p53, viral inactivation and cancer

It is a self evidence that where ever a phenomenon in biology, there is always a claim that nutrition has a place in the process. Maybe. This might be true.
Cancer is an omnipresent candidate for nutritional cause and cure. This paper is a wake up call that there are other more scientifically based possible causes of cancer.
The transcription factor p53 (also known as TP53) guards against tumour and virus replication and is inactivated in cancers. p53-activated transcription of target genes is thought to be synonymous with the stabilization of p53 in response to oncogenes and DNA damage. During adenovirus replication, the degradation of p53 by E1B-55k is considered essential for p53 inactivation, and is the basis for p53-selective viral cancer therapies. This paper shows a dominant epigenetic mechanism that silences p53-activated transcription, irrespective of p53 phosphorylation and stabilization. An adenoviral protein, E4-0RF3, inactivates p53 independently of E1B-55k by forming a nuclear structure that induces H3K9me3 heterochromatin formation at p53 target promoters, preventing p53-DNA binding. This suppressive nuclear web is highly selective in silencing p53 promoters and operates in the backdrop of global transcriptional changes that oncogenic replication. These findings are important for understanding how high levels of wild-type p53 might also be inactivated in cancer as well as the mechanisms that induce aberrant epigenetic silencing of tumour-suppressor loci. This study changes the longstanding definition of how p53 is inactivated in adenovirus infection and provides key insights that could enable the development of true p53-selective oncolytic viral therapies.
Soriaet al 2010 Heterochromatin silencing of pS3 target genes by a small viral protein. Nature vol 466, pp 1076-1081

drug treatment of excess weight

Few safe and effective drug treatments are available. A combination treatment with sustained-release naltrexone and bupropion has been developed to produce complementary actions in CNS pathways regulating bodyweight. Two key systems are identified, the hypothalamic melanocortin sytem which integrates input related to energy balance and produces anorexigenic signalling and mesolimbic reward system which modulates reward value and goal orientated behaviour.
The Contrave Obesity Research I (COR-I) study assessed the effect of such treatment on bodyweight in overweight and obese participants.
1742 men and women aged 18-65 years who had a body-mass index (BMI) of 30-45 kg/m2 and uncomplicated obesity or BMI 27-45 kg/m2 with dyslipidaemia or hypertension were recruited to this randomised, double-blind, placebo-controlled, phase 3 trial.
Participants were prescribed mild hypo caloric diet and exercise and were randomly assigned in a 1:1:1 ratio to receive sustained-release naltrexone 32 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB32), sustained-release naltrexone 16 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NBI6), or matching placebo twice a day, given orally for 56 weeks. The trial included a 3-week dose escalation.
The endpoints at 56 weeks were percentage change in bodyweight and proportion of participants who achieved a decrease in bodyweight of 5% or more.
Pparticipants were enrolled and randomised to double-blind treatment (naltrexone 32 mg plus bupropion, n=583; naltrexone 16 mg plus bupropion, and completed 56 weeks of treatment Mean change in bodyweight was -1• 3% in the placebo group, -6 •1% in the naltrexone 32 mg plus bupropion group and -5•0% (0•3) in the naltrexone 16 mg plus bupropion group
84 (16%) participants assigned to placebo had a decrease in bodyweight of 5% or more compared with 226 (48%) assigned to naltrexone 32 mg plus bupropion (pThe report concluded that there was some place for such treatment.

Greenway et al 2010 Effect of naltrexone plus bupropion on weight loss in
overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial The Lancet vol 376 595-605

bones and metabolism

Most scientists believe the function of the bone is limited to support and mineral exchange.
A stimulating article in Nature discusses the possibility that bone remodelling be linked to metabolism. This makes real sense as metabolism is interconnected and a stand alone system cannot be efficient.
The article discusses the work generated by Karsenty and Ducy on this topic.
Bone remodelling includes both bone building by osteoblasts and removal by ostosclasts. This is an energy intensive process and interacts with metabolism in a number of ways. The hormone Leptin which is secreted by fat cells and affects appetite inhibits osteoblast formation and osteocalcin, a bone related protein production. Osteoblasts increase concentrations of inactive osteocalcin.
Bone removal activates osteocalcin. Osteocalcin stimulates pancreatic β-cells to produce insulin. And straight into metabolism.
Katsnelson 2010 The bones of contention. Nature vol 466 pp 914-915

