Posts Tagged ‘osteosarcoma’

Rational Therapeutics, Inc. Personalized Cancer Treatment

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Posted 07 Apr 2010 — by James Street
Category Human osteosarcoma research

Rational Therapeutics is dedicated to identifying unique characteristics of each cancer subtype, such as osteosarcoma, to enable oncologists to treat them with targeted therapies.

Rational Therapeutics is directed by Dr. Robert A. Nagourney.

Patients their oncologists can find out more about Dr. Nagourney’s work at:

Rational Therapeutics

Rational Theapeutics is located at:

750 E 29th St., Long Beach, CA 90806, United States

(562)989-6455, (562)989-8160 fax,

inactivation of SMO may be a useful approach to the treatment of patients with osteosarcoma

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Posted 16 Mar 2010 — by James Street
Category genetic research

The Hedgehog signaling pathway functions as an organizer in embryonic development. Recent studies have demonstrated constitutive activation of Hedgehog pathway in various types of malignancies.

However, it remains unclear how Hedgehog pathway is involved in the pathogenesis of osteosarcoma. To explore the involvement of aberrant Hedgehog pathway in the pathogenesis of osteosarcoma, we investigated the expression and activation of Hedgehog pathway in osteosarcoma and examined the effect of SMOOTHENED (SMO) inhibition.

Results: To evaluate the expression of genes of Hedgehog pathway, we performed real-time PCR and immunohistochemistry using osteosarcoma cell lines and osteosarcoma biopsy specimens.

To evaluate the effect of SMO inhibition, we did cell viability, colony formation, cell cycle in vitro and xenograft model in vivo. PCR revealed that osteosarcoma cells over-expressed Hedgehog, PTCH, SMO, and GLI.

Real-time PCR revealed over-expression of SMO, PTCH, and GLI2 in osteosarcoma biopsy specimens’. These findings showed that Hedgehog pathway is activated in osteosarcomas.

Inhibition of SMO by cyclopamine, a specific inhibitor of SMO, slowed the growth of osteosarcoma in vitro. Cell cycle analysis revealed that cyclopamine promoted G1 arrest.

Cyclopamine reduced the expression of accelerators of the cell cycle including cyclin D1, cyclin E1, SKP2, and pRb. On the other hand, p21cip1 protein was up-regulated by cyclopamine treatment.

In addition, knockdown of SMO by SMO shRNA prevents osteosarcoma growth in vitro and in vivo.

Conclusions: These findings suggest that inactivation of SMO may be a useful approach to the treatment of patients with osteosarcoma.

Author: Masataka HirotsuTakao SetoguchiHiromi SasakiYukihiro MatsunoshitaHui GaoHiroko NagaoOsamu KunigouSetsuro Komiya
Credits/Source: Molecular Cancer 2010, 9:5

The Absurdities of Water Fluoridation

Posted 15 Mar 2010 — by James Street
Category Flouridation and osteosarcoma, Molecular Osteosarcoma Studies
ater fluoridation is a peculiarly American phenomenon. It started at a time when Asbestos lined our pipes, lead was added to gasoline, PCBs filled our transformers and DDT was deemed so “safe and effective” that officials felt no qualms spraying kids in school classrooms and seated at picnic tables. One by one all these chemicals have been banned, but fluoridation remains untouched.
By Paul Connett, PhD

Toronto adds poisonous fluoride to your drinking water. It’s a toxic waste product and many health officials decry its use as causing bone cancer, mottled teeth and for being ineffective at reducing cavities when drunk.

Water fluoridation is a peculiarly American phenomenon. It started at a time when Asbestos lined our pipes, lead was added to gasoline, PCBs filled our transformers and DDT was deemed so “safe and effective” that officials felt no qualms spraying kids in school classrooms and seated at picnic tables. One by one all these chemicals have been banned, but fluoridation remains untouched.

For over 50 years US government officials have confidently and enthusiastically claimed that fluoridation is “safe and effective”. However, they are seldom prepared to defend the practice in open public debate. Actually, there are so many arguments against fluoridation that it can get overwhelming.

To simplify things it helps to separate the ethical from the scientific arguments.

