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NEWSLETTER #7 - "Fluoride & Thyroid
©2000 PFPC (Feel free to distribute)
December 20, 2000
(See PFPC's other newsletters at: www.bruha.com/fluoride/html/newsletter.html
IN THIS ISSUE:
2) WHAT IS CANCER?
3) WHAT ARE G PROTEINS?
4) HOW DO G PROTEINS ACTIVATE CANCER CELLS?
5) WHAT IS ADENYL CYCLASE?
6) ADENYL CYCLASE, TSH AND THE THYROID
7) EVIDENCE: FLUORIDE ACTIVITY
8) FLUORIDE AND I131 UPTAKE
9) FINAL COMMENT
This is our last Newsletter for the year. It deals with fluoride and thyroid cancer. For us this is a very important issue as we have some parents in our group whose children were overexposed to fluorides in infancy (formula, too much toothpaste, supplements etc.) and who subsequently suffered from hypothyroidism and were diagnosed with thyroid cancer in their teens. Needless to say, they also suffer from dental fluorosis.
There is just so much evidence available here
that the continued denial of the fluoride/thyroid cancer connection by public
health officials, dental organizations, and "scientific reviews" will
surely one day prove more embarassing than the denial by cigarette manufacturers
that smoking causes lung cancer.
We thank you all for your past support - despite our angry outbursts at times. We wish we could have more patience, but it often proves hard for us to put up with the ignorance and seemingly purposeful falsifying of information. This so-called "dental health success" has greatly harmed our children's health, and is killing millions of children worldwide.
Thank you for your understanding.
Blessings to all, and best wishes for a safe and happy holiday season!
Parents of Fluoride Poisoned Children (PFPC)
Vancouver, BC, Canada
"A report in the 1955 New England Journal of Medicine shows a 400 percent increase in thyroid cancer in San Francisco during the period that the city has had fluoridated drinking water", so report Gladys Caldwell and Philip Zanfagna, MD, in their 1974 book "Fluoridation and Truth Decay"
In 1974 Leo Kinlen of Oxford compared the occurrence of cancers in fluoridated and non-fluoridated areas (2, 2a). 100 thyroid cancer cases were observed compared to 81 expected ones, an 18% increase. Unbelievably, the authors then contradicted their own findings and stated that "there is no significant excess of cancer of any site in fluoridated areas as compared with nearby fluoridated areas." Those familiar with the recent York Review might remember similar words.
In China fluoride is openly acknowledged as cause of thyroid cancer and government programs have re-settled many thousands of farmers living in fluoride-contaminated areas (3).
In 1997 the US Federal Register published the petition of Bayer to establish new residue tolerance levels for products imported into the US for a pesticide called Tolylfluanid, a pesticide which is illegal in the US but applied almost everywhere else in the world - and therefore therefore makes its way into North America in many foods, i.e. tomato products from Italy, grape juices from from Africa, or apple juice from South America. The apple juice issue is of particular and urgent concern as apple juice is the first juice beverage for most infants, and 60% of all apple juice is imported (4, 5).
Tolylfluanid had been banned for use in the US largely because it had caused thyroid tumors (adenomas) in rats, in a non-linear fashion (-> not dose/concentration-related). Kidney damage occured "probably attributable to the effects of fluoride on renal tubules." Regarding the thyroid adenomas the Bayer petition further stated that, "..Mechanistic studies with tolylfluanid have shown that these tumors are induced through a nonlinear threshold mechanism similar to that discussed in EPA's thyroid policy document."(6)
[NOTE: For an updated and downloadable version of this most interesting EPA Thyroid Policy Statement, see: http://www.epa.gov/ncea/thyroid.htm . All should know that IF this thyroid policy were to be properly applied to the vast data available on fluoride compounds and thyroid function, fluoride in all forms would be immediately banned! Repeated efforts have been made by the PFPC within the last two years to have the fluoride issue assessed according to this thyroid policy, and we have asked the EPA, and also the NTEU to investigate this vital issue, but to no avail to date.]
In 1998 the late great John Yiamouyiannis sent us the results of the National Toxicology Program cancer bioassay on sodium fluoride (7). Again, the data showed incidences of thyroid adenomas, as well as the same "nonlinear" mechanism as had been observed with tolylfluanid. However - as is well-known by now - the final published version of the NTP report downgraded the "clear evidence of carcinogenicity " to "equivocal evidence of carcinogenicity". It was this change in classification which prompted Dr. William Marcus, who was then Senior Science Adviser and Toxicologist in the Office of Drinking Water, to blow the whistle about the issue, which led to his firing by the U.S. Environmental Protection Agency (EPA). Dr. Marcus sued the EPA, won his case and was reinstated with back pay, benefits and compensatory damages.(8) However, the issue itself - fluoride CAUSING cancers as identified by Dr. Marcus and others - remains denied to this date.
