Discovery of novel anti-tumor proteins in patients with Down’s syndrome.
In a very interesting study published in Nature this month, scientists from Harvard Medical School have zeroed in on a gene that might explain why patients with Down’s syndrome have a very low rate of cancer compared to the general population (Baek et al., 2009).
Down syndrome is one of the most common inherited causes of mental retardation. It occurs with an approximate frequency of 1:700 births. The association between Down's syndrome and decreased cancer incidence had earlier been explored by Harvard's Dr. Judah Folkman who died last year. Dr. Folkman had noticed that cancer is rare among Down's patients, except for leukemia. He studied nearly 18,000 Down's patients and showed that they had 10 percent the expected rate of cancer.
Down’s syndrome is characterized by the presence of an extra copy of chromosome 21 in the genome (trisomy 21). Chromosome 21 has 231 genes in it. Scientists have proposed that a protein coded for by one of the genes on the 21st chromosome called “Down's syndrome candidate region-1” (DSCR1, also known as RCAN1) may explain the low incidence of cancer in Down’s syndrome. This protein inhibits Vascular Endothelial Growth Factor (VEGF). VEGF is one of the many factors that help cancer cells to stimulate formation of new blood vessels (angiogenesis). Inhibition of this factor by DSCR 1 can therefore retard the growth of cancers. People with Down syndrome have three copies of this gene while normal individuals only have two. It was shown that the levels of this protein is higher in patients with Down’s syndrome. In this study, the scientists also developed a mouse model of trisomy 21. The mouse model, like the humans, showed higher levels of DSCR-1 protein, and as expected, was resistant to development of tumors.
It is possible that more genes on the 21st chromosome can have anti-tumor properties that will explain the rarity of cancer in Down’s syndrome. Further research will reveal some of these genes. As of now, researchers say that three new proteins have been identified as potential targets in treatment of cancer. One is DSCR-1 and the others are calcineurin (a protein regulated by DSCR-1) and DYRK1A (a DSCR-1 like protein).
References:
Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, Lensch MW, Park IH, Yoon SS, Minami T, Korenberg JR, Folkman J, Daley GQ, Aird WC, Galdzicki Z, Ryeom S (2009) Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature. 2009 May 20.
http://www.ncbi.nlm.nih.gov/pubmed/19458618?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Monday, May 25, 2009
Hypertension, an infectious disease!!??
Cytomegalovirus Infection Causes an Increase of Arterial Blood Pressure
PLoS Pathog. 2009 May.
Jilin Cheng1, Qingen Ke, Zhuang Jin, Haibin Wang, Olivier Kocher, James P. Morgan, Jielin Zhang1, Clyde S. Crumpacker
Free full text: http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000427
The debate on the role played by chronic CMV infection in the pathogenesis of atheroschlerosis and associated cardiovascular diseases is not new. While some studies have supported this association (Grahame-Clarke C et al., 2003, Valantine et al., 1999, Hsich et al., 2001), others have not (Zhou et al., 1996, Adler et al, 1998, Saetta et al., 2000, Stassen et al., 2006).
In this paper, this group of authors from Harvard Medical School has shown, using in vitro and in vivo methods, that CMV infection increases arterial blood pressure and accelerates atheroschlerosis in mice fed with a high cholesterol diet. The authors say, “CMV infection alone causes an increase in blood pressure. CMV infection augments the increased blood pressure induced by a high cholesterol diet. CMV infection alone, however, does not cause atherosclerosis in aortas. CMV infection along with a high cholesterol diet, however, causes the classic atherosclerotic plaque formation in the main artery connected to the heart. Further studies show that CMV infection induces renin and angiotensin II (Ang II) expression in blood and in vessel cells, in a persistent infection manner. An increased expression of renin and Ang II has been known to cause an increase in blood pressure or hypertension in humans. Expression of viral genes and viral persistent infection of blood vessel endothelial cells resulting in an increased expression of inflammatory cytokines, including renin and Ang II, may underpin the molecular mechanism by which CMV infection induces an increase in blood pressure. Therefore, non-lytic CMV infection and the perturbed cellular gene expression, specifically the components of RAS, underlie a molecular mechanism by which CMV infection causes an increase of blood pressure”.
