The Natural Thyroid Diet

Thyroid Factor

Thyroid Factor is a program that was created by Dawn Sylvester to help women deal with thyroid issues. Dawn Sylvester is a 57 years old lady that has worked with 1,000's of real women. She has over the time tried to investigate the underlying reason why majority of women lose energy and also struggle with belly fat and fatigue as they age. It is a comprehensive program thatcomprises of Thyro pause, 11 kinds of thyroid saving foods that will work to help you boost fat burning Free T3. The program also teaches you all the hidden causes of thyroid which are making you fat and later a highly reliable Thyroid reboot plan which is an excellent plan you need to tackle your weight. Additionally, there are tips to reduce bulging fat fast and eventually obtain a healthy body. You also get several bonuses all aimed at helping you solve all the problems that comes with being overweight. The three bonuses you get are 21 Day Thyroid weight loss system, 101 Thyroid boosting foods and Thyroid Jumpstart Guide. More here...

Thyroid Factor Summary

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Vitamin D3 and Thyroid Receptors

Thyroid hormone receptors (TRa and TRjS) exhibit multiple modes of DNA binding, including both homodimerization and RXR het-erodimerization on a number of diverse response elements, where they can both activate and silence transcription, depending on the promoter context. The TRs are activated by triiodothyro-nine (T3), and physiological roles for these receptors include regulation of thyroid and pituitary tropic hormone production, affecting a variety of CNS and metabolic functions. Dominant human mutations within the TRfi gene (but not TRa) have been characterized, and individuals carrying these mutations display clinical symptoms of generalized resistance to thyroid hormone.362 The mutations interfere with ligand binding but not dimerization or DNA binding and likely represent dominant negative mutations.

Hashimotos thyroiditis

Hashimoto's thyroiditis is a disease of middle-aged women that results from a B- and T-cell response to different components of the thyroid gland such as thyroglobulin and epithelial cell microsomes. There is an intense lymphocyte infiltration of the gland and the thyroid follicles are progressively destroyed. In an attempt to regenerate the gland becomes enlarged with a rubbery hard consistency, but patients are ultimately rendered hypothyroid. Treatment during the acute phase is with steroids and thyroxine. If pressure symptoms develop, a subtotal thyroidectomy should be performed (Fig. 11.14).

Mechanism of Thyroid Hormone Action

As previously discussed, the major hormone secreted by the thyroid gland is thyroxine, or tetraiodothyronine (T4). Like steroid hormones, thyroxine travels in the blood attached to carrier proteins (primarily to thyroxine-binding globulin, or TBG). The thyroid also secretes a small amount of triiodothyronine, or T3. The carrier proteins have a higher affinity for T4 than for T3, however, and, as a result, the amount of unbound (or free ) T3 in the plasma is about ten times greater than the amount of free T4. Approximately 99.96 of the thyroxine in the blood is attached to carrier proteins in the plasma the rest is free. Only the free thyroxine and T3 can enter target cells the protein-bound thyroxine serves as a reservoir of this hormone in the blood (this is why it takes a couple of weeks after surgical removal of the thyroid for the symptoms of hypothyroidism to develop). Once the free thyroxine passes into the target cell cytoplasm, it is en-zymatically converted into T3. As...

Thyroid and Parathyroid Glands

The thyroid secretes thyroxine (T4) and triiodothyronine (T3), which are needed for proper growth and development and which are primarily responsible for determining the basal metabolic rate (BMR). The parathyroid glands secrete parathyroid hormone, which helps to raise the blood Ca2+ concentration. The thyroid gland is located just below the larynx (fig. 11.21). Its two lobes are positioned on either side of the trachea and are connected anteriorly by a medial mass of thyroid tissue called the isthmus. The thyroid is the largest of the pure endocrine glands, weighing between 20 and 25 grams. On a microscopic level, the thyroid gland consists of numerous spherical hollow sacs called thyroid follicles (fig. 11.22). Figure 11.22 A photomicrograph (250x) of a thyroid gland. Numerous thyroid follicles are visible. Each follicle consists of follicular cells surrounding the fluid known as colloid, which contains thyroglobulin. These follicles are lined with a simple cuboidal epithelium...

Production and Action of Thyroid Hormones

The thyroid follicles actively accumulate iodide (I-) from the blood and secrete it into the colloid. Once the iodide has entered the colloid, it is oxidized to iodine and attached to a specific amino acid (tyrosine) within the polypeptide chain of a protein called thyroglobulin. The attachment of one iodine to tyrosine produces monoiodotyrosine (MIT) the attachment of two iodines produces diiodotyrosine (DIT). The transport of thyroid hormones through the blood and their mechanism of action at the cellular level was described earlier in this chapter. Through the activation of genes, thyroid hormones stimulate protein synthesis, promote maturation of the nervous system, and increase the rate of cell respiration in most tissues of the body. Through this action, thyroxine (after it is converted into T3) elevates the basal metabolic rate (BMR, discussed in chapter 19), which is the resting rate of calorie expenditure by the body. Calcitonin, secreted by the parafollicular cells of the...

Diseases of the Thyroid

Thyroid-stimulating hormone (TSH) from the anterior pituitary stimulates the thyroid to secrete thyroxine however, it also exerts a trophic (growth-stimulating) effect on the thyroid. This trophic effect is evident in people who develop an iodine-deficiency (endemic) goiter, or abnormal growth of Thyroid follicle Thyroid uptake of iodide Thyroid Thyroid Figure 11.23 The production and storage of thyroid hormones. Iodide is actively transported into the follicular cells. In the colloid, it is converted into iodine and attached to tyrosine amino acids within the thyroglobulin protein. MIT (monoiodotyrosine) and DIT (diiodotyrosine) are used to produce T3 and T4 within the colloid. Upon stimulation by TSH, the thyroid hormones, bound to thyroglobulin, are taken into the follicular cells by pinocytosis. Hydrolysis reactions within the follicular cells release the free T4 and T3, which are secreted. Figure 11.24 Endemic goiter is caused by insufficient iodine in the diet. A lack of iodine...