Between 1975 and 1996 the incidence of thyroid cancer rose 42.1% in the United States, and incidence of diagnosed thyroid cancer has now climbed up to 8.0 per 100,000. Canada reports a yearly 6% increase in thyroid cancer.
The most prevalent carcinomas in US children and adolescents younger than 20 years are now thyroid carcinomas (35.5%); more prevalent than the more publicized melanomas (30.9%). Approximately 75% of the thyroid carcinomas occurred in adolescents aged 15 -19 years of age (9).
Thyroid cancer in most cases is a slow-progressing cancer - in children average time from onset to diagnosis is thought to be 15 years. It is therefore clear that onset occurs during infancy and early childhood.
In the elderly, thyroid disease is very common. Upon autopsy, the find of a "normal thyroid gland" is rare, testifying to the incredible high prevalence of thyroid disorders among the elderly. Fleischman in 1999 reviewed over 800 autopsies and only found 25% of thyroids to be "normal".
Fluorides cause thyroid cancer. All common anti-thyroid agents are thought to be cancer causing, as they influence the natural feedback mechanism which regulates the thyroid-pituitary axis and cause increased levels of thyrotropin, the thyroid-stimulating-hormone (TSH), which then in turn activates cancer cells by activating an enzyme system called adenyl cyclase.
Propylthiouracil (PTU), which replaced fluoride compounds in the treatment of hyperthyroidism in the early 1940s, is now considered a carcinogenic for the same reason (10).
PTU administered in the drinking water induced increased incidences of thyroid carcinomas and adenomas in rats of both sexes, identical to the findings by the NTP regarding fluoride (7).
The FDA regulates the use of propylthiouracil as a pharmaceutical to treat hyperthyroidism under the Food, Drug, and Cosmetic Act (FD&CA).
Why NOT fluoride?
WHY is fluoride, although it had been used as most-effective anti-thyroid medication for more than three decades - either alone or with PTU - NOT declared a carcinogenic?
2) WHAT IS CANCER?
by Bob Johannsen
Cancer is the popular general term used to describe over 100 diseases that are characterized by the uncontrolled growth and spread of abnormal cells in the body. Cancerous masses can grow and develop from a single abnormal cell in any tissue of the body. These abnormal cells are often called "mutations". The name given to a particular cancer stems from the tissue in which it originated, for example a hepatocellular carcinoma is called a liver cancer. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Dissemination of cancer cells throughout the body will allow secondary tumors or neoplasms to be established in other organs. This process is known as metastases.
Normally cells reproduce and divide in an orderly fashion through the cell cycle. This enables the body to grow, and to repair worn out or damaged tissue. Every cell in the body has the potential to form a new growth. This occurs not only in humans but in all living organisms (plants and animals), simply because all living organisms are made up of cells. Cells grow by dividing in half, such that one cell will become two, two become four, and so on. These new cells are then called "daughter cells".
Cancer is a direct consequence of the loss of the cell cycle control. Most of the genetic events that lead to cancer occur over the lifetime of an individual and often originate in childhood.
The realization of the stepwise progression of cancer has been the most significant contribution to the understanding of the cancer disease process since U.S. President Nixon first declared the so-called "War on Cancer" back in 1971.
The discovery of G-proteins has helped tremendously in understanding cancer and its progress.
3) WHAT ARE G PROTEINS?
In essence, G proteins are "On/Off" switches which regulate cellular communication - relaying information received from outside the cell to the inside, or from one cell to another.
This process of cell communication is called "signal transduction", a term first applied in molecular biology by Martin Rodbell, who with Alfred Gilman received the 1994 Nobel Prize in medicine and physiology for their independent work leading to the discovery of G proteins.
As G proteins are vital in all cell communication, uncontrolled G protein signaling can often lead to cancer in humans. Over 30% of all cancers are now thought to be caused by G protein mutations.
For example, the ras oncogene (member of the G protein subfamily) was first found in human bladder cancer cells and is now also thought to be also responsible for up to 40% of all colon cancers, as well as 90% of pancreatic cancers . Studer et al (11) identified ALL thyroid goiter nodules examined to contain areas where the epithelial cells were morphologically grossly altered and heavily loaded with p21ras, which has now further been identified in breast, bladder and prostate cancers.
Fluoride compounds are known and established p21ras pathway activators (12-23).
4) HOW DO G PROTEINS ACTIVATE CANCER CELLS?