The significance of these findings lies in the fact that CMV infection is very prevalent all over the world. Several studies have shown that the prevalence of chronic CMV infection in the general population to vary between 60 to 99%. Hypertension and cardiovascular diseases are also very common in the general population. If CMV infection is proved to play an important role, either in the initiation of atheroschlerosis or in its evolution, control of CMV infection (using drugs or vaccines) may provide a new strategy to prevent cardiovascular diseases in the population.
References:
Grahame-Clarke C, Chan NN, Andrew D, Ridgway GL, Betteridge DJ, et al. (2003) Human cytomegalovirus seropositivity is associated with impaired vascular function. Circulation 108: 678–683
Valantine HA, Gao SZ, Menon SG, Renlund DG, Hunt SA, et al. (1999) Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis: a post hoc analysis of a randomized, placebo-controlled study. Circulation 100: 61–66.
Hsich E, Zhou YF, Paigen B, Johnson TM, Burnett MS, et al. (2001) Cytomegalovirus infection increases development of atherosclerosis in Apolipoprotein-E knockout mice. Atheroslcerosis 156: 23–28.
Zhou YF, Leon MB, Waclawiw MA, Popma JJ, Yu ZX, et al. (1996) Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy. N Engl J Med 335: 624–630.
Adler SP, Hur JK, Wang JB, Vetrovec GW (1998) Prior infection with cytomegalovirus is not a major risk factor for angiographically demonstrated coronary artery atherosclerosis. J Infect Dis 177: 209–212.
Saetta A, Fanourakis G, Agapitos E, Davaris PS (2000) Atherosclerosis of the carotid artery: absence of evidence for CMV involvement in atheroma formation. Cardiovasc Pathol 9: 181–183.
Stassen FR, Vega-Cordova X, Vliegen I, Bruggeman CA (2006) Immune activation following cytomegalovirus infection: more important than direct viral effects in cardiovascular disease? J Clin Virol 35: 349–353.
PLoS Pathog. 2009 May.
Jilin Cheng1, Qingen Ke, Zhuang Jin, Haibin Wang, Olivier Kocher, James P. Morgan, Jielin Zhang1, Clyde S. Crumpacker
Free full text: http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000427
The debate on the role played by chronic CMV infection in the pathogenesis of atheroschlerosis and associated cardiovascular diseases is not new. While some studies have supported this association (Grahame-Clarke C et al., 2003, Valantine et al., 1999, Hsich et al., 2001), others have not (Zhou et al., 1996, Adler et al, 1998, Saetta et al., 2000, Stassen et al., 2006).
In this paper, this group of authors from Harvard Medical School has shown, using in vitro and in vivo methods, that CMV infection increases arterial blood pressure and accelerates atheroschlerosis in mice fed with a high cholesterol diet. The authors say, “CMV infection alone causes an increase in blood pressure. CMV infection augments the increased blood pressure induced by a high cholesterol diet. CMV infection alone, however, does not cause atherosclerosis in aortas. CMV infection along with a high cholesterol diet, however, causes the classic atherosclerotic plaque formation in the main artery connected to the heart. Further studies show that CMV infection induces renin and angiotensin II (Ang II) expression in blood and in vessel cells, in a persistent infection manner. An increased expression of renin and Ang II has been known to cause an increase in blood pressure or hypertension in humans. Expression of viral genes and viral persistent infection of blood vessel endothelial cells resulting in an increased expression of inflammatory cytokines, including renin and Ang II, may underpin the molecular mechanism by which CMV infection induces an increase in blood pressure. Therefore, non-lytic CMV infection and the perturbed cellular gene expression, specifically the components of RAS, underlie a molecular mechanism by which CMV infection causes an increase of blood pressure”.