Hypothalamic PituitaryThyroid Axis

TSH-producing cells in the anterior pituitary are positively regulated by TRH, while TSH-inhibiting substances include dopamine, somato-statin, T3 (triiodothyronine), and cortisol. Given sufficient iodine levels, the biologically inactive form thyroxine (tetraiodothyronine, T4) is released through TSH binding at the thyroid gland. The conversion to bioactive T3 mostly happens in target tissue, such as the liver. T3 influences growth and development, oxygen consumption, and heat production (Joffe, 2002). Hyperthyroidism, i.e., a functional hyperac-tivity of the thyroid gland marked by increased T3 and T4 levels, coincides with hyperme-tabolic activity, weight loss, increased heart rate, increased cold tolerance, tremulousness, fatigue, anxiety, restlessness, irritability, dyspho-ric mood, weakness, poor concentration, and cognitive deficits (Lesser and Flores, 2007). On the contrary, a deficient secretion of thyroid hormones in hypothyroidism is characterized by facial puffiness, dry...

Parathyroid Glands

The small, flattened parathyroid glands are embedded in the posterior surfaces of the lateral lobes of the thyroid gland, as shown in figure 11.28. There are usually four parathyroid glands a superior and an inferior pair, although the precise number can vary. Each parathyroid gland is a small yellowish-brown body 3 to 8 mm (0.1 to 0.3 in.) long, 2 to 5 mm (0.07 to 0.2 in.) wide, and about 1.5 mm (0.05 in.) deep. 1. Describe the structure of the thyroid gland and list the effects of thyroid hormones. 2. Describe how thyroid hormones are produced and how their secretion is regulated. Thyroid gland Thyroid gland parathyroids are embedded in the tissue of the thyroid gland.

Thyroid Hormone

Spontaneous and stimulated GH secretion is markedly attenuated in clinical and biochemical hypothyroidism in humans this abnormality corrects during thyroid hormone replacement (7,57,58). Thyroid hormone deficiency is associated with reduced hypothalamic GHRH production, leading to GH deficiency and down-regulation of GHRH receptor numbers on pituitary somatotropes (7,59). Thyroid hormone facilitates binding of GHRH to its receptor. GH secretion is reduced in hypothyroid subjects following Hyperthyroid subjects have significant increases in 24-h GH pulse frequency, augmented GH pulse amplitude, and 3.7-fold higher GH production rates, similar to the effects of sex steroids on GH secretion (63). These observations of enhanced GH secretion in hyperthyroidism suggest some alteration in GH neuroregulatory control including increased somatotrope responsiveness to GHRH or a reduction in somatostatin tone, and is independent of IGF concentration (63). On the other hand, other investigators...

Thyroid arteries

The superior thyroid artery arises at the origin of the external carotid artery, runs downwards to the superior pole of the thyroid lobe, divides into 2-3 branches and enters the lobe on its posterior aspect. The inferior thyroid artery arises from the thyro-cervical trunk which originates from the first part of the subclavian artery. It ascends initially, then turns medially at the level of the cricoid cartilage. From here it passes posterior to the internal jugular vein, the common carotid artery and the vagus nerve in the carotid sheath, and also behind the sympathetic trunk. It enters the posterior aspect of the thyroid at about the middle of the lobe. The thyroid ima artery is rare and enters the thyroid isthmus inferiorly. It may arise from the brachiocephalic trunk, the left common carotid artery or even the aortic arch.

Thyroid Tumors

Thyroid tumors are the second tumor type for which the U.S. EPA has developed generic guidance for risk assessment (55). The agency efforts have been directed specifically at tumors of the thyroid follicular cells, but some of the information gained from analysis of these tumors will likely be applicable to other endocrine tumor sites in the future. Clinical manifestation of thyroid cancer in humans in the United States is uncommon and largely nonfatal. The only known human thyroid carcinogen is X-radiation, which causes an increase in papillary tumors. Human thyroid follicular cell cancer is most often diagnosed histologically as a papillary tumor. The rodent thyroid neoplasms rarely metastasize, whereas the human cancers frequently metastasize. The molecular events that lead to thyroid follicular cell tumors are not fully known. In rodents, these tumors arise from mutation, perturbation of thyroid and pituitary hormone status with increased stimulation of thyroid cell growth by...

Hormonal Carcinogenesis

It was Furth9 who first tentatively suggested that hormones might be directly carcinogenic not by a genotoxic mechanism per se but by influencing the rate of cell division and thereby increasing the potential for spontaneous mutations. Drawing partially on the work of others, he suggested that while DNA molecules replicate, some copying mistakes might go unrepaired. In fact, the chromosomal instability at mitosis, could produce cells carrying new karyotypes, which are potential ancestors of novel clones liable to become malignant tumors. 9 Furth9 went on to describe five lines of evidence to support the hypothesis of carcinogenesis without an extrinsic, genotoxic carcinogen. This evidence drew heavily on his own experience with thyroid carcinogenesis in the rat. logically, identifiable murine mammary tumor virus or type B virus in human breast milk. We undertook our first epidemiological study of breast cancer in young women to address the possibility that a transmissible agent...

Anaesthetic Emergencies

Many anaesthetists would then perform a cryco-thyroid puncture with a large bore (14 G or 16 G) cannula, and connect it to the plunger of a 2 ml syringe. The plunger can then be connected to the catheter mount of a 6 mm tracheal tube, which in turn connects to a standard breathing system.