G proteins regulate an enzyme system called adenyl cyclase. This system is at the convergence of multiple neuronal, hormonal, and environmental inputs. Permanently ("constitutively") activated adenyl cyclase will lead to abnormal cell growth - thus to cancer.
There are two broad groups of G proteins : stimulating ones -> G(s), and inhibiting ones, ->G(i) .
G(s) describes a G protein which STIMULATES the activation of adenyl cyclase (AC). For example, when it is stimulated in the heart muscle, cardiac output increases. In the case of cholera, a G(s) protein remains stuck in its active "ON" state, so AC and thus cAMP is overproduced, leading to massive sodium water transport across intestinal epithelial cells; hence diarrhea and the often life-threatening loss of water and salts.
By contrast pertussis toxin (whooping cough)
does the same thing to G(i), preventing its interaction with AC, so that the
cells cannot INHIBIT the cyclase activity, resulting in the accumulation of
pulmonary fluid as seen in whooping cough.
G protein dysfunction or mutations involve either gain or loss of function.
5) WHAT IS ADENYL CYCLASE?
The adenyl cyclase is as a multi-component system embedded in the lipid bilayer of the plasma membrane which serves as a signal transduction system in apparently every cell type of higher organisms (24).
The complete system consists of various receptor molecules, which sensitize the external ligands, the effector enzyme adenylate cyclase, which catalyzes the formation of cyclicAMP from ATP, and two G proteins, which transduce the signals from the receptors to the adenylate cyclase. Depending on the receptor type activated by a ligand, stimulatory or inhibitory, either the stimulatory or the inhibitory G protein is activated and induces stimulation or inhibition of adenylate cyclase with subsequent increase or decrease in cellular cyclic AMP levels (25).
Anything that activates AC is thought to be a cancer promoter for elevation can cause increase in cancer cell growth. Patients with constitutively active adenyl cyclase (permanently "ON") have what are called hyperactive or overfunctioning tumors, such as are seen in the fluoride-related literature.
While knowledge of G proteins is virtually non-existent not only among the general public, but also among most general practitioners, research on G proteins has been one of the hottest biological pursuits of the past decade, mainly because of the experience gained from advanced investigations into G proteins as "programmable messengers", as Rodbell had called them. Pharmacologists estimate that up to 60% of all medicines used today exert their effects through G protein signaling pathways (26). This industry frenzy had been forecasted by Gilman who - in a 1992 Scientific American article on G proteins authored together with Maurice Linder - had predicted that scientists would eventually diagram the cellular players involved in communication and be able to predict how those cells will operate in response to different combinations of signals.
"For those who would hope to develop drug therapies such discoveries would be like giving a thief a wiring diagram to the alarm system at a bank", the authors wrote (27).
Gilman further said, "The ultimate dream is to design drugs that will prevent aberrant G-protein action."
In a press conference in Maryland following the announcement of the 1994 Nobel Prize, Rodbell had critized the current state of the commercialization of science. . ."The tenor is changed, the world ain't the same, everything is targeted, everything is bottom line, how to make a buck, " he said, adding that it is crucial to "capture knowledge for its own sake and for humanity" (28).
6) ADENYL CYCLASE, TSH AND THE THYROID
Stimulation of proliferation, thyroid hormone synthesis, and expression of thyroid-specific genes are transmitted by the adenyl cyclase system via thyrotropin, the thyroid-stimulating-hormone (TSH).
It is TSH that mediates iodine, zinc and selenium (29). TSH stimulates all metabolic and cellular processes involved in synthesis which occur in thyroid and peripheral tissue. TSH also stimulates intermediary metabolism and thyroid growth. TSH initiates release of thyroxine (T4) and triiodothyronine (T3) from thyroglobulin. It is TSH excess which ultimately causes goiter.
TSH is generally accepted to be the main regulator of thyroid growth and function and is considered the "natural" universal G protein activator (30). The TSH receptor belongs to a broad class of receptors known as "seven-loop receptors" because they contain a long stretch of amino acids which cross the cell membrane seven times.
[At this point it is important to realize that TSH receptors are not only found in the thyroid gland, but also in the liver, cardiac muscle, gastrointestinal tract , thymus, peripheral blood mononuclear cells, orbital tissue, fibroblasts, peripheral lymphocytes, fat, cardiac muscle, osteoblasts and osteosarcoma cells, and of course the brain - where they are overexpressed in patients with Down Syndrome or Alzheimer's Disease (31-38)]
It has been established that even small increases in serum TSH is sufficient to promote thyroid tumors (39, 40). Because of this fact, thyroid cancer survivors are required to keep their TSH levels suppressed, so as not to promote growth and multiplication of any remaining cancerous cells after removal of the cancerous thyroid gland (thyroidectomy).