p53 and metabolism

The tumour suppressor gene p53 is important in halting the cycle and death when there is DNA damage.
P53 also has a role in cellular metabolism. The inactivation of p53 is common in tumours . P53 contributes to a shift from oxidative phosphorylation to glycolysis. This shift originally described by Warburg is a feature of tumour cells.
GLS2 an enzyme involved in oxidative phosphorylation is regulated by p53 under stressed and non stressed conditions. GLS2 increases the respiration rate in mitochondria with resultant increased production of ATP.
Meline 2010 Journal Club . Nature vol 466 p 905

anxiety and the brain

Some people are naturally more anxious than others.
How anxiously we react to threat or adversity is part of our personality. This characteristic is called trait anxiety, and those with high trait anxiety are more prone to mental disorders such as depression, substance abuse and psychosis. Trait anxiety is heritable, with genes explaining much of the variability between individuals.
Oler et al have investigated genetic effects on the activity of brain regions that mediate trait anxiety.
The subjects of this study were rhesus monkeys, from several generations of a single-family pedigree - at an average age corresponding to that of humans just before puberty. The authors exposed the animals to a human intruder, a social-threat procedure that reveals an anxiety trait. They found, by examining both blood levels of the stress hormone cortisol and behaviours such as 'freezing: that some monkeys reacted with high anxiety, and others with less.
Oler et al. also measured metabolic activity in the brain by injecting the monkeys with 18FDG, a radioactive analogue of glucose that is taken up and trapped in nerve cells according to their activity at the time of exposure to the social threat. The authors then anaesthetized the monkeys in order to image, using positron emission tomography, a 'snapshot' of regional brain metabolism during the preceding stress procedure.
The results indicate that, in anxious monkeys, brain activity is higher in a variety of areas, but most prominently in two key signalling structures for negative emotion, the amygdala and the anterior hippocampus. Activity in these two structures explained a sizeable proportion of the variance in anxiety behaviour from monkey to monkey
Much research in anxiety has focused on the amygdala , which signals environmental danger and triggers 'fight-or-flight' responses. But extensive evidence also links the anterior hippo¬campus, an essential structure for 'declarative' memory - to anxious behaviour and trait anxiety. Furthermore, there are strong interactions between the amygdala and hippocampus, which mediate emotional memory.
Activity in the anterior hippocampus is under greater genetic influence but found no significant heritability in the amygdala.

Oler et al 2010 Amygdala and hippocampal substrates of anxious temperament differ in their heritability vol 466 pp 864-868.
Meyer-Lindenberg 2010 Genes and the anxious brain Nature vol 466 pp827-8

paternal and maternal genes

Some genes exclusively express only their maternal or paternal copy.
Mammals inherit one copy (allele) of each gene from their mother and another copy from their father. Yet for many genes, only one of these alleles is always expressed in a cell. The choice of which allele is expressed is random in some cell types - notably those of the olfac¬tory and immune systems; for others, such as those of the developing placenta and brain, certain genes are 'imprinted". The hallmark of imprinted genes is that some are expressed only when inherited from the mother and others only when inherited from the father.
Imprinted genes were thought to be fewer than 100 in number.
Studies published in the Journal Science by Gregg and colleagues identify 1,308 candidate imprinted genomic regions in the mouse brain, encompassing 824 annotated genes as well as the entire X chromosome.
It has already been shown that, in the mouse placenta, the X chromosome is imprinted, with genes from the maternal X being exclusively expressed, thereby avoiding immunological rejection of foreign fetal proteins that might be encoded by the paternal X chromosome",