Pacemaker Cells Control Heart Rate

This process occurs about 60 to 100 times each minute, resulting in the spontaneous heart beat. Cells in the AV node also have pacemaker potentials, but they are slower to reach threshold (only about 40 beats min) and thus the SA node dominates with its faster rhythm. Purkinje fibers also have intrinsic pacemaker activity. An isolated strip of Purkinje fibers will spontaneously generate action potentials with a frequency of about 25 to 40 action potentials min, a rate slower than that of either SA or AV nodal cells. The AV node and Purkinje fibers are called latent pacemakers because they will assume the pacemaker role should the signals from the more proximate and dominant pacemaker be interrupted. Thus the AV node takes over when there is SA nodal arrest, and the pacemaker moves to Purkinje fibers when conduction below the AV node is interrupted, blocking transmission of the impulse generated by higher pacemakers. The firing rate of the SA node can be modulated by both sympathetic...

Complications And Prognosis

Existing longitudinal studies of persons with SS show that the clinical course of SS is slowly progressive and is life altering, rather than life threatening, for most patients. One study found no overall increased mortality in a population of individuals with SS when compared to controls (12). Those with SS also do not have increased cardiovascular mortality, as do individuals with SLE, despite the apparent overlap in signs and symptoms. Salivary glands in SS begin with focal lymphocytic infiltrates but can progress to a lymphoepithelial lesion (lymphoepithelial sialadenitis). This is often associated with chronic clinical enlargement of major salivary glands, occurring in about one-third of patients. Rarely, it may progress to a MALT lymphoma, an indolent tumor progressing for years, or become a high-grade B-cell non-Hodgkin's lymphoma. Various studies have shown a significantly higher prevalence of lymphoma in SS patients than in the general population. Lymphomas occur most...

Ovarian Germ Cell Tumors

Most teratomas involve only one ovary, but bilat-erality is found in about 15 of cases. Histologically, the solid teratomas are composed of various mature somatic tissues derived from all three embryonic germ layers. Glial and neural tissue may be prominent, but in contrast to immature teratomas, there are no embryonic neuroectodermal structures. Cystic teratomas are predominantly composed of skin and skin appendages, including hair and sebaceous glands. Teeth, neural tissue, retinal epithelium, many mesenchymal tissues (such as cartilage, bone, fat tissue, and muscles), and endodermal derivatives (such as bronchial and intestinal components) may be found. Thyroid tissue is the most common endocrine tissue found. Occasionally, teratomas may be associated with benign tumors such as Brenner tumor.46 Struma ovarii, composed of thyroid tissue, represents the most common monodermal teratoma (Figure 4-8). These tumors are usually solid but may be cystic, and they are often confused with...

Metastatic Carcinoma of Unknown Primary Origin

In most patients, the site of origin of a metastatic carcinoma of unknown primary origin cannot be reliably determined by light microscopy (Hammar, 1998). Almost 60 of metastatic carcinomas of unknown primary origin are adenocarcinomas. Some metastatic adenocarcinomas (e.g., colonic adenocarcinomas) have distinctive histologic features that allow for determination of their site of origin. For most other metastatic adenocarcinomas of unknown primary origin, immunohistochemical analysis can help to identify the primary site. Immunophenotyping for cytokeratin 7, cytokeratin 20 (Chu et al, 2000), and other antigens used in conjunction with histologic analysis is effective in narrowing the potential primary site of origin of adenocarcinomas (Table 2-2), although these and other antigens are not absolutely site specific and cannot be reliably used to determine the site of origin. Other antigens that help determine the site of origin are thyroglobulin for thyroid, prostate-specific antigen...

John M Rosenfeld Hungying Kao Ronald M Evans

Lipophilic hormones, including steroids, thyroids, and retinoids, regulate complex processes in cellular differentiation, metabolic homeosta-sis, and animal development. Their ability to diffuse into target cells and bind with high affinity and specificity to their cognate intracellular receptors allows these molecules to coordinate physiological responses by regulating the expression of gene networks. The proteins directly involved in transducing these hormonal signals are known broadly as nuclear receptors (NRs). Upon binding to their specific ligand, NRs modulate the transcription of target genes through interactions with discrete DNA-binding sites known as hormone response elements, cofactor molecules, and general transcriptional machinery. As ligand-activated transcription factors, hormone NRs are indispensable for proper growth and development and often perform essential roles in specifying cell lineages, inducing differentiation, and controlling cellular growth and function....

Evolution of the Nuclear Receptor Superfamily

Detailed comparative sequence analysis of receptors across species predicts that the DNA-binding function of these proteins evolved prior to ligand-binding capacity. All NRs from organisms that evolved prior to chordates, arthropods, and nematodes are more similar to orphan receptors that lack known ligands than to steroid or thyroid family members, suggesting that the prototypes of NRs were orphans.9,13,14 Steroid hormone receptors are apparently restricted to vertebrates, with the exception of the insect ecdysone receptor (EcR), representing the prototypical steroid receptor. The insect EcR, which most closely resembles the farnesoid X receptor (FXR) in primary sequence, is required for virtually every aspect of insect larval meta-morphosis.15 The primary function of EcR in this process is to induce expression of numerous orphan NRs (several of which have vertebrate homologs of unknown function) and establish a temporal regulatory hierarchy of NR activity.16 Interestingly, EcR...

Other Breast Cancer Genes High Risk Breast Cancer Genes

Breast cancer is involved in two other hereditary syndromes, for which causative genes have been identified. The Li-Fraumeni syndrome is characterized by childhood sarcoma and early-onset breast cancer, brain tumors, and a variety of other cancers. Most families with Li-Fraumeni syndrome appear to be due to germline mutations in the TP53 gene. TP53 mutations confer a very high risk of breast cancer (approaching 100 by age 50) but are much rarer than BRCA1 or BRCA2 mutations (45,46). Cowden's syndrome is a rare syndrome characterized by hamartomas, multiple hamartomas, thyroid cancer, and mucocutaneous lesions and is due to germline mutations in PTEN (61). The risk of breast cancer associated with Cowden's syndrome has not been well estimated, but it is of the order of 30 to 50 lifetime (47).