The significance of these findings lies in the fact that CMV infection is very prevalent all over the world. Several studies have shown that the prevalence of chronic CMV infection in the general population to vary between 60 to 99%. Hypertension and cardiovascular diseases are also very common in the general population. If CMV infection is proved to play an important role, either in the initiation of atheroschlerosis or in its evolution, control of CMV infection (using drugs or vaccines) may provide a new strategy to prevent cardiovascular diseases in the population.
References:
Grahame-Clarke C, Chan NN, Andrew D, Ridgway GL, Betteridge DJ, et al. (2003) Human cytomegalovirus seropositivity is associated with impaired vascular function. Circulation 108: 678–683
Valantine HA, Gao SZ, Menon SG, Renlund DG, Hunt SA, et al. (1999) Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis: a post hoc analysis of a randomized, placebo-controlled study. Circulation 100: 61–66.
Hsich E, Zhou YF, Paigen B, Johnson TM, Burnett MS, et al. (2001) Cytomegalovirus infection increases development of atherosclerosis in Apolipoprotein-E knockout mice. Atheroslcerosis 156: 23–28.
Zhou YF, Leon MB, Waclawiw MA, Popma JJ, Yu ZX, et al. (1996) Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy. N Engl J Med 335: 624–630.
Adler SP, Hur JK, Wang JB, Vetrovec GW (1998) Prior infection with cytomegalovirus is not a major risk factor for angiographically demonstrated coronary artery atherosclerosis. J Infect Dis 177: 209–212.
Saetta A, Fanourakis G, Agapitos E, Davaris PS (2000) Atherosclerosis of the carotid artery: absence of evidence for CMV involvement in atheroma formation. Cardiovasc Pathol 9: 181–183.
Stassen FR, Vega-Cordova X, Vliegen I, Bruggeman CA (2006) Immune activation following cytomegalovirus infection: more important than direct viral effects in cardiovascular disease? J Clin Virol 35: 349–353.
Sunday, May 3, 2009
A simple drug, a complex mechanism of action
Lithium levels in drinking water and risk of suicide.
Ohgami H, Terao T, Shiotsuki I, Ishii N, Iwata N.
Br J Psychiatry. 2009 May;194(5):464-5
A group of Japanese researchers have suggested that lithium in drinking water could decrease the risk of suicide in the general population. The researchers did a systematic study of lithium content of drinking water in 18 municipalities in the prefecture of Oita, Kyushu, Japan. They compared the drinking water lithium levels and the suicide rate in the municipalities during 2002 to 2004. They found that lithium in drinking water was significantly negatively correlated to suicide in the general population.
Lithium has potent mood stabilizing properties and is widely used in psychiatric practice in the treatment of serious mood disorders. It is known to reduce the risk of suicide in such patients. However, its presence in drinking water and its effect on suicide risk in the general population had not been established yet. An earlier study done in 27 counties in Texas had also suggested that lithium in drinking water significantly reduced the incidence of suicides (Shrauzer et al., 1990). Other studies, however, have not supported this claim (Oliver et al., 1976).
The authors of this paper have called for further research to confirm their findings in other countries but they stopped short of any suggestion that lithium be added to drinking water. The discussion around adding fluoride to water to improve dental health has proved controversial and has been criticized by many as mass involuntary medication.
Lithium is perhaps the only metal that is used in the treatment of organic disease. Its therapeutic properties were discovered by Dr. John Cade. As with all landmark discoveries, the discovery of lithium had its fair share of serendipity and happy coincidences.
Dr. John Cade was a World War II veteran having served in the Australian Army Medical Corps. After the fall of Singapore to Japan in 1942, he spent three years as a prisoner of war in the Changi Prison in Singapore. During his stay in the prison, Dr. Cade observed many of his fellow inmates suffer from strange vacillating behavior that he believed was caused by a toxin that was excreted in the urine.