For those for whom ethical concerns are paramount, the issue of fluoridation is very simple to resolve. It is simply not ethical; we simply shouldn’t be forcing medication on people without their “informed consent”. The bad news is that ethical arguments are not very influential in Washington, DC unless politicians are very conscious of millions of people watching them. The good news is that the ethical arguments are buttressed by solid common sense arguments and scientific studies which convincingly show that fluoridation is neither “safe and effective” nor necessary. I have summarized the arguments in several categories:

Fluoridation is UNETHICAL because:

1) It violates the individual’s right to informed consent to medication.
2) The municipality cannot control the dose of the patient.
3) The municipality cannot track each individual’s response.
4) It ignores the fact that some people are more vulnerable to fluoride’s toxic effects than others. Some people will suffer while others may benefit.
5) It violates the Nuremberg code for human experimentation.

As stated by the recent recipient of the Nobel Prize for Medicine (2000), Dr. Arvid Carlsson:

“I am quite convinced that water fluoridation, in a not-too-distant future, will be consigned to medical history…Water fluoridation goes against leading principles of pharmacotherapy, which is progressing from a stereotyped medication – of the type 1 tablet 3 times a day – to a much more individualized therapy as regards both dosage and selection of drugs. The addition of drugs to the drinking water means exactly the opposite of an individualized therapy.”

As stated by Dr. Peter Mansfield, a physician from the UK and advisory board member of the recent government review of fluoridation (McDonagh et al 2000):

“No physician in his right senses would prescribe for a person he has never met, whose medical history he does not know, a substance which is intended to create bodily change, with the advice: ‘Take as much as you like, but you will take it for the rest of your life because some children suffer from tooth decay. ‘ It is a preposterous notion.”

Fluoridation is UNNECESSARY because:

1) Children can have perfectly good teeth without being exposed to fluoride.
2) The promoters (CDC, 1999, 2001) admit that the benefits are topical not systemic, so fluoridated toothpaste, which is universally available, is a more rational approach to delivering fluoride to the target organ (teeth) while minimizing exposure to the rest of the body.
3) The vast majority of western Europe has rejected water fluoridation, but has been equally successful as the US, if not more so, in tackling tooth decay.
4) If fluoride was necessary for strong teeth one would expect to find it in breast milk, but the level there is 0.01 ppm , which is 100 times LESS than in fluoridated tap water (IOM, 1997).
5) Children in non-fluoridated communities are already getting the so-called “optimal” doses from other sources (Heller et al, 1997). In fact, many are already being over-exposed to fluoride.

Fluoridation is INEFFECTIVE because:

1) Major dental researchers concede that fluoride’s benefits are topical not systemic (Fejerskov 1981; Carlos 1983; CDC 1999, 2001; Limeback 1999; Locker 1999; Featherstone 2000).
2) Major dental researchers also concede that fluoride is ineffective at preventing pit and fissure tooth decay, which is 85% of the tooth decay experienced by children (JADA 1984; Gray 1987; White 1993; Pinkham 1999).
3) Several studies indicate that dental decay is coming down just as fast, if not faster, in non-fluoridated industrialized countries as fluoridated ones (Diesendorf, 1986; Colquhoun, 1994; World Health Organization, Online).
4) The largest survey conducted in the US showed only a minute difference in tooth decay between children who had lived all their lives in fluoridated compared to non-fluoridated communities. The difference was not clinically significant nor shown to be statistically significant (Brunelle & Carlos, 1990).
5) The worst tooth decay in the United States occurs in the poor neighborhoods of our largest cities, the vast majority of which have been fluoridated for decades.
6) When fluoridation has been halted in communities in Finland, former East Germany, Cuba and Canada, tooth decay did not go up but continued to go down (Maupome et al, 2001; Kunzel and Fischer, 1997, 2000; Kunzel et al, 2000 and Seppa et al, 2000).