Hormone Response Elements and the DNABinding Domain

Figure 3.3 The nuclear receptor DNA-binding domain and the hormone response element (HRE). A The HREs are composed of either direct repeats (DRs), inverted repeats (IRs), or everted repeats (ERs). The preferred half-site sequence for class I receptors is 5'-AGAACA-3', while the preferred halfsite sequence for class II, III, and IV is 5'-AGGTCA-3'. B The nuclear receptor DNA-binding domain (DBD) is distinguished by two zinc fingers. The zinc fingers of human thyroid receptor beta (TR 8) are depicted. Residues contributing to the P box and D box are indicated as open squares. C A list of individual

Nuclear Receptor Coactivators

The p160 family of coactivators consists of three members, designated steroid receptor coactivator 1-3 (SRC-1-3).149,150 SRC-2 represents the molecules known variously as activating cofactor of thyroid and retinoid receptors (ACTR), receptor-associated coactivator 3 (RAC3), amplified in breast cancer 1 (AIB1), thyroid receptor activator molecule 1 (TRAM1), and CBP cointegrator protein (p CIP). SRC-3 is also known as the glucocorticoid receptor interacting protein (GRIP1) and transcription intermediary factor 2 (TIF2). In general, these proteins interact with NRs in an AF-2- and lig-and-dependent manner. Several NRs appear to activate transcription constitutively, independent of apparent ligand availability. The class IV receptors ERR1, ERR2 and ERR3, for example, seem to activate transcription by recruiting p160 family coactivators through the LBD.151,152 Class I and class II receptors, however, bind p160 family proteins in a ligand-dependent manner.

Cellular and tissue host range in vivo

Endothelial cells seem to represent another important target for infection in vivo as suggested by endothelial cell activation and or damage secondary to HHV-6 reactivation, which may predispose to the development of thrombotic micro-angiopathy (Matsuda et al., 1999 Takatsuka et al., 2003). Finally, in healthy subjects, HHV-6 DNA has been demonstrated ex vivo in several tissues including tonsils, salivary glands, thyroid, brain, liver, myocardium, kidney, and thyroid (Fox et al., 1990 Corbellino et al., 1993 Luppi et al., 1994a Chan et al., 2001 Grivel et al., 2001 Ozaki et al., 2001 Roush et al., 2001 Ishikawa et al., 2002 Donati et al., 2003 Harma et al., 2003). Nevertheless, it is unclear to what extent the detection of viral DNA reflects the ability of HHV-6 to infect tissue-specific resident cells or, alternatively, infiltrating lymphoid and monocytic cells.

Risk Factors and Neurocognition

Various hormones are known to have a direct biological influence on the brain while potentially promoting diseases that affect cognitive function. In that regard, low levels of estrogen and androgens (Sherwin, 2003, 2006) and both low and high levels of thyroid hormones (Smith et al, 2002) have been related to poorer cognitive function. Hormone therapy in post-menopausal women may help prevent cognitive decline (Sherwin, 2003). Numerous studies have revealed associations between higher resting cortisol levels and lowered levels of cognitive performance, particularly on tests of learning and memory (Lupien et al, 2005). It has also been noted that stress-induced cortisol elevations are associated with decreased cognitive performance (Kirschbaum et al, 1996).

Human Chorionic Gonadotropin

Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH). The P subunit is biologically active and structurally and antigenically distinct, allowing for the production of specific antibodies used in immunoassays.9 However, at times, these antibodies may cross-react with the P subunit of LH, which is 70 homologous to that of hCG. In addition, hCG, at high levels, may clinically mimic these pituitary hormones. Hyperthyroidism has been reported,10 and the 5 of GCT patients who develop gynecomastia are believed to do so secondary to a testosterone estrogen imbalance caused by the effect of hCG on the Leydig's cells.

Nuclear Receptor Corepressors

ErbA.167 It potentiates transcriptional repression by TR and Rev-ErbA and represses transcription when fused to a heterologous DBD. Interestingly, SUN-CoR also interacts with N-CoR. Alien interacts with TR, DAX-1, and COUP-TFI but not with RXR, RARa, or GR.168 Addition of thyroid hormone leads to dissociation of Alien from TR. Alien is a highly conserved protein showing 90 identity between the human and Drosophila homologs. Drosophila Alien shows similar activities in that it interacts in a hormone-sensitive manner with TR and harbors an autonomous silencing function. The mechanism underlying its repression activity, however, has not been demostrated. The nuclear protein SMRT and its isoform thyroid receptor associated cofactor 2 (TRAC2) were isolated by a yeast two-hybrid assay using RXR as bait.105,169-171 It contains four autonomous repression domains and two receptor interaction domains,170 and can interact with a panel of receptors, including unliganded RAR, TR, PPARa, PPARy,...

Function of Brown

The amount of brown fat in the body is greatest at the time of birth. Brown fat is the major site for thermogenesis (heat production) in the newborn, and is especially prominent around the kidneys and adrenal glands. Smaller amounts are also found around the blood vessels of the chest and neck. In response to regulation by thyroid hormone (see chapter 11) and norepinephrine from sympathetic nerves (see chapter 9), brown fat produces a unique

Crosstalk Between Nuclear Receptors and Other Transcription Factors

Figure 3.8 Chemical structures of steroid and thyroid hormone receptor ligands. Natural hormones and examples of high-affinity synthetic agonists and antagonists are presented for each of the steroid and thyroid classes of receptor. Agonist activity is defined as the ability to induce receptor-dependent transcription of natural or synthetic response element reporters in cotransfection experiments and, in most cases, is supported by in vitro ligand-receptor binding studies. ER, estrogen receptor PR, progesterone receptor AR, androgen receptor GR, glucocorticoid receptor MR, mineralocorticoid receptor VDR, vitamin D receptor TR, thyroid hormone receptor. Figure 3.11 Cross-talk between nuclear receptors and activator protein 1 (AP-1), nuclear factor kappa B (NF-kB), and signal transducer and activator of transcription 5 (STAT5) documenting how nuclear receptors may influence the activity of other transcription factors. The effects of nuclear receptor cross-talk are indicated as +,...