Why are these survivors not also advised to "suppress" fluoride intake? The biological effects are identical. Low amounts of fluoride stimulate AC, high doses inhibit AC (41) - effects IDENTICAL to TSH.
When faced with the fluoride/G protein issue, many pro-fluoridationists serve up a standard reply stating that the amount of fluoride required to activate G proteins are a "thousand times higher" than are seen in the human plasma. They then usually cite some papers where very high amounts of fluorides are used to activate inhibiting G(i) proteins.
The fact is that low amounts of fluoride activate stimulating G proteins G(s) while high doses activate G(i) - again, this is identical to TSH effects. Rat experiments have shown that the amount of fluoride required for AC activation in the thyroid is IDENTICAL to the one at which fluoride causes dental fluorosis (42, 43).
Therefore - if fluoride activates AC at such low concentrations, it obviously activates G proteins, as activation of AC is absolutely dependent on the regulatory G proteins (44).
It is important that all recognize such statements as the one above as complete scientific nonsense.
Here is some devastating evidence of fluoride effects - on HUMAN thyroid cancers.
7) EVIDENCE: FLUORIDE ACTIVITY
compiled by Wendy Small
"The adenylcyclase (AC) activity of crude human thyroid plasma membranes were studied in some detail and conditions for optimal cyclic AMP-production established. Membranes from eight "cold" and two "hot" thyroid adenomas were investigated and compared to membranes from corresponding normal, paranodular tissues. The investigated membranes were found to contain similar basal AC activities, which were stimulated three to five times with TSH and ***20--30 times with fluoride***." (!!!)
Walinder O, Karlsson FA, Dahlberg PA - "Adenyl cyclase activity in human thyroid plasma membranes from normal human thyroid tissue and thyroid adenomas" Acta Endocrinol (Copenh) 92(1):95-104 (1979) http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=227209&form=6&db=m&Dopt=b
"In the hyperfunctional follicular carcinoma the basal adenylate cyclase is much higher than in control tissue, carcinoma adenylate cyclase does not respond to TSH and prostaglandin E1, ***whereas it responds normally to fluoride****."
Macchia V, Mandato E, Carella C, Pisano G, Biscaglia G - "The adenylate cyclase-cyclic AMP-phosphodiesterase system in pathological human thyroid" J Endocrinol Invest 1(4):337-45 (1978)
Kalderon AE, Sheth V - "Secretion and adenylate cyclase in thyroid nodules" Arch Pathol Lab Med 102(7):381-86 (1978)
"Thyrotropin (TSH)- and ***sodium fluoride (NaF)-sensitive adenylate cyclase (AC) activity was measured in ten cases of "cold" thyroid nodules and compared with perinodular tissue. Findings were correlated with the ultrastructure of the nodular and perinodular tissue. Comparisons of the results of assay studies revealed an increase of basal and*** NaF- and TSH-stimulated AC activity in cold lesions."
F- stimulation in normal tissue 3 times higher than TSH:
"We observed an increased adenylate cyclase activity in cold nodules as compared to normal. More importantly, this activity was much more responsive to TSH in cold nodules than in normal ....Also, maximal TSH stimulation was similar to that elucited by ***fluoride in the cold nodules but only one-third in normal tissue...."
Orgiazzi J, Chopra IJ, Solomon DH, Williams DE - "Comparison of the effect of TSH and fluoride on the adenylate cyclase activity of cold thyroid nodules" Ann Endocrinol (Paris) 37(2):107-8 (1976)
"... The localization of adenylate cyclase and 5'-nucleotidase activities in the follicular cells of adenomatous goiter and normal thyroid was studied by light and electron microscopy. Simultaneous biochemical measurement for both activities was carried out to confirm the histochemical findings. Adenylyl-imidodiphosphate (AMP-PNP) was used as an effective substrate for adenylate cyclase. The specificity of the adenylate cyclase reaction was also examined by adding oxalacetic acid or PCMB as an adenylate cyclase inhibitor, and by adding ***sodium fluoride or TSH*** as an adenylate cyclase stimulator to the reaction mixture...."
Mizukami Y, Matsubara F, Matsukawa S - "Localization of adenylate cyclase and 5'-nucleotidase activities in human thyroid follicular cells" Histochemistry 74(1):9-19(1982)
"The adenylate cyclase system was studied in hyperfunctioning autonomous nodules in comparison with normal thyroid tissue. The basal, TSH- and**** NaF-stimulated adenylate cyclase activities were tested in purified plasma membrane preparations..."