After the war, the battle scarred doctor returned to work in the Bundoora Repatriation Mental Hospital in Melbourne. Here, he converted an unused kitchen in the hospital into a laboratory where he performed experiments that would eventually lead to the discovery of the therapeutic properties of lithium. Dr. Cade believed that a toxin that is excreted in the urine was responsible for mental illnesses like schizophrenia and depression. He injected the urine of mentally ill patients into the peritoneal cavity of guinea pigs. He found that the urine of mentally ill patients was more toxic to the animals compared to that from healthy controls. The prevailing belief that uric acid present in urine had important effects on neuronal function lead Dr. Cade to investigate the effects of intraperitoneal injections of uric acid. In an effort to increase the solubility of uric acid, he used a lithium salt of urate. He found that lithium urate had a remarkable calming effect on the guinea pigs. However, due the careful use of controls, Dr. Cade was able to conclude that the calming effect was a property of the lithium ion itself. He published his finding in the Australian Medical Journal in 1949.
The discovery of lithium was landmark in treatment of psychiatric disorders. It provided a valuable alternative to shock treatments, lobotomies and Freudian psychotherapy which were the main treatments for depression at that time. However the use of lithium as a drug was not welcomed by all, especially the drug companies. Lithium was a cheap and commonly available metal that could not be patented. It was not a drug that could rake in the big bucks for the pharmaceutical industry. It was not until 1970 (20 years after Dr. Cade’s discovery) that FDA approved the use of lithium in the treatment of bipolar disorders in the USA.
Despite the use of lithium for well over five decades now, its mechanism of action has not been fully elucidated. Some theories that have been put forward are:
1. Lithium may produce its effects by interacting with the transport of monovalent or divalent cations in neurons. However, because it is a poor substrate at the sodium pump, it cannot maintain a membrane potential and only sustains a small gradient across biological membranes.
2. Lithium may deactivate the glycogen synthase kinase 3B (GSK-3B) enzyme. The regulation of GSK-3B by lithium may affect the circadian clock. When GSK-3B is activated, the protein Bmal1 is unable to reset the "master clock" inside the brain. As a result, the body's natural circadian cycle is disrupted. When the cycle is disrupted, the routine schedules of many functions (metabolism, sleep, body temperature) are disturbed. This may explain many of the features of mania and depression. Lithium, by inhibiting GSK-3B, may restore normal brain function after it is disrupted in some people.
3. Lithium treatment has been found to inhibit the enzyme inositol monophosphatase leading to disruption of the phosphoinositide cycle. This interferes in the formation of phosphoinositide diphosphate which is important in the intracellular signaling pathway of several neurotransmitters.
Evidence from both in vitro and in vivo studies has demonstrated that lithium exerts multiple effects on neurotransmitter/receptor-mediated signaling, ion transport, signal transduction cascades, hormonal and circadian regulation, and profoundly alters gene expression. It is surprising that a small ion like lithium that has many properties that are similar to sodium could exert such diverse effects.
References:
Oliver SL, Comstock GW, Helsing KJ. 1976. Mood and lithium in drinking water. Arch Environ Health. Mar-Apr;31(2):92-5.
Schrauzer GN, Shrestha KP. 1990. Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions. Biol Trace Elem Res. May; 25(2):105-13.
Ohgami H, Terao T, Shiotsuki I, Ishii N, Iwata N.
Br J Psychiatry. 2009 May;194(5):464-5
A group of Japanese researchers have suggested that lithium in drinking water could decrease the risk of suicide in the general population. The researchers did a systematic study of lithium content of drinking water in 18 municipalities in the prefecture of Oita, Kyushu, Japan. They compared the drinking water lithium levels and the suicide rate in the municipalities during 2002 to 2004. They found that lithium in drinking water was significantly negatively correlated to suicide in the general population.
Lithium has potent mood stabilizing properties and is widely used in psychiatric practice in the treatment of serious mood disorders. It is known to reduce the risk of suicide in such patients. However, its presence in drinking water and its effect on suicide risk in the general population had not been established yet. An earlier study done in 27 counties in Texas had also suggested that lithium in drinking water significantly reduced the incidence of suicides (Shrauzer et al., 1990). Other studies, however, have not supported this claim (Oliver et al., 1976).