Molecular Pathophysiology

Amino acid substitutions at each of 20 separate positions cause constitutive activation of TSH or LH CG receptors 9 . The TSH receptor has been particularly fertile in activating mutations because of the fact that somatic mutations leading to activation of the TSHr cause a readily detectable thyroid phenotype (i.e., autonomous toxic adenomas) 10 . Much less frequent are germline mutations with similar activating effects. When affecting the TSHr or LH CGr, they cause autosomal dominant hyperthyroidism or pseudo precocious puberty of the male, respectively 3,9 . Except for a single anecdotal case, no disease has been associated with activating mutations of the FSHr 4 .

The Genotoxic Mechanism

Growth Factor-Induced Cell Proliferation. Hormones. Rodent thyroid follicular cell tumor in contrast to human thyroid tumors that are mostly induced by ionizing radiation, thyroid follicular cell tumors in rodents are induced by genotoxic or nongenotoxic carcinogens. Several nongenotoxic chemicals (such as perchlorate, thiorueas, lithium, lupiditine) are known to perturb the balance of the thyroid stimulating hormone (TSH) in rodents. These chemicals are referred to as goitrogens and their modes of action are different. They may deplete iodine accumulation by inhibiting iodine trapping in the thyroid or by blocking binding of iodine and coupling of iodothyronine to form thyroxine and triiodothyronine. Alternately, they may inhibit thyroid hormone secretion by pro-teolysis or enhance metabolism of thyroxine by inducing liver metabolic enzymes (78). Disruption of thyroxine function activates the pituitary-thyroid feedback mechanism, which increases the production of TSH. An increase...

Conclusions and Perspectives

E., and Vassart G. (2001). Thyroid disorders, in Scriver, C., Ed., The Metabolic and Molecular Bases of Inherited Diseases, pp. 4029-4076. McGraw-Hill, New York. 10. Parma J., Duprez L., Van Sande J., Cochaux P., Gervy C., Mockel J., Dumont J. E., and Vassart G. (1993). Somatic mutations in the thy-rotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 365, 649-651. 28. Hauser, F., Nothacker, H. P., and Grimmelikhuijzen, C. J. (1997). Molecular cloning, genomic organization, and developmental regulation of a novel receptor from Drosophila melanogaster structurally related to members of the thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone choriogonadotropin receptor family from mammals. J. Biol. Chem. 272, 1002-1010. 38. Osuga, Y., Liang, S. G., Dallas, J. S., Wang, C., and Hsueh, A. J. (1998). Soluble ecto-domain mutant of thyrotropin (TSH). Receptor incapable of binding TSH neutralizes the action of thyroid-...

B TAFContaining Complexes

Human Mediator, first purified from HeLa cells as a protein complex that associates with the thyroid hormone receptor a (TR a) in a ligand-dependent manner, was able to potentiate TRa-mediated transcription in vitro (Fondell et al., 1996). This TR-associated protein complex (TRAP) contains many protein subunits subsequently found also present in other coactivator complexes, such as SRB MED-containing cofactor complex (SMCC Ito et al., 1999), vitamin D receptor-interacting protein complex (DRIP Rachez et al., 1998), activator-recruited complex (ARC Naar et al., 1999), positive cofactor 2 (PC2 Malik et al., 2000), cofactor required for Spl activation (CRSP Ryu et al., 1999), and negative regulator of activated transcription (NAT Sun et al., 1998). In humans, at least two forms of Mediator complexes, Mediator-P.5 and Mediator-P.85 isolated individually from 0.5 M and 0.85 M KC1 fractions of the Pll phosphocellulose ion-exchange column, have been identified and demonstrated to enhance...

Retinoblastoma susceptibility gene rb abnormalities in cancer

The rb gene is expressed in all normal tissues and cell lines (Lee et al., 1987b). It is expressed in a mutated form or absent in retinoblastomas (Lee et al., 1987b, 1990 Horowitz et al., 1990). Abnormalities of this gene have been described in several other human tumours, e.g. small cell lung cancer (SCLC) (Harbour et al., 1988 Hensel et al., 1990 Mori et al., 1990). Harbour et al. (1988) found that 13 of primary SCLC and 18 of SCLC-derived cell lines showed structural abnormalities of rb and 60 of SCLC-derived cell lines showed a loss of the gene. Loss of gene expression has been reported in 30 of primary non-SCLCs (Xu et al., 1991) and it appears also from this study that altered rb expression may be related to tumour stage. Inactivation of rb was reported in two bladder cancer cell lines and lack of expression without gross gene deletion in another cell line (Ishikawa et al., 1991). Of considerable interest is the suggestion of rb inactivation with tumour progression. For these...

Detection and Assessment

A physical examination and laboratory screening (e.g., complete blood count, liver function, serum testosterone level, serum vitamin B12, thyroid function) may be performed to exclude potential systemic causes of depressive symptomatology. Testosterone deficiency associated with depressive symptomatology (e.g., anhedo-nia, fatigue, and sexual dysfunction) has been described in males with PD and may possibly be managed with testosterone replacement therapy (120). Likewise, symptoms of hypothyroidism (e.g., anxiety, difficulty with concentration, dysphoria, fatigue, irritability, and motor retardation) resemble depressive symptomatology and are treatable with thyroid replacement. It is also important to ensure that patients are on optimal doses of antiparkinson drugs to minimize motor fluctuations that may contribute to mood fluctuations.