Toccafondi RS, Rotella CM, Tanini A, Fani P, Arcangeli P - "Thyrotrophin-responsive adenylate cyclase activity in thyroid toxic adenoma" Acta Endocrinol (Copenh) 92(4):658-68 (1979)
"Low concentrations of NaF and Gpp(NH)p stimulated AC activity [in human thyroid neoplasms] whereas high concentrations of NaF and Gpp(NH)p assayed either together or separately inhibited AC activity."
Clark OH, Gerend PL - "Thyrotropin regulation of adenylate cyclase activity in human thyroid neoplasms" Surgery 97(5):539-46 (1985)
9) FLUORIDE AND I131 UPTAKE
As if fluoride activity on AC wasn't bad enough, there is one more important factor to consider. Officialy, the only verified cause of thyroid cancer remains ionizing radiation such as radioactive iodine (I131), with children again being at greatest risk. We are currently seeing the aftermath of the Chernobyl disaster and increasing thryoid cancers are now seen in the children affected by the disaster.
Many studies within the last 50 years have shown that fluoride greatly enhances the uptake of I131 - even when only slightly iodine deficient (45, 46, 47, 48, 49), and at F- in water levels even BELOW the amount deemed "optimal" for caries prevention (48).
10) FINAL COMMENT
Thyroid cancer cells are not the only ones activated by fluoride. All hormone-related cancers such as breast, ovary, uterine, prostate, testis, thyroid and osteosarcoma, etc. share a unique mechanism of carcinogenesis. These cancerous cells are activated by adenyl cyclase. These cancerous cells are activated by fluoride. This is why there is an increase in osteosarcomas observed in fluoridated areas (50), as is uterine cancer (51), etc..
"Everything causes cancer? Perhaps. Conceivably even a single electron at the other side of the universe. The real question is, how likely is any one particular cause? In point of fact, fluoride causes more human cancer, and causes it faster, than any other chemical."
- Dean Burk, Chief Chemist Emeritus, U.S. National Cancer Institute
1) Caldwell G, Zanfagna PE - "Fluoridation and Truth Decay" Top-Ecol Press, Library of Congress No. 74-80847 (1974)
also, see: Gotzsche A-L - "The Fluoride Question: Panacea or Poison?" Stein & Day (New York) ISBN 0-8128-1974-X (1975)
2) Kinlen L - " Cancer incidence in relation to fluoride level in water supplies" Community Health 6:69 (1974)
[1.09 to 0.91 -> Observed to expected ratios in fluoridated and non-fluoridated cities respectively. This means an increase of 18 to 19 percent.]
data also in:
2a) Kinlen L - " Cancer incidence in relation to fluoride level in water supplies" Br Dent J 138(6):221-4 (1975)
3) MA LIE, China Daily staff, 12/08/1999 Copyright© by China Daily
"Shaanxi to move poorest of the poor from hills"
XI'AN -- Shaanxi, an inland province in Northwest China, plans to move its poor farmers from high mountainous slopes within the next three years as part of a poverty eradication drive here. Zhang Wei, deputy governor in charge of the programme, said Shaanxi still has nearly 2 million people living below the poverty line. About 244,700 people are kept poor by geography, as they live in areas that prevent them from having basic living amenities, as farmland and water. "In southern Shaanxi's Qinba Mountains, some farmers are living on high mountainside where crops cannot be planted in the extreme cold weather," Zhang said.
In some other places farmers suffer from Kaschin-Beck's disease and thyroid tumours because of fluoridated underground water, Zhang said. "In the past these farmers got relief from the local government every year, but in such poor geographical conditions, they could not lift themselves out of poverty, so the government decided to move them to better places," the deputy governor said.The poorest farmers live mostly in northern Shaanxi's Baiyu Mountains and southern Shaanxi's Qinba Mountains, will be moved to rural plains areas in the county and resettled in newly built villages.
The provincial and county-level governments will invest 489.4 million yuan (US$59 million) in the resettlement programme over three years, at an average of 2,000 yuan ($241) per farmer, the deputy governor said. Farmers will be allowed to decide whether or not to move, or given the option to move elsewhere. The local government will also sign contracts with farmers to safeguard their rights, Zhang said.
The resettlement programme, which has already been put into place on a trial basis, has already relocated more than 20,000 people. The province plans to resettle another 70,000 this year. In order to ensure success, the provincial government also signed agreements with county-level officials, Zhang said. Neighbouring Gansu Province and the Ningxia Hui Autonomous Region, which have the same problems, have relocated at least 700,000 people through similar efforts.
"The central government desires that
poverty-stricken farmers be lifted out of poverty by 2000, and we can meet the
goal in Shaanxi if we are successful in the resettlement programme, because the
244,700 farmers are the hardest cases," Zhang said.