Many of the genes on the X chromosome are also expressed in the brain. In males (XY), the single X copy always originate from the mother, but in females ( XX) either the maternal or the paternal copy of the X chromosome is inactivated early in embryonic development, and this occurs at random. Gregg et al report preferential expression of the maternal X chromosome in two brain regions. Compared with the paternal X, the expression of the maternal X chromosome was 11 % higher in glutamate-secreting neurons of the cortex, and 19% higher in the preoptic region of the basal forebrain.
In general, the expression of imprinted genes is exclusively either maternal or pater¬nal, with loss of exclusivity usually leading to expression of both alleles. This suggests that the biased gene expression described by Gregg et al. may be due to selection of cells express¬ing the maternal X chromosome, rather than imprinting. DNA replication errors increase with the number of cell divisions, which are an order of magnitude higher in the production of sperm than female oocytes
Keverne 2010 A mine of imprinted genes Nature vol 466 pp 823-4

ocean oxygen concentration

In July 2002, scientists with the Oregon Department of Fish and Wild¬life found unusual numbers of bottom¬feeding sculpin lying lifeless on the ocean floor, which would normally be teeming with life. Crabs were also dying, and they washed up onto some beaches in large numbers.
Ocean surface waters normally contain 5-8 millilitres of oxygen per litre of water, which declines rapidly with depth. At a depth of 50 metres the inner coastal waters off Oregon were hypoxic - oxygen levels there were lower than 1.43 millilitres per litre, so low that fish can't survive,
Many regions of the world have hypoxic coastal waters, usually caused by agricul¬tural fertilizers leaking into the ocean. The excess nutrients fuel plankton blooms, which consume oxygen.
Every summer since then, much of the oxygen has disappeared from a large patch of inner continental-shelf waters. In the most extreme case, in 2006, the waters lost all detectable oxygen for four weeks. Starfish and mussels died, and rockfish and other mobile fish fled the hypoxic zone, which grew to 3,000 square kilometres .
The phenomenon has worried the fishing industry in Oregon, which brings in hun¬dreds of millions of dollars each year and
This is phenomenon is being pound elsewhere in the world. It is not clear if this is secondary to Global Warming. But warmer water temperatures may be important contributory factors.
Usually in the spring , occasional periods of Northerly winds blow surface water off shore, allowing cool water, rich in nutrients but poor in oxygen to rise form deeper offshore layers.
Gewin 2010 Dead in the water Nature vol 104 pp 812-3

oat bran molecular weight and cholesterol lowering effect

The physical form of food may well be a factor in its metabolism in the gastro intestinal tract. In this study, the authors looked at the cholesterol-lowering effects of different oat bran (oat bran) preparations, differing and their peak molecular weight (MWp) of β-glucans (2348,1311,241,56, 2l or < l0kDa), in mice. The diets were designed to be atherogenic (0•8 % cholesterol and O•l % cholic acid), and they reflected the Western diet pattern (41 % energy fat). All oat bran preparations that were investigated significantly reduced plasma cholesterol when compared with a cellulose-containing control diet, regardless of the molecular weight of β-glucan. Moreover, the difference in viscous properties between the processed oat bran (from 0•l1 to 17•7I1g) did not appear to play a major role in the cholesterol-lowering properties.
There was no correlation between the molecular weight of β-g1ucan and the amount of propionic acid formed in caecum.There was a significant correlation between the ratio of (propionic acid + butyric acid)/acetic acid and the MWp of β -glucans: the ratio increased with increasing molecular weight. The results of the present study suggest that the molecular weights and viscous properties of β-glucan in oat products may not be crucial parameters for their cholesterol-lowering effects.
Immerstrand et al 2010 Effects of oat bran, processed to different molecular weights of β -glucan, on plasma lipids and caecal formation of SCFA in mice Brit Journal Nutrition vol 104 364-373