Dean Filandrinos Thomas R Yentsch and Katie L Meyers

John's wort has demonstrated clinical efficacy for mild to moderate depression and compares favorably to other more potent or toxic antidepressants. Low side effects and potential benefits warrant its use as a first-line agent for select patients with mild to moderate depression or anxiety-related conditions. Benefits related to other reported uses such as an antimicrobial, agent to treat neuropathic pain, antiinflammatory, treatment alternative for atopic dermatitis, and antioxidant are either not well documented or evidence is encouraging but not conclusive and further study is needed. St. John's wort has an inherently wide margin of safety when taken by itself, with most reported adverse drug reactions (ADRs) being related to skin reactions. Isolated, but more significant ADRs have been reported in relation to neurological effects, impact on thyroid function, and increased prothrombin time. Of greatest concern is the potential for interactions between St. John's wort and...

Alumediated interchromosomal recombination in Ewing sarcoma

Gene fusion is a phenomenon arising from interchromosomal reorganisation. The fusion of RET and ELE1 genes occurs in radiation-induced thyroid carcinomas. We know from the investigation by Nikiforov et al. (1999) that the breakpoints culminating in the formation of the fusion gene seem to be distributed in the introns of the genes in a rather random manner. However, they do point out that there is a cluster of breakpoints in the Alu repeats of ELE1 gene.

Venous Thromboembolism

Venous thromboembolism (VTE) has long been known as a complication ofcancer. Venous thromboembolisms are usually divided into deep venous thrombosis (DVT) and pulmonary embolism (PE). When DVTs affect the proximal veins of the lower extremities they are usually treated as a PE. We discuss VTE with all brain tumor patients at the initial consultation. Mechanism of action for VTE includes, venous stasis (immobility), intimal injury, and alterations in coagulation. In brain tumor patients, Sawaya et al. (46) has shown alterations in the fibrinolytic system and an underlying coagulopathy as causes of VTE. Other associations include age, prior DVT, smoking, oral contraceptives, and obesity. During surgery, brain tumor patients often have induced dehydration and hyperosmolality that increase the VTE risk. Malignant brain tumor patients have also been shown to display an increased risk of VTE with reports of upward of 28 of patients having symptomatic events (47). At our institution we have...

Component Malignancies

Component malignancies in CS include breast, thyroid (16), and endometrial carcinomas (Table 2) (17). The most common malignancy seen in CS is adenocarcinoma of the breast, with lifetime risks in female CS patients estimated to be 25 to 50 compared with the lifetime risk of 12 to 13 in the general population (18,19). As commonly described in other hereditary breast cancer predisposition syndromes, the average age of breast cancer diagnosis is lower in patients with CS compared with that in sporadic cases. In CS, the average age of diagnosis is between 38 and 46 years while the average age of diagnosis is 55 to 65 years in sporadic cases (19). There has only been a single systematic study looking at histologies in CS-related breast carcinomas, but without knowing the germline PTEN status (20). In this study of 59 breast neoplasias belonging to 19 unrelated CS cases, 35 (59 ) had some malignant pathology. All cases of invasive breast cancer were ductal histology, with the exception of a...

Preserving Structures

Tongue, floor of the mouth, and buccal mucosa metastasize first to the nodes in the submandibular triangle. Some metastases may skip the submandibular and upper deep jugular nodes and go directly to the midjugular nodes on either side of the neck. The Lindberg study, and a subsequent study by Skolnik, observed that oral cavity and oropharynx tumors rarely metastasize to posterior or lower deep jugular nodes in the absence of metastases in the upper jugular and submaxillary nodal groups. Shah's 1990 retrospective review of radical neck dissection specimens from patients with oral, laryngeal, and pharyngeal cancers concluded that oral cavity cancers metastasize most often to levels I, II, and III, whereas oropharynx cancers most often go to levels II, III, and IV. When cancerous nodes were found in other levels, they were usually positive in the areas of highest risk too. Bocca and others have observed that supraglottic cancers rarely metastasize to the submental and submandibular nodal...

Behavioral plasticity

To address the third question, physiological correlates of learning are known for at least several learning phenomena brain areas responsible for spatial learning are larger in males of those vole species whose spatial learning is better than females, but not in those without such a sex difference. The olfactory bulb in the brain of a young ferret during the critical period of olfactory food imprinting is larger than before or after this time. We also know that thyroxine, the hormone of the thyroid gland, is responsible for neurological changes during food imprinting in this species, and that oxytocin, a pituitary hormone, is necessary in the brain of monogamous animals to learn who their specific partner is during pair formation. Several areas in the limbic system of the brain, particularly the hippocampus, have been identified as being responsible for exploratory behavior and learning.

Nonmalignant Solid Organ Involvement

Benign thyroid lesions including adenomas, hamartomas, and multinodular goiter occur in 50 to 67 of all affected patients (16). It is suspected that Hashimoto thyroiditis occurs at an increased frequency in CS, especially in patients who are of non-Asian ancestry this belief is supported by early literature describing Hashimoto thyroiditis as a component of BRRS (8). Currently, functional disorders of the thyroid resulting in hyperthyroidism or hypothyroidism in the absence of adenomas or goiter are not considered components of CS.

Alu elements in genetic transcription

The promoters of certain genes that contain binding sites for thyroid hormone receptor, ER and RA receptors also contain Alu repeats. Norris et al. (1995) reported that a class of Alu elements seemed to function as enhancers of oestrogen-dependent transcription, and further that they might have diverged into a special class of repeats. Norris et al. (1995) found that anti-oestrogens abolished this enhancer activity. Li, Yeh et al. (2000) have characterised the ERP promoter and have identified an Alu sequence containing an enhancer of ER-dependent transcription. However, there is a possibility that Alu repeats might be involved in other pathways of oestrogen function, namely via inactivation of progesterone receptors. Alu insertions may be found in PgR (Rowe etal., 1995). The thyroid hormone receptors, ER and RA bind to the nucleotide sequence AGGTCA. This motif may be duplicated and distributed with defined spacing and orientation, and they occur in Alu repeats (Babich et al., 1999).