4) FEDERAL REGISTER AUGUST 11, 1997 Fungicide Tolylfluanid
5) PFPC Special Edition: Pesticides http://www.bruha.com/fluoride/html/pesticides.html
SIDENOTE: South African grapes were found to contain residues of 8 mg of tolylfluanid - AFTER normal washing! [Tests carried out by Planteforsk Pesticidlaboratoriet, Norway, April 1998]
6) ASSESSMENT OF THYROID FOLLICULAR CELL TUMORS EPA/630/R-97/002 March 1998
7) National Toxicology Program -"Toxicology and carcinogenesis studies of sodium fluoride (CAS No. 7681- 49) in F344/N rats and B6C3f, mice (Drinking Water Studies)" US DHHS, NIH Publication no. 91- 2848. Technical Report 393
(1990) also see: http://www.fluoridation.com/calgaryh.htm
8) STATEMENT OF Dr. J. WILLIAM HIRZY, NATIONAL TREASURY EMPLOYEES UNION CHAPTER 280 BEFORE THE SUBCOMMITTEE ON WILDLIFE, FISHERIES AND DRINKING WATER
UNITED STATES SENATE JUNE 29, 2000 http://www.senate.gov/~epw/hir_0629.htm
9) [PROPYLTHIOURACIL, CAS No. 51-52-5, First Listed in the Fourth Annual Report on Carcinogens
10) NCI - Cancer Incidence and Survival among Children and Adolescents: United States SEER Program (1975-1995), SEER Homepage: http://www.seer.cancer.gov
11) Studer H, Gerber H, Zbaeren J, Peter HJ - "Histomorphological and immunohistochemical evidence that human nodular goiters grow by episodic replication of multiple clusters of thyroid follicular cells." J Clin
Endocrinol Metab 75(4):1151-8 (1992) http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=1400886&form=6&db=m&Dopt=b
12) Xu S, Khoo S, Dang A, Witt S, Do V, Zhen E, Schaefer EM, Cobb MH - "Differential regulation of mitogen-activated protein/ERK kinase (MEK)1 and MEK2 and activation by a Ras-independent mechanism" Mol Endocrinol (1997)11(11):1618-25 http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=9328344&form=6&db=m&Dopt=b
13) Kleuss C, Raw AS, Lee E, Sprang SR, Gilman AG - "Mechanism of GTP hydrolysis by G-protein alpha subunits" Proc Natl Acad Sci U S A 91(21):9828-31 (1994)
14) Coleman DE, Berghuis AM, Lee E, Linder ME, Gilman AG, Sprang SR - "Structures of active conformations of Gi alpha 1 and the mechanism of GTP hydrolysis" Science 265(5177):1405-12 (1994)
15) Diaz JF, Escalona MM, Kuppens S, Engelborghs Y - "Role of the switch II region in the conformational transition of activation of Ha-ras-p21" Protein Sci 9(2):361-8 (2000)
16) Diaz JF, Sillen A, Engelborghs Y - "Equilibrium and kinetic study of the conformational transition toward the active state of p21Ha-ras, induced by the binding of BeF3- to the GDP-bound state, in the absence of GTPase-activating proteins" Biol Chem 272(37):23138-43(1997)
17) Kuppens S, Diaz JF, Engelborghs Y - "Characterization of the hinges of the effector loop in the reaction pathway of the activation of ras-proteins. Kinetics of binding of beryllium trifluoride to V29G and I36G mutants of Ha-ras-p21" Protein Sci 8(9):1860-6 (1999) http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=10493587&form=6&db=m&Dopt=b
18) Yuspa SH, Kilkenny A, Cheng C, Roop D, Hennings H, Kruszewski F, Lee E, Strickland J, Greenhalgh DA - "Alterations in epidermal biochemistry as a consequence of stage-specific genetic changes in skin carcinogenesis" Environ Health Perspect 93:3-10(1991)
19) Camp LA, Hofmann SL - "Purification and properties of a palmitoyl-protein thioesterase that
cleaves palmitate from H-Ras" J Biol Chem 268(30):22566-74 (1993) http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=7901201&form=6&db=m&Dopt=b
"The induction of cancer on mouse skin by
initiation-promotion protocols occurs through stages in which a benign squamous
papilloma is an obligate precursor of squamous cell carcinoma..... Activation of
the Ha-ras gene is sufficient to produce the papilloma phenotype.....However,
c-Ha-ra keratinocytes have a high basal level of phosphatidylinositol (PI)
turnover, which is additive with several other inducers of this pathway,
including Ca2+ and aluminum fluoride."