omega 3 fatty acids and the heart

Much evidence shows that the marine omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid have beneficial effects in various cardiac disorders, and their use is recommended in guidelines for management of patients after myocardial infarction. Questions have been raised about their usefulness alongside optimum medical therapies with agents proven to reduce risk of cardiac events in high-risk patients. Additionally, there is some evidence for a possible pro-arrhythmic effect in subsets of cardiac patients. Some uncertainly exists about the optimum dose needed to obtain beneficial effects and the relative merit of dietary intake of omega-3 polyunsaturated fatty acids versus supplements. This review looks at the evidence for the effects of omega-3 polyunsaturated fatty acids on various cardiac disorders and the risk factors for cardiac disease.
Dietary intake of fish is the best way to increase marine n-3 PFA intake. 1 gram per day of omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic supplement is equivalent to 55-85 g of fresh tuna, sardine, salmon or trot or 650 g Atalntic cod.
The amount of PUFA intake to educe triglycerides cannot be achieved by diet alone.
Marine n-3 PUFAs act as pleiotropic agents on the cardiovascular system with a diverse range of effects, most of which are beneficial. So far, the most important effect seems to be related to reduction in mortality after a myocardial infarction. Although findings from several studies have suggested the possibility of an anti¬arrhythmic effect, other clinical studies have not convincingly supported this mode of action. The overall effect of n-3 PUFAs in patients with coronary ischaemia without previous myocardial infarction is not established, with a potential benefit in the reduction of ischaemic coronary events set against an ongoing controversy over a possible rise in the risk of arrhythmic events. The anti-¬inflammatory, anti-atherosclerotic, and anti-immuno¬modulatory effects have not yet been proven to give clinical benefits.

Saravanan et al 2010 , Cardiovascular effects of marine omega- 3 fatty acids . The Lancet vol 376 pp 540-550

Survival factors

The factors in behaviour that can influence survival after quitting smoking have been
studied. Strong relationships has the strongest effect in improving survival. Having strong social relationships seems to have an effect on survival comparable to that of quitting smoking and larger than con¬trolling traditional risk factors, such as obes¬ity or hypertension. A meta-analysis of social relationships and mortality looked at 308849 participants aged 63.9, on average, at baseline; 29% died during the follow-up of 7.5 years.
Overall, strong social relationships improved the odds of survival by 5 %. Similar results were found for two aspects of relationships, defined by the researchers as structural (integration in social networks) and func¬tional (received or perceived social support), although the link with integration was some¬what stronger.
Reported in BMJ 14August 2010 vol 341 p 325

Japan and age

Longest lifespan Japan is struggling to cope with the rising welfare costs of its rapidly ageing society, as Japanese women continue to hold the 25-year record for the longest lifespan: an average of 86•44 years. This record is attributed to improvements in the treatment of cardiac disorders, strokes, and cancer, three of the main causes of death in Japan.
Lancet August 7th 2010

Clean water and the UN

Irrespective of politicking at the UN, 884 million people worldwide do not have regular access to clean water, and 2•6 billion do not have access to basic sanitation. The 2010 Millennium Development Goal 7 report states that the target of halving the number of people without access to safe water is on course to be met by 2015, but provision of sanitation is not. The practice of open defecation by 1•1 billion people is not only "an affront to human dignity", but also the key source of faecal-oral transmitted diseases such as diarrhoea, which causes 1•3 million deaths per year in children younger than 5 years.
A little more than 5 years through the UN General Assembly's Water for Life Decade, adequate supply of water and sanitation is far from universal. When the Human Rights Commission's report is published, the hope is that no country obstructs a binding commitment to provide clean water and sanitation for all. •
The Lancet August 7th 2010 p 390

Children's diet in UK by ethnicity

In the UK, South Asian adults have increased risks of CHD, type 2 diabetes and central obesity. Black African-Caribbeans, in contrast, have increased risks of type 2 diabetes and general obesity but lower CHD risk. There is growing evidence that the risk differences emerge in early life and that nutritional factors may be important. This study looks at the variations in nutritional composition of the diets of South Asian, black African-Caribbean and white European children, using 24h recalls of dietary intake collected during a cross-sectional survey of cardiovascular health in eighty-five primary schools in London, Birmingham and Leicester.
In all, 2209 children aged 9-10 years took part, including 558 of South Asian, 560 of black African-Caribbean and 543 of white European ethnicity. Compared with white Europeans, South Asian children reported higher mean total energy intake; their intake of total fat, polyunsaturated fat and protein (both absolute and as proportions of total energy intake) were higher and their intakes of carbohydrate as a proportion of energy (particularly sugars), vitamin C and D, Ca and haem Fe were lower.
These differences were especially marked for Bangladeshi children. Black African-Caribbean children had lower intakes of total and saturated fat (both absolute and as proportions of energy intake), Dietary Fibre , vitamin D and Ca. The lower total and saturated at intakes were particularly marked among black African children. Appreciable ethnic differences exist in the nutritional composition of children's diets, which may contribute to future differences in chronic disease risk.
Donin et al 2010 Nutritional composition of the diets of South Asian, black African-Caribbean and white European children in the United Kingdom: The Child Heart and Health Study in England (CHASE) British J Nutrition vol 104 276-285