Molecular Weight and Structural Characteristics

The p-subunit is identical to the enzyme protein disulfide isomerase (8-11). The p-subunits also provide retention and docking signals for prolyl hydroxylase within the endoplasmic reticulum (2). In addition, Wilson et al. (9) have provided data that the p-subunit acts as a chaperone for procollagen chain assembly. Of interest, there is also partial sequence homology between the p-subunit and thyroid hormone-binding protein, phospholipase C, thioredoxin, and the estrogen-binding domain of the estrogen receptor (2, 3).

Genotype Phenotype Correlation in CS

Approximately two-thirds of germline PTEN mutations are found in exons 5, 7, and 8, and approximately 40 of all CS mutations are located in exon 5, although this exon represents only 20 of the coding sequence (1,14). This reflects the biological significance of this domain, which encodes the phosphatase core motif. There is a correlation between the presence of germline PTEN mutations and breast carcinoma in probands meeting operational criteria for CS (14). In other words, the risk of breast cancer may be higher in those patients and families with a clinical diagnosis of CS who harbor germline PTEN mutations. Additionally, mutations within the phosphatase core motif and 5' of it appear to be associated with involvement of five or more organs, suggesting a correlation between mutations in this region of PTEN and disease severity (14). A recent study has demonstrated that promoter mutations are present in 10 of mutation negative patients with CS (47). Importantly, the functional...

Other Potential Regulators

GHRs are also regulated by thyroid hormones. The growth-promoting effects of exogenously administered GH are blunted in hypothyroid rats, hepatic GH binding sites are reduced in hypothyroidism, and elevated binding is observed in hyperthyroid rats (54). The authors have recently observed reduced GHR mRNA expression in the ARC in response to thyroidectomy, an effect that is rapidly restored by thyroid hormone replacement (P. A. Bennett, unpublished observations).

Extension in the Dwarf

Dwarf mice are remarkably long-lived. Congenital deficiency of growth hormone (GH), prolactin, and thyroid-stimulating hormone (TSH) due to mutations at the Pit1 or Prop1 loci, as well as GH resistance due to targeted disruption of the GH receptor gene lead to major increase in both average and maximal lifespan. Prolonged longevity of Snell dwarf (Pit1dw), Ames dwarf (Prop1df), and GHRKO mice is associated with a major extension of ''health span'' and multiple symptoms of delayed aging. Suspected mechanisms of prolonged longevity of hypopituitary and GH resistant mice include reduced peripheral levels of IGF-1 and insulin, enhanced sensitivity to insulin actions, reduced generation of reactive oxygen species, enhanced anti-oxidant defenses and stress resistance, and delayed onset of fatal neoplastic and nonneoplastic disease. Although negative correlation of body size and longevity applies to genetically normal mice and to other species, it remains to be determined whether reduced GH...

Management of Malignancy in CS

Thyroid cancer should be treated with total thyroidectomy. Additionally, it is expert opinion that patients with thyroid adenomas, in whom surgery is deemed necessary, also be treated with complete thyroidectomy given the very high prevalence of benign thyroid neoplasias in CS that may make surveillance after hemithyroidectomy extremely difficult. In addition, the risk of developing a malignancy in the remaining thyroid tissue and the difficulty of repeated thyroid resection support this opinion.

Distribution Of

The contents of Cu,Zn-SOD, Mn-SOD, and EC-SOD were determined in tissues from mammalian species (2). Various tissues contain the Cu,Zn-SOD activity, and Cu,Zn-SOD activities are especially high in metabolically active organs, such as liver and kidney. The Mn-SOD content is high in organs with high respiration, such as liver, kidney, and heart. The tissue distribution of EC-SOD is different from those of other isoforms, and it is present at high levels in lung, thyroid gland, and uterus. EC-SOD is the least abundant SOD isoform in tissues, and 90-99 of the EC-SOD in the body is located in the interstitial spaces of tissues. EC-SOD is a major SOD form in extracellular fluids such as plasma, lymph, and synovial fluid. Recently, it was reported that the blood vessel walls, particularly the walls of the arteries, contain large amounts of EC-SOD (3).

Retinoic Acid Receptors and Gene Regulation

Vitamin A exerts its effects via retinoic acid and retinoid receptors, which are found in the nucleus of the cell. Retinol is converted to all-trans-retinoic acid and 9-cis retinoic acid in the cytoplasm. Retinoic acid influences gene activation through specific receptors which belong to the superfamily of thyroid and steroid receptors (231). Retinoic acid receptors (RARs) act as transcriptional activators for many specific target genes. The R AR is expressed as isoforms, referred to as RAR a, P, and y, and retinoid-x receptor (RXR) is also expressed as isoforms, referred to as RXR a, P, and y (232). All-trans retinoic acid is a ligand for RARs, whereas 9-cis retinoic acid is a ligand for both RARs and RXRs. 9-cis-retinoic acid is functionally distinct from all-trans-retinoic acid, and inter-conversion may exist between the two isomers. Each RAR and RXR has a specific DNA-binding domain by which these nuclear receptors may effect transcriptional activity. The DNA sequences which...

Chemical Classification of Hormones

These are hormones derived from the amino acids tyrosine and tryptophan. They include the hormones secreted by the adrenal medulla, thyroid, and pineal glands. Thyroid gland and those that are nonpolar, and thus insoluble in water. Since the nonpolar hormones are soluble in lipids, they are often referred to as lipophilic hormones. Unlike the polar hormones, which cannot pass through plasma membranes, lipophilic hormones can gain entry into their target cells. These lipophilic hormones include the steroid hormones and thyroid hormones. The major thyroid hormones are composed of two derivatives of the amino acid tyrosine bonded together (fig. 11.3). When the hormone contains four iodine atoms, it is called tetraiodothyronine (T4), or thyroxine. When it contains three atoms of iodine, it is called triiodothyronine (T3). Although these hormones are not steroids, they are like steroids in that they are relatively small, nonpolar molecules. Steroid and thyroid hormones are active...