20) Matyas GR, Fishman PH - "Lipid signalling pathways in normal and ras-transfected NIH/3T3
cells" Cell Signal 1(4):395-404(1989) http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=2561989&form=6&db=m&Dopt=b
21) O'Shea JJ, Urdahl KB, Luong HT, Chused TM, Samelson LE, Klausner RD - "Aluminum fluoride induces phosphatidylinositol turnover, elevation of cytoplasmic free calcium, and phosphorylation of the T cell antigen receptor in murine T cells" J Immunol 139(10):3463-9(1987) http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=2824607&form=6&db=m&Dopt=b
22) Spina A, Di Donato A, Colella G, Illiano G - "Increased adenylate cyclase activity in rat thyroid epithelial cells expressing viral ras genes" Biochem Biophys Res Commun 142(2):527-35 (1987) http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=3028415&form=6&db=m&Dopt=b
23) Haliotis T, Trimble W, Chow S, Mills G, Girard P, Kuo JF, Govindji N, Hozumi N - "The cell biology of ras-induced transformation: insights from studies utilizing an inducible hybrid oncogene system" Anticancer Res 8(5A):935-45 (1988)
"Owing to their similarity to G proteins, regulatory elements interposed between cell-surface receptors and their effector enzymes, it has been postulated that p21, the ras oncogene protein, mediates its transforming effects by constitutive activation of proliferative signal transduction pathways.... We studied the effect of ras expression on the regulation of adenylate cyclase (A.C.), key enzyme of one such major pathway. We found that ras expression correlated with a dampening of responsiveness of A.C. to several stimuli, including hormones such as isoproterenol and other agents such as GMP-PNP, forskolin and fluoride-ion"
24) Reithmann C, Gierschik P, Jakobs KH - "Stimulation and inhibition of adenylyl cyclase" Symp Soc Exp Biol 44:207-24 (1990)
25) Jakobs KH, Minuth M, Bauer S, Grandt R, Greiner C, Zubin P - "Dual regulation of adenylate cyclase. A signal transduction mechanism of membrane receptors" Basic Res Cardiol 81(1):1-9 (1986)
26) Roush W - "Regulating G protein signaling" Science 271 (5252):1056-8 (1996)
27) Linder ME, Gilman AG - "G proteins" Sci Am 267(1):56-61, 64-5 (1992)
28) BOSTON GLOBE, October 11, 1994 http://w:www.boston.com/globe/search/stories/nobel/1994/1994l.html
29) Bellisola G, Bratter P, Cinque G, Francia G, Galassini S, Gawlik D, Negretti de Bratter VE, Azzolina L - "The TSH-dependent variation of the essential elements iodine, selenium and zinc within human thyroid tissues" Trace Elem Med Biol 12(3):177-82 (1998)
30) Laugwitz KL, Allgeier A, Offermanns S, Spicher K, Van Sande J, Dumont JE, Schultz G - "The human thyrotropin receptor: a heptahelical receptor capable of stimulating members of all four G protein families." Proc Natl Acad Sci U S A 93(1):116-20 (1996) http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=8552586&form=6&db=m&Dopt=b
31) Drvota V, Janson A, Norman C, Sylven C, Haggblad J, Bronnegard M, Marcus C - "Evidence for the presence of functional thyrotropin receptor in cardiac muscle" Biochem Biophys Res Commun 211(2):426-31(1995)
Karolinska Institute, Dept of Medicine, Huddinge University Hospital, Sweden.