pancreatic circadian rhythmn

Circadian clocks have profound effects on metabolism and behaviour , in plants and mammals.
In 1972, a study demonstrated that within the brain hypothalamus, the suprachiasmatic nucleus, which is close to the optic nerves, is required for daily rhythms in animal behaviour.. The suprachias¬matic nucleus receives light signals through the optic nerves, and so uses daylight cues to set the clock time and to couple light-dark transi¬tions to behavioural outputs.
Subsequent genetic studies identified several genes that mediate rhythmic behaviour.
The mammalian circadian clock is a molecular oscillator based on a nega¬tive- feedback loop in which the transcription factors CLOCK (or the related protein NPAS2) and BMALl work together to drive the expres¬sion of many genes, including the period (PERl, PER2 and PER3) and the cryptochrome (CRYl and CRY2) proteins.

Now it is clear that clocks outside the suprachiasrnatic nucleus have physiological roles?
First, expression of enzymes, transporters and receptors that regulate metabolism fluctuate robustly throughout the day.
Second circadian clocks outside the suprachiasmatic nucleus are adjusted on the basis of feeding time rather than the light-dark schedule For example, the cellular energy sensor AMPK controls the stability of cryptochromes and may contribute to nutrient entrainment of the clock in the liver.
Marcheva et al. have shown that the mouse pan¬creas also has a functional circadian clock, with individual pancreatic islets having clock function even when outside their normal tissue environment. The islet clock seems to consist of the same components as other mammalian circadian clocks, and drives rhythmic expression of genes involved in insulin sensing, glucose sensing, and islet growth and development. These clocks are therefore crucial for the specific metabolic needs and functions of islet cells .
Lamia and Evans 2010 Tick, tock , a β-cell clock Nature vol 466, 571-2
Marcheva et al 2010 Disruption of the clock components CLOCK and BMAL1 leads to hyper- insulinaemia and diabetes Nature vol 466 627-631

HDL cholesterol and cardiovascular risk

Cardiovascular disease is the leading cause of death worldwide. Reducing concentrations of LDL cholesterol with statin therapy has resulted in reductions of 23% in cardiovascular risk for every 1•03 mmol/L (40 mg/dL) decrease in LDL cholesterol. However, despite a reduction in LDL cholesterol with high-dose statins to 1•6 mmol/L in patients with stable coronary heart disease, and to 2•0 mmol/L in those with acute coronary syndrome, the risk of cardiovascular disease remains substantial at 8-7% after 4•9 years of follow-up, and 22-4% after 24 months' follow-up, respectively. Low concentrations of HDL cholesterol might contribute to this residual cardiovascular risk."
Population-based studies show that low concentrations of HDL cholesterol «1•03 mmol/L) are a risk factor for cardiovascular disease. thus increasing HDL cholesterol by 0•03 mmol/L can reduce cardiovascular risk by 2-3% per year.
Paul Ridker and colleagues, for the JUPITER Trial Study Group, challenge whether HDL cholesterol concentrations are predictive of cardiovascular risk at low concentrations of LDL cholesterol.
Raising HDL cholesterol remains a major treatment strategy for the reduction of cardiovascular risk in the large majority of patients who do not have very low LDL cholesterol; the problem, in most cases, is how to achieve this strategy.
Lifestyle changes, such as more aerobic exercise, weight loss, smoking cessation, moderate alcohol intake, and dietary changes might result in modest increases in HDL choiesterol.
Drugs that specifically raise HDL cholesterol concentrations are less available, with niacin being the most effective current agent. Others include the fibrates, the thiazolidinediones, and the qlitazars.
Hausenloy et al 2010 Dissociating HDL cholesterol from cardiovascular risk Lancet vol 376, pp 305-6
Ridker PM et al 2010 HDL cholesterol and residual risk of first cardiovascular events after events after treatment with statin : an analysis from the JUPITER trial vol 376 333-39