Hormones That Bind to Nuclear Receptor Proteins

Unlike the water-soluble hormones, the lipophilic steroid and thyroid hormones do not travel dissolved in the aqueous portion of the plasma rather, they are transported to their target cells attached to plasma carrier proteins. These hormones must then dissociate from their carrier proteins in the blood in order to pass through the lipid component of the plasma membrane and enter the target cell, within which their receptor proteins are located (fig 11.4). The nuclear hormone receptors are said to constitute a su-perfamily composed of two major families the steroid family and the thyroid hormone (or nonsteroid) family. In addition to the receptor for thyroid hormone, the latter family also includes the receptors for the active form of vitamin D and for retinoic acid (derived from vitamin A, or retinol). Vitamin D and retinoic acid, like the steroid and thyroid hormones, are lipophilic molecules that play important roles in the regulation of cell function and organ physiology.

Hypothalamic Control of the Anterior Pituitary

At one time the anterior pituitary was called the master gland because it secretes hormones that regulate some other endocrine glands (fig. 11.14 and table 11.6). Adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), and the gonadotropic hormones (FSH and LH) stimulate the adrenal cortex, thyroid, and gonads, respectively, to secrete their hormones. The anterior pituitary hormones also have a trophic effect on their target glands in that the health of these glands depends on adequate stimulation by anterior pituitary hormones. The ante-

Pituitary and Placenta

Pit-1 is a 33kd pituitary-specific transcription factor that is necessary for GH, thyroid-stimulating hormone (TSH), and prolactin gene transcriptional activation, and for somatotroph, lactotroph, and thyrotroph establishment (32). The protein is a product of the POU-domain gene family and has three regions a transcriptional activation domain, a 60 amino acid sequence necessary for high-affinity DNA binding known as the POU homeodomain (POU-HD), and a 76 amino acid highly-conserved region that potentiates POU-HD binding, known as the POU specific domain (33). In humans, the gene encoding pit-1 has been mapped to chromosome 3p11.

Feedback Control of the Anterior Pituitary

Anterior pituitary secretion of ACTH, TSH, and the gonadotropins (FSH and LH) is controlled by negative feedback inhibition from the target gland hormones. Secretion of ACTH is inhibited by a rise in corticosteroid secretion, for example, and TSH is inhibited by a rise in the secretion of thyroxine from the thyroid. These negative feedback relationships are easily demonstrated by removal of the target glands. Castration (surgical removal of the gonads), for example, produces a rise in the secretion of FSH and LH. In a similar manner, removal of the adrenals or the thyroid results in an abnormal increase in ACTH or TSH secretion from the anterior pituitary. Thyroid-stimulating hormone (TSH) Thyroid-stimulating hormone (TSH) Thyroid Figure 11.16 The hypothalamus-pituitary-thyroid axis (control system). The secretion of thyroxine from the thyroid is stimulated by thyroid-stimulating hormone (TSH) from the anterior pituitary. The secretion of TSH is stimulated by thyrotropin-releasing...

End Organ Targets and Receptors

The IGF-1 gene, located on the long arm of chromosome 12, spans 95 kb and contains at least six exons (102,103). Although GH appears to be the primary regulator of IGF-1 gene expression, transcriptional control is complex. It is influenced by nutritional status, GH, hCS, prolactin, glucocorticoids, sex steroids, thyroid hormones and insulin (104-107). The IGF-2 gene is 35 kb in length, contains nine exons, and is located adjacent to the insulin gene on the short arm of chromosome 11 (102,108).

D Ghrhr Organization and Regulation

Thyroid hormones also influence GHRHR expression. Indeed, the decrease in GHRHR expression caused by thyroidectomy can be reversed by thyroxine (T4) replacement therapy.87 Although in humans no thyroid hormone receptor response element was found in the promoter region of GHRHR, this could be present outside of the areas studied to date.6,79 Indeed, triiodothyronine (T3) causes a dose-dependent increase in GHRHR mRNA in rat primary pituitary cells82 and T3 responsive elements were later found in the 5' flanking region of the rat GHRHR gene.88 In a recent study, T3 has been shown to have little effect on GHRHR expression in rat cells derived from a mammotrophic

Transcriptional Repressors and Repression Mechanisms

In addition to the factors mentioned above, DNA-binding repressors also directly interact with TBP or GTFs to inhibit transcription (Fig. 9. ID). This mechanism is called direct repression . For instance, Even-skipped (Eve), a Drosophila homeodomain protein, interacts with TBP in vitro and in tissue culture (Austin and Biggin, 1995 Li and Manley, 1998 Um et al., 1995). A repression domain of Eve directly contacts the C-terminal region of TBP, leading to inhibition of TFIID binding to the promoter. This repression is independent of the distance between the promoter and the Eve binding sites in vitro transcription assays. Unliganded thyroid hormone receptor (TR) also interacts with TBP and inhibits the formation of preinitiation complex in vitro, however TR bound to its ligand activates transcription by interacting with TFIIB (Baniahmad et al., 1993 Fondell et al., 1996 Fondell et al, 1993). Similarly, TFIIEbeta binds to a dimeric form of Kr ppel in vitro, a Drosophila zinc finger...

Familial adenomatous polyposis coli FAP

FAP is a highly penetrant autosomal dominant disorder, clinically characterised by the development of hundreds to thousands of adenomatous polyps of the colon and rectum. This rare syndrome has an annual incidence of around 1 7000 live births (Bisgaard et al., 1994). However malignancy is virtually inevitable if surgery is not undertaken and thus accounts for 0.2 of all colorectal neoplasia. There are a number of extra-colonic features such as multiple craniofacial and long bone osteomata, epidermoid cysts, retinal pigmentation, gastroduodenal polyposis and malignancy, desmoid tumors and an increased risk of peri-ampullary, papillary thyroid, brain tumors and sarcomas.

Rare dominant disorders

Cowden disease is a rare autosomal dominant disorder characterized by the development of oral and facial papules in concert with hamartomatous lesions of the thyroid, breast, skin and digestive tract and occasionally with neