoma genome, 23,000 in the lung cancer genome.

A fascinating aspect of this work is discovery of traces of pre-disease history in the mutated genes including the efforts of the body’s genetic repair mechanisms.  “These are the two main cancers in the developed world for which we know the primary exposure,” explains Professor Mike Stratton, from the Cancer Genome Project at the Wellcome Trust Sanger Institute. “For lung cancer, it is cigarette smoke and for malignant melanoma it is exposure to sunlight. With these genome sequences, we have been able to explore deep into the past of each tumour, uncovering with remarkable clarity the imprints of these environmental mutagens on DNA, which occurred years before the tumour became apparent. — “We can also see the desperate attempts of our genome to defend itself against the damage wreaked by the chemicals in cigarette smoke or the damage from ultraviolet radiation. Our cells fight back furiously to repair the damage, but frequently lose that fight(ref).”

A companion December 16 advance online publication A small-cell lung cancer genome with complex signatures of tobacco exposure relates to the mutational process leading from tobacco smoking to lung cancer and how the footprints of this process can be found in the mutated genes found in the cancer cells. “Using massively parallel sequencing technology, we sequenced a small-cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. A total of 22,910 somatic substitutions were identified, including 134 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general, expression-linked repair pathway were evident.” Lung cancer kills about 1.3 million people a year worldwide.“

“In the melanoma sample, we can see sunlight’s signature writ large in the genome,” says Dr Andy Futreal, from the Wellcome Trust Sanger Institute. “However, with both samples, because we have produced essentially complete catalogues, we can see other, more mysterious processes acting on the DNA. Indeed, somewhere amongst the mutations we have found lurk those that drive the cells to become cancerous. Tracking them down will be our major challenge for the next few years(ref).”

The work leaves many questions still to be answered such as:  One is “Which gene mutations are primary and essential to the cancer and which ones are just going along for the ride?” Which gene mutations lead to which others, how, when and why?”  Expanding the research to include more people with the same cancers and people with other cancers may help to answer the questions.  There are perhaps 100 other kinds of cancer that can be studied in the same way, so there is a long ways yet to go. 

Benefits of genomic profiling of cancers could be enormous in the realm of personalized medicine, such as:

·         identification of cancer susceptibilities long before occurrence of actual cancers,

·         being able to know how far along a cancer-susceptible person is from actually manifesting the disease,

·         knowing how to stop disease progression at that point,

·         new lifestyle, drug, genetic and epigenetic interventions to prevent occurrence of and cure of specific cancers.

There is already some payoff being realized from knowledge of certain specific gene mutations, for example the BRCA1 and BRCA 2 mutations. These mutations are both known to be associated with increased risk for breast and ovarian cancers. The December 17, 2009 report Gene Mutation in Cancer Patients Leads to Earlier Diagnosis “Breast cancer patients with a particular gene mutation are diagnosed years earlier than the previous generation who also had the disease, according to a study conducted at The University of Texas M.D. Anderson Cancer Center.  — Background information provided in the study’s paper revealed that it is estimated that 5% to 10% of all breast cancers are associated with either the BRCA1 or 2 mutation, both of which are associated with an increased risk for breast and ovarian cancers. Furthermore, according to the American Cancer Society (ACS), women with BRCA1 or 2 have a 60% lifetime risk of developing breast cancer, compared to a 12% risk for women in the general population.”

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16. December 2009 by admin.

I have covered a number of new-science approaches to detecting, preventing or curing cancers in this blog and in other writings.  The context was set in an early blog entry From four-pound hammer to smart molecules – on cancer treatments.  Here is a listing of the new approaches and twists on old ones, citing relevant blog and writing entries:

*  DNA demethylation:  See DNA demethylation – a new way of coming at cancers.  Also Homicide by DNA methylation, and Embryonic Stem cell research news.  In my treatise see the candidate theory of aging Epigenomic Changes in DNA Methylation and Histone Acetylation and the blog entry Epigenetics, Epigenomics and Aging.

*  Use of terminator stem cells:  See Terminator stem cells in the early pipeline.  See also Trojan-horse stem cells might offer an important new cancer therapy, and Progress in fighting glioblastoma.

*  Using TRAIL to kill cancer cells: See On the TRAIL of a selective cancer treatment.  Also note Terminator stem cells in the early pipeline.

*  Keeping telomeres long:   See Revisiting telomere shortening yet-again.  The discussion in the treatise section Telomere Shortening and Damage is relevant for background.

*  Telomerase activation affect on cancer stem cells:  See Extra-telomeric benefits of telomerase – good news for telomerase activators. 

*  Gene therapy: See for example A Fascinating dance of death and life – Fas, FasL and diseases. 

*  Targeting the Factor 5A1 gene: See Senesco and the Factor 5A1 gene

* Inhibition of expression of NF-kappaB:  See in my treatise discussions in the Susceptibility to Cancers Firewall and in the Programmed Epigenomic Changes Firewall.

*  Taking advantage of the NRG1 GENE:  See The NRG1 Gene – an important new tumor suppressor gene?, Also see DNA demethylation – a new way of coming at cancers

*  Targeting the Nrf2 gene: see Nrf2 and cancer chemoprevention by phytochemicals.  Also Phytochemicals – focus on caffeic acid and Health and longevity benefits of dark chocolate.

* Targeting cancer stem cells:  see News on disabling cancer stem cells, Big Pharma is targeting cancer stem cells, Update on cancer stem cells, and On cancer stem cells.

*  Plant-derived substances:   See Progress in fighting glioblastoma re curcumin,  see Cordyceps militaris and cancer, and Blueberries and health – the research case.

*  Chemotherapy combinations and substances in clinical trials for lymphomas: see Autoimmune diseases and lymphoma – Part III: focus on lymphomas 

*  Cancer immunotherapy:  See Dendritic cell cancer immunotherapy 

*  DHMEQ:  See More on DHMEQ and a no-no mind bender and DHMEQ.

* Prevention of oncogenic radiation-induced DNA damage:  See my paper Protection Against Radiation - The Second Line of Defense.

For the time being it appears that the multiple forms of cancer offer multiple challenges and that multiple approaches  will be needed to deal with these challenges.  Thus, each of the above approaches and others yet may turn out to have their roles. I will continue to monitor these and other emerging developments.

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15. December 2009 by admin.

Newly-reported research involves progress in disabling cancer stem cells via the notch pathway.  Regarding cancer stem cells, see the blog entry Big pharma is targeting cancer stem cells. “As I wrote in my July 2009 post On cancer stem cells, most cancer therapies are based on killing cancer cells – as many cells as possible.  But cancers frequently and persistently recur after bouts of radiation or chemotherapy.  The culprit is thought to be cancer stem cells, where any surviving ones simply go about making new cancer cells.  A new therapeutic concept is therefore to focus on killing the cancer stem cells.  “While normal stem cells are essential for development, play a key role in tissue maintenance, and aid in repair, cancer stem cells are believed responsible for tumorigenesis, metastases, and cancer recurrence(ref).”  I reported further research regarding cancer stem cells in my August 2009 blog post Update on cancer stem cells.”  

I also briefly discussed how the Notch pathway is involved in tumorgenesis in the blog post Niche, Notch and Nudge.

A news report appeared yesterday indicating “Studies in animals and women with advanced breast cancer showed the experimental compound MK-0752, under development by Merck & Co Inc, was able to kill off cancer stem cells that linger in the breast after chemotherapy. — In the latest study, supported by funding from Merck, Chang and colleagues injected mice with breast cancer cells taken from patients and grew human tumors in the mice that were identical to those growing in women. The team then studied the specific properties of the cancer stem cells, and focused on the Notch pathway, which is important for normal development of breast tissue.  “We found this was also active in cancer stem cells,” Chang said in a telephone interview. Chang said breast cancer stem cells were dependent on the Notch pathway for survival. Merck’s drug MK-0752, a compound called a gamma-secretase inhibitor, blocks that pathway. When the team combined the drug with regular chemotherapy in mice, “we found we managed to hit cancer stem cells,” Chang said.”

The team also did a small human study involving 35 women with advanced breast cancer. Breast cancer biopsies before and after treatment show the MK-0752 treatment reduces the number of breast cancer stem cells.  “In the human studies, the researchers evaluated the stem cells or tumor initiating cells in biopsies taken before and after treatment. In both human and animal studies, inhibition of the pathway reduced the population of these tumor-originating cells that would otherwise remain after chemotherapy. — The next step in research is to take this into larger studies involving patients (Phase III clinical studies), Chang said. “If what we believe is true, we would eventually start using this therapy earlier in treatment,” said Chang(ref).”

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13. December 2009 by admin.

The nanotechnology and epigenomics fields are barely 10 years old.  Both show enormous future potential.  An important application has recently emerged that involves both of them as pointed out in a recent research announcement New DNA Test Uses Nanotechnology to Find Early Signs of Cancer. 

I have discussed DNA methylation several times before.  See the blog posts Epigenetics, Epigenomics and Aging and DNA methylation, personalized medicine and longevity in this blog.  Also the blog entry Homicide by DNA methylation which discusses the possibility that DNA methylation may be the cause of aging and death in higher organisms. DNA methylation involves the chemical attachment of a methyl group to a cytosine nucleotide in the DNA on chromosomes.  DNA methylation happens throughout life and modifies the epigenomic state of a cell, that is, helps determine which genes are turned on and which genes are turned off.  In general, methylation silences genes, that is turns them off.  When key tumor-suppressor genes are silenced due to methylation, vulnerabilities to cancers exist.  Knowledge that tumor suppressor genes are methylated is potentially valuable to alert disease susceptibility and to allow preventive measures to be taken.

Tests for silenced tumor suppressor genes exist but they are awkward, involve multi-step laboratory procedures, and less sensitive than the new method.  The new discovery possibly opens the door for widespread economic testing for multiple cancer-related methylation patterns.

“Using tiny crystals called quantum dots, Johns Hopkins researchers have developed a highly sensitive test to look for DNA attachments that often are early warning signs of cancer. This test, which detects both the presence and the quantity of certain DNA changes, could alert people who are at risk of developing the disease and could tell doctors how well a particular cancer treatment is working.  – When the quantum dots are exposed to certain types of light, they transfer the energy to fluorescent molecules, shown as pink globes, that emit a glow. This enables researchers to detect and count the DNA strands linked to cancer(ref).”

The new testing method is reported in the paper MS-qFRET: A quantum dot-based method for analysis of DNA methylation in the August issue of Genome Research. Samples were collected by spitting on a chip.  “Here we report an ultrasensitive and reliable nanotechnology assay, MS-qFRET, for detection and quantification of DNA methylation. Bisulfite-modified DNA is subjected to PCR amplification with primers that would differentiate between methylated and unmethylated DNA. Quantum dots are then used to capture PCR amplicons and determine the methylation status via fluorescence resonance energy transfer (FRET). Key features of MS-qFRET include its low intrinsic background noise, high resolution, and high sensitivity. This approach detects as little as 15 pg of methylated DNA in the presence of a 10,000-fold excess of unmethylated alleles, enables reduced use of PCR (as low as eight cycles), and allows for multiplexed analyses. The high sensitivity of MS-qFRET enables one-step detection of methylation at PYCARD, CDKN2B, and CDKN2A genes in patient sputum samples that contain low concentrations of methylated DNA, which normally would require a nested PCR approach. The direct application of MS-qFRET on clinical samples offers great promise for its translational use in early cancer diagnosis, prognostic assessment of tumor behavior, as well as monitoring response to therapeutic agents.”  

While this post describes a better means for detecting cancer-related DNA methylation, my November 1 post discusses the hope of reversing such methylation once it is detected DNA demethylation – a new way of coming at cancers.

This work is another example of how technologies from diverse disciplines are coming together so as to accelerate the state-of-the-arts of disease prevention, detection, and therapy.  And, of course, these will also extend average longevity.  Like a multitude of other developments, the practical benefits of the most basic discoveries are probably 4-15 years out.  See, for example, yesterday’s post Terminator stem cells in the early pipeline, the December 6 post Personalized medicine and genetic drug interaction, the November 24 post It’s a long way to stem cell treatment, and the November 11 item A gene therapy home run.

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13. December 2009 by admin.

The concept here is engineering stem cells so they differentiate into body cells that target, go after and kill “bad” cells, such as cells infected with HIV or cancer cells.  It is a fairly new approach.  Since stem cells have an uncanny ability to be welcomed in the body and get around in it, they potentially make very attractive seek-and-destroy cells.

A December 8 2009 Science Daily story Stem Cells Can Be Engineered to Kill HIV, Scientists Show is a this-week example.  “Researchers from the UCLA AIDS Institute and colleagues have for the first time demonstrated that human blood stem cells can be engineered into cells that can target and kill HIV-infected cells –.  Taking CD8 cytotoxic T lymphocytes — the “killer” T cells that help fight infection — from an HIV-infected individual, the researchers identified the molecule known as the T-cell receptor, which guides the T cell in recognizing and killing HIV-infected cells. These cells, while able to destroy HIV-infected cells, do not exist in enough quantities to clear the virus from the body. So the researchers cloned the receptor and genetically engineered human blood stem cells, then placed the stem cells into human thymus tissue that had been implanted in mice, allowing them to study the reaction in a living organism.  – The engineered stem cells developed into a large population of mature, multifunctional HIV-specific CD8 cells that could specifically target cells containing HIV proteins. The researchers also found that HIV-specific T-cell receptors have to be matched to an individual in much the same way that an organ is matched to a transplant patient. — The next step is to test this strategy in a more advanced model to determine if it would work in the human body –”This approach could be used to combat a variety of chronic viral diseases,” said Zack, who is also a professor of microbiology, immunology and molecular genetics (at UCLA). “It’s like a genetic vaccine.”” 

A May 2009 Science Daily story Adult Stem Cells From Bone Marrow Made To Kill Metastatic Lung Cancer Cells In Mice describes another example.  “Researchers in London have demonstrated the ability of adult stem cells from bone marrow (mesenchymal stem cells, or MSCs) to deliver a cancer-killing protein to tumors. — The genetically engineered stem cells are able to home to the cancer cells, both in culture and in mouse models, and deliver TNF-related apoptosis-inducing ligand (TRAIL), destroying the tumor cells while sparing normal cells.”  This story was covered in the blog entry Trojan-horse stem cells might offer an important new cancer therapy.  And, regarding the payload TRAIL, see the blog entry On the TRAIL of a selective cancer treatment.

A 2005 Science Daily story Researchers Use Human Embryonic Stem Cells To Kill Cancer Cells described an earlier related development.  In this case, human embryonic stem cells were coaxed to differentiate into NK (natural killer) cells.  “Natural killer cells (or NK cells) are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses. The cells kill by releasing small cytoplasmic granules of proteins called perforin and granzyme that cause the target cell to die by apoptosis(ref).”

A related but not quite terminator-cell approach is described in an October 2009 Science Daily story The Stem Cells Which ‘Fool Immune System’ May Provide Vaccination For Cancer.  In this case “Scientists from the United States and China have revealed the potential for human stem cells to provide a vaccination against colon cancer, reports a study published in Stem Cells. — “This finding potentially opens up a new paradigm for cancer vaccine research,” said Dr. Zihai Li. “Cancer and stem cells share many molecular and biological features. By immunizing the host with stem cells, we are able to ‘fool’ the immune system to believe that cancer cells are present and thus to initiate a tumor-combating immune program –‘ .The team vaccinated laboratory mice with human embryonic stem (hES) cells and discovered a consistent immune response against colon cancer cells. The team witnessed dramatic decline in tumor growth within the immunized mice. This revealed that immunized mice could generate a strong anti-tumour response through the application of hES cells.”

These four stem-cell approaches to disease immunization or cure show potential promise but each is still in an early stage of development and is yet to be tested in humans.   I would guess that 8-15 years will be required for any of them to become part of clinical practice.

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12. December 2009 by admin.

I remember an old Star Trek movie where severely debilitated people without functional vocal chords could readily speak to each other by merely thinking their sentences.  Recent research is bringing us closer to having such a capability.  The article A Wireless Brain-Machine Interface for Real-Time Speech Synthesis in the current issue of Plos One lays out the progress.

“Brain-machine interfaces (BMIs) involving electrodes implanted into the human cerebral cortex have recently been developed in an attempt to restore function to profoundly paralyzed individuals. — In the current study we use a novel approach to speech restoration in which we decode continuous auditory parameters for a real-time speech synthesizer from neuronal activity in motor cortex during attempted speech. –  Neural signals recorded by a Neurotrophic Electrode implanted in a speech-related region of the left precentral gyrus of a human volunteer suffering from locked-in syndrome, characterized by near-total paralysis with spared cognition, were transmitted wirelessly across the scalp and used to drive a speech synthesizer. A Kalman filter-based decoder translated the neural signals generated during attempted speech into continuous parameters for controlling a synthesizer that provided immediate (within 50 ms) auditory feedback of the decoded sound. Accuracy of the volunteer’s vowel productions with the synthesizer improved quickly with practice, with a 25% improvement in average hit rate (from 45% to 70%) and 46% decrease in average endpoint error from the first to the last block of a three-vowel task.”

I take this to mean that machine-training is necessary and that generating normal fluent speech is not yet possible.  My impression is that a lot more needs to be done to understand and encode the relationships between neural events and continuous speech.  This may take some time.  Computer speech recognition research started in the 1950s and decent recognition of continuous speech was not achieved until around 2000.  The authors conclude “Our results support the feasibility of neural prostheses that may have the potential to provide near-conversational synthetic speech output for individuals with severely impaired speech motor control. They also provide an initial glimpse into the functional properties of neurons in speech motor cortical areas.”

I speculate that if and as this technology is perfected it would have a number of additional applications for normal non-debilitated people including:

·         Telephone calls without talking aloud for privacy or in noisy places or so as not to disturb others,

·         Rapid writing or recording of thoughts for people who can think faster than they can talk,

·         Private voice conversations not obvious to those you are with, even sneakier than text messaging can be, and

·         Controlling machinery or even driving a car with just internally vocalized thoughts.

In the future the situation could get even more extreme when electronics also can short-circuit the human hearing apparatus and thoughts can fly electronically from one brain into another.  I don’t want to go there for now.  If I live as long as I want to, however, there will surely come a point when I will have to decide whether or not to have a brain implant for voiceless speech synthesis.

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