Fluoridation is UNSAFE because:

1) It accumulates in our bones and makes them more brittle and prone to fracture. The weight of evidence from animal studies, clinical studies and epidemiological studies on this is overwhelming. Lifetime exposure to fluoride will contribute to higher rates of hip fracture in the elderly.
2) It accumulates in our pineal gland, possibly lowering the production of melatonin a very important regulatory hormone (Luke, 1997, 2001).
3) It damages the enamel (dental fluorosis) of a high percentage of children. Between 30 and 50% of children have dental fluorosis on at least two teeth in optimally fluoridated communities (Heller et al, 1997 and McDonagh et al, 2000).
4) There are serious, but yet unproven, concerns about a connection between fluoridation and osteosarcoma in young men (Cohn, 1992), as well as fluoridation and the current epidemics of both arthritis and hypothyroidism.
5) In animal studies fluoride at 1 ppm in drinking water increases the uptake of aluminum into the brain (Varner et al, 1998).
6) Counties with 3 ppm or more of fluoride in their water have lower fertility rates (Freni, 1994).
7) In human studies the fluoridating agents most commonly used in the US not only increase the uptake of lead into children’s blood (Masters and Coplan, 1999, 2000) but are also associated with an increase in violent behavior.
8) The margin of safety between the so-called therapeutic benefit of reducing dental decay and many of these end points is either nonexistent or precariously low.

Fluoridation is INEQUITABLE, because:

1) It will go to all households, and the poor cannot afford to avoid it, if they want to, because they will not be able to purchase bottled water or expensive removal equipment.
2) The poor are more likely to suffer poor nutrition which is known to make children more vulnerable to fluoride’s toxic effects (Massler & Schour 1952; Marier & Rose 1977; ATSDR 1993; Teotia et al, 1998).
3) Very rarely, if ever, do governments offer to pay the costs of those who are unfortunate enough to get dental fluorosis severe enough to require expensive treatment.

Fluoridation is INEFFICIENT and NOT COST-EFFECTIVE because:

1) Only a small fraction of the water fluoridated actually reaches the target. Most of it ends up being used to wash the dishes, to flush the toilet or to water our lawns and gardens.
2) It would be totally cost-prohibitive to use pharmaceutical grade sodium fluoride (the substance which has been tested) as a fluoridating agent for the public water supply. Water fluoridation is artificially cheap because, unknown to most people, the fluoridating agent is an unpurified hazardous waste product from the phosphate fertilizer industry.
3) If it was deemed appropriate to swallow fluoride (even though its major benefits are topical not systemic) a safer and more cost-effective approach would be to provide fluoridated bottle water in supermarkets free of charge. This approach would allow both the quality and the dose to be controlled. Moreover, it would not force it on people who don’t want it.

Fluoridation is UNSCIENTIFICALLY PROMOTED. For example:

1) In 1950, the US Public Health Service enthusiastically endorsed fluoridation before one single trial had been completed.
2) Even though we are getting many more sources of fluoride today than we were in 1945, the so called “optimal concentration” of 1 ppm has remained unchanged.
3) The US Public health Service has never felt obliged to monitor the fluoride levels in our bones even though they have known for years that 50% of the fluoride we swallow each day accumulates there.
4) Officials that promote fluoridation never check to see what the levels of dental fluorosis are in the communities before they fluoridate, even though they know that this level indicates whether children are being overdosed or not.
5) No US agency has yet to respond to Luke’s finding that fluoride accumulates in the human pineal gland, even though her finding was published in 1994 (abstract), 1997 (Ph. D. thesis), 1998 (paper presented at conference of the International Society for Fluoride Research), and 2001 (published in Caries Research).
6) The CDC’s 1999, 2001 reports advocating fluoridation were both six years out of date in the research they cited on health concerns.

Fluoridation is UNDEFENDABLE IN OPEN PUBLIC DEBATE.

The proponents of water fluoridation refuse to defend this practice in open debate because they know that they would lose that debate. A vast majority of the health officials around the US and in other countries who promote water fluoridation do so based upon someone else’s advice and not based upon a first hand familiarity with the scientific literature. This second hand information produces second rate confidence when they are challenged to defend their position. Their position has more to do with faith than it does with reason.