32) Endo T, Ohno M, Kotani S, Gunji K, Onaya T - "Thyrotropin receptor in non-thyroid tissues" Biochem Biophys Res Commun 190(3):774-9 (1993) http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=8439328&form=6&db=m&Dopt=b
33) Inoue M, Tawata M, Yokomori N, Endo T, Onaya T - "Expression of thyrotropin receptor on clonal osteoblast-like rat osteosarcoma cells" Thyroid 8(11):1059-64 (1998)
34) Janson A, Rawet H, Perbeck L, Marcus C - "Presence of thyrotropin receptor in infant adipocytes" Pediatr Res 43(4 Pt 1):555-8 (1998)
35) Labudova O, Cairns N, Koeck T, Kitzmueller E, Rink H, Lubec G - "Thyroid stimulating hormone-receptor overexpression in brain of patients with Down syndrome and Alzheimer's disease" Life Sci 64(12):1037-44 (1999)
36) Crisp MS, Lane C, Halliwell M, Wynford-Thomas D, Ludgate M - "Thyrotropin receptor transcripts in human adipose tissue" J Clin Endocrinol Metab 82(6):2003-5 (1997)
37) Duntas LH, Papanastasiou L, Mantzou E, Jehle P, Mantzos I, Koutras DA - "Inhibitory action of oral thyrotropin-releasing hormone on the glucoregulatory response of the oral glucose tolerance test." Thyroid 8(10):929-33 (1998)
38) Paschke R, Geenen V - "Messenger RNA expression for a TSH receptor variant in the
thymus of a two-year-old child" Mol Med 73(11):577-80 (1995) http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=8751142&form=6&db=m&Dopt=b
39) Hood A, Liu YP, Gattone VH 2nd, Klaassen CD - "Sensitivity of thyroid gland growth to thyroid stimulating hormone (TSH) in rats treated with antithyroid drugs." Toxicol Sci 49(2):263-71 (1999)
40) Ledent C, Dumont JE, Vassart G, Parmentier M - "Thyroid expression of an A2 adenosine receptor transgene induces thyroid hyperplasia and hyperthyroidism." EMBO J 11(2):537-42 (1992)
41) Clark OH, Gerend PL - "Thyrotropin regulation of adenylate cyclase activity in human thyroid neoplasms" Surgery 97(5):539-46 (1985) http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=2986305&form=6&db=m&Dopt=b
42) Jenq SF, Jap TS, Hsieh MS, Chiang H - "The characterization of adenyl cyclase activity in FRTL-5 cell line." Chung Hua I Hsueh Tsa Chih (Taipei) 51(3):159-65 (1993)
RATS: "Sodium fluoride stimulation study demonstrated dual actions of fluoride on adenylate cyclase; when the cells were assayed with increasing concentration of NaF, the AC activity increased as the concentration of NaF increased from 0.01 to 1 mM, but decreased strikingly as that concentration increased from 1 mM to 100 mM...." [Fisher rat thyroid cell line]
43) Angmar-Mansson B, Ericsson Y, Ekberg O - "Plasma fluoride and enamel fluorosis" Calcif Tissue Res 22(1):77-84 (1976)
RATS: "... The results indicate that
temporary peak values rather than elevated fasting values are responsible for
the occurrence of enamel fluorosis and that the peak values must approach about
10 muM in order to block enamel formation by the ameloblasts. "
44) Totsuka Y, Nielsen TB, Field JB - "Roles of GTP and GDP in the regulation of the thyroid adenylate cyclase system" Biochim Biophys Acta 718(2):135-43 (1982)
45) Bachinskii PP, Gutsalenko OA, Naryzhniuk ND, Sidora VD, Shliakhta AI - "Action of the body fluorine of healthy persons and thyroidopathy patients on the function of hypophyseal-thyroid the system" Probl Endokrinol (Mosk)
(-> reduced T3, increased TSH and increased I131 uptake)
46) Zhao W, Zhu H, Yu Z, Aoki K, Misumi J, Zhang X - "Long-term Effects of Various Iodine and Fluorine Doses on the Thyroid and Fluorosis in Mice" Endocr Regul 32(2):63-70 (1998) [complete paper downloadable at : http://www.elis.sk/endo/endo298.htm ]
47) Henning K, Fritz H - "Fluor und die Schilddrüse" Schweiz Med Wochenschr (91):79-81 (1961)
48) Lin Fa-Fu, Aihaiti, Zhao Hong-Xin, Lin Jin, Jiang Ji-Yong, Maimaiti, and Aiken - "The Relationship of a Low-Iodine and High-Fluoride Environment to Subclinical Cretinism in Xinjiang" IDD Newsletter, Volume 7 Number 3 August 1991
49) Korrodi H, Wegman T, Galletti P, Held HR- "Sind bei der Cariesprophylaxe mit Fluor Rueckwirkungen auf die Schilddruese zu erwarten?" Schweiz Med Wochenschr 85:1016 (1955)
50) Cohn, Perry D. Ph.D. - "An Epidemiological Report on Drinking Water Fluoridation and Osteosarcoma in Young Males" New Jersey Department of Health, Environmental Health Service, Trenton NJ November 8, 1992)
51) Tohyama E - "Relationship between fluoride concentration in drinking water and mortality rate from uterine cancer in Okinawa prefecture, Japan" Epidemiol 6(4):184-91 (1996)
Veroni MC, Michelangeli VP, Heaney TP, Ng KW, Partridge NC, Larkins RG - "Adenylate cyclase responsiveness of human insulinomas" Horm Metab Res 13(5):254-9 (1981)
"... Adenylate cyclase of both tumours responded to 5'-guanylyl-imidodiphosphate, sodium fluoride, glucagon and prostaglandin E2..."
About Dean Burk:
FLUORIDE & THYROID
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