The authors of this paper have called for further research to confirm their findings in other countries but they stopped short of any suggestion that lithium be added to drinking water. The discussion around adding fluoride to water to improve dental health has proved controversial and has been criticized by many as mass involuntary medication.
Lithium is perhaps the only metal that is used in the treatment of organic disease. Its therapeutic properties were discovered by Dr. John Cade. As with all landmark discoveries, the discovery of lithium had its fair share of serendipity and happy coincidences.
Dr. John Cade was a World War II veteran having served in the Australian Army Medical Corps. After the fall of Singapore to Japan in 1942, he spent three years as a prisoner of war in the Changi Prison in Singapore. During his stay in the prison, Dr. Cade observed many of his fellow inmates suffer from strange vacillating behavior that he believed was caused by a toxin that was excreted in the urine.
After the war, the battle scarred doctor returned to work in the Bundoora Repatriation Mental Hospital in Melbourne. Here, he converted an unused kitchen in the hospital into a laboratory where he performed experiments that would eventually lead to the discovery of the therapeutic properties of lithium. Dr. Cade believed that a toxin that is excreted in the urine was responsible for mental illnesses like schizophrenia and depression. He injected the urine of mentally ill patients into the peritoneal cavity of guinea pigs. He found that the urine of mentally ill patients was more toxic to the animals compared to that from healthy controls. The prevailing belief that uric acid present in urine had important effects on neuronal function lead Dr. Cade to investigate the effects of intraperitoneal injections of uric acid. In an effort to increase the solubility of uric acid, he used a lithium salt of urate. He found that lithium urate had a remarkable calming effect on the guinea pigs. However, due the careful use of controls, Dr. Cade was able to conclude that the calming effect was a property of the lithium ion itself. He published his finding in the Australian Medical Journal in 1949.
The discovery of lithium was landmark in treatment of psychiatric disorders. It provided a valuable alternative to shock treatments, lobotomies and Freudian psychotherapy which were the main treatments for depression at that time. However the use of lithium as a drug was not welcomed by all, especially the drug companies. Lithium was a cheap and commonly available metal that could not be patented. It was not a drug that could rake in the big bucks for the pharmaceutical industry. It was not until 1970 (20 years after Dr. Cade’s discovery) that FDA approved the use of lithium in the treatment of bipolar disorders in the USA.
Despite the use of lithium for well over five decades now, its mechanism of action has not been fully elucidated. Some theories that have been put forward are:
1. Lithium may produce its effects by interacting with the transport of monovalent or divalent cations in neurons. However, because it is a poor substrate at the sodium pump, it cannot maintain a membrane potential and only sustains a small gradient across biological membranes.
2. Lithium may deactivate the glycogen synthase kinase 3B (GSK-3B) enzyme. The regulation of GSK-3B by lithium may affect the circadian clock. When GSK-3B is activated, the protein Bmal1 is unable to reset the "master clock" inside the brain. As a result, the body's natural circadian cycle is disrupted. When the cycle is disrupted, the routine schedules of many functions (metabolism, sleep, body temperature) are disturbed. This may explain many of the features of mania and depression. Lithium, by inhibiting GSK-3B, may restore normal brain function after it is disrupted in some people.
3. Lithium treatment has been found to inhibit the enzyme inositol monophosphatase leading to disruption of the phosphoinositide cycle. This interferes in the formation of phosphoinositide diphosphate which is important in the intracellular signaling pathway of several neurotransmitters.
Evidence from both in vitro and in vivo studies has demonstrated that lithium exerts multiple effects on neurotransmitter/receptor-mediated signaling, ion transport, signal transduction cascades, hormonal and circadian regulation, and profoundly alters gene expression. It is surprising that a small ion like lithium that has many properties that are similar to sodium could exert such diverse effects.
References:
Oliver SL, Comstock GW, Helsing KJ. 1976. Mood and lithium in drinking water. Arch Environ Health. Mar-Apr;31(2):92-5.
Schrauzer GN, Shrestha KP. 1990. Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions. Biol Trace Elem Res. May; 25(2):105-13.
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