Those who pull the strings of these public health ‘puppets’, do know the issues, and are cynically playing for time and hoping that they can continue to fool people with the recitation of a long list of “authorities” which support fluoridation instead of engaging the key issues. As Brian Martin made clear in his book Scientific Knowledge in Controversy: The Social Dynamics of the Fluoridation Debate (1991), the promotion of fluoridation is based upon the exercise of political power not on rational analysis. The question to answer, therefore, is: “Why is the US Public Health Service choosing to exercise its power in this way?”

Motivations – especially those which have operated over several generations of decision makers – are always difficult to ascertain. However, whether intended or not, fluoridation has served to distract us from several key issues. It has distracted us from:

a) The failure of one of the richest countries in the world to provide decent dental care for poor people.
b) The failure of 80% of American dentists to treat children on Medicaid.
c) The failure of the public health community to fight the huge over consumption of sugary foods by our nation’s children, even to the point of turning a blind eye to the wholesale introduction of soft drink machines into our schools. Their attitude seems to be if fluoride can stop dental decay why bother controlling sugar intake.
d) The failure to adequately address the health and ecological effects of fluoride pollution from large industry. Despite the damage which fluoride pollution has caused, and is still causing, few environmentalists have ever conceived of fluoride as a ‘pollutant.’
e) The failure of the US EPA to develop a Maximum Contaminant Level (MCL) for fluoride in water which can be scientifically defended.
f) The fact that more and more organofluorine compounds are being introduced into commerce in the form of plastics, pharmaceuticals and pesticides. Despite the fact that some of these compounds pose just as much a threat to our health and environment as their chlorinated and brominated counterparts (i.e. they are highly persistent and fat soluble and many accumulate in the food chains and our body fat), those organizations and agencies which have acted to limit the wide-scale dissemination of these other halogenated products, seem to have a blind spot for the dangers posed by organofluorine compounds.

So while fluoridation is neither effective nor safe, it continues to provide a convenient cover for many of the interests which stand to profit from the public being misinformed about fluoride.

Unfortunately, because government officials have put so much of their credibility on the line defending fluoridation, it will be very difficult for them to speak honestly and openly about the issue. As with the case of mercury amalgams, it is difficult for institutions such as the American Dental Association to concede health risks because of the liabilities waiting in the wings if they were to do so.

However, difficult as it may be, it is nonetheless essential – in order to protect millions of people from unnecessary harm – that the US Government begin to move away from its anachronistic, and increasingly absurd, status quo on this issue. There are precedents. They were able to do this with hormone replacement therapy.

But getting any honest action out of the US Government on this is going to be difficult. Effecting change is like driving a nail through wood – science can sharpen the nail but we need the weight of public opinion to drive it home. Thus, it is going to require a sustained effort to educate the American people and then recruiting their help to put sustained pressure on our political representatives. At the very least we need a moratorium on fluoridation (which simply means turning off the tap for a few months) until there has been a full Congressional hearing on the key issues with testimony offered by scientists on both sides. With the issue of education we are in better shape than ever before. Most of the key studies are available on the internet and there are videotaped interviews with many of the scientists and protagonists whose work has been so important to a modern re-evaluation of this issue.

With this new information, more and more communities are rejecting new fluoridation proposals at the local level. On the national level, there have been some hopeful developments as well, such as the EPA Headquarters Union coming out against fluoridation and the Sierra Club seeking to have the issue re-examined. However, there is still a huge need for other national groups to get involved in order to make this the national issue it desperately needs to be.

I hope that if there are RFW readers who disagree with me on this, they will rebut these arguments. If they can’t than I hope they will get off the fence and help end one of the silliest policies ever inflicted on the citizens of the US. It is time to end this folly of water fluoridation without further delay. It is not going to be easy. Fluoridation represents a very powerful “belief system” backed up by special interests and by entrenched governmental power and influence.

Paul Connett. All references cited can be found at http://www.slweb.org/bibliography.html

All references cited can be found at http://www.slweb.org/bibliography.html

2010-03-15 16:44:47

Bone implants that support and release chemotherapeutical agents in ciclodextrin nanocapsule

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Posted 15 Mar 2010 — by James Street
Category Bone repair, Human osteosarcoma research

15. March 2010 06:35

For the localized treatment of tumors

Bone implants with the ability to carry chemotherapeutical drugs in conception in CICECO

Chemotherapy, followed by the surgical removal of the affected tissue is the treatment usually adapted to bone tumors. An implant which can fill the areas of subtraction, while releasing chemotherapeutical agents locally, in a controlled manner, during the treatment period, is the aim of a research led by the Research Centre in Ceramic Material and Composites (CICECO/UA). In these experiences, specialists are using potential “anti-tumor” drugs coated by nanocapsules.

The osteosarcoma is the most common malignant primary bone tumor. Its major incidence is in children and youngsters and usually involves the amputation of arms and legs. The treatment for this type of tumor implies chemotherapy, followed by the surgical removal of the affected tissue with a safety area, in order to avoid the tumor’s reappearance. This area is then filled with a bone or synthetic biomaterial implant.

Considering how important it is to avoid repeating new chemo or radiotherapy treatments in these cases when neutralizing possible residual focus, 11 researchers from the Universities of Aveiro and Coimbra intend to develop an implant which can contain chemotherapeutical agents of specific ranges of action, and also release these components in a controlled manner for a specific and adequate period of time.

“The bone implants we are studying will serve as a support and releasing agent of capsulated drugs in a ciclodextrin nanocapsule. We are currently experimenting with an active molecule with anti-cancer properties specifically directed to osteosarcomas. Nevertheless, it is intended to broaden its application to other types of cancer“.

For this person, and as explained by Prof. Rui Correia, project coordinator, there is the need to proceed with the study of its mechanic and biological characteristics. “When we develop projects for these purposes, we must bear in mind their mechanic resistance, as well as other characteristics which must be taken in consideration when performing its implant in the bone. In this specific case, we are working with porous supports that contain a silica gel, manipulated to function both as a nanocapsule deposit and releaser. Its physical form will vary according to the bone area to fill.

The gel matrix will receive the anti-tumor compost (cisplatin and metallic composts), capsulated at a molecular level with ciclodextrin, coloured gello capsules which are nothing more and nothing less that sugar rings.

Prof. Ana Gil explains this innovative technique:

“A subgroup within our team, lead by researcher Susana Braga, is by the one hand, developing new metallic composts with a therapeutic potential and, by the other hand, promoting its capsulation in ciclodextrins. The use of the ciclodextrin on the coating of the medicinal molecule increases the efficiency of the drug and reduces the necessary amount. To work at a nanometric scale allows us to improve the properties, both concerning its solubility and its range of activity, allowing us to make it more specific”.

The nanocapsule protects the therapeutic agent from the contact with proteins which are irrelevant to the treatment and makes its located application simpler. The use of ciclodextrins as nanocapsules should protect the organism from the expected high toxicity of the new agents to the healthy cells.

This project, financed by the foundation for the Science and Technology, also presents an innovative aspect in what concerns the study of the metabolic effects of the new compounds (capsulated or not) on the human osteosarcoma cells, as explained by the researcher: “It is important to know the response of the cancer cells to the drugs, in order to be able to adjust and adapt the drug’s nature and dosage, for an effective treatment. These studies use the spectroscopy of the RMN- Magnetic Nuclear Resonance in the characterization of the cells’ metabolic profile and the application of adequate statistic treatments, which help identifying specific metabolic changes and their relation with the patterns of cellular death”.

With the drug in nanocapsules, there will be two types of implants to choose from: permanent titanium and biodegradable (for regenerative purposes) implants. The differences between these two are clarified by Prof. Rui Correia: “The porous supports which will allow the introduction of a chemic component in the organism are conceived from two types of biomaterials: a bio-stable one (non-degradable and biocompatible) and a polymeric, with biodegradable characteristics. The first one will be used in cases where there is a lack of ability to regenerate the bone tissue and the second in situations where there is the probability of a full natural recovery of the bone. In this last case the implant will be absorbed and progressively replaced by the natural bone”.

Besides the microstructural analysis, the researchers are proceeding with mechanic, physics and chemistry and in vitro rehearsals. There will also be performed metabolomics essays with cellular cultures which are subjected to the therapeutic agents, either molecularly encapsulated or not.

SOURCE Research Centre in Ceramic Material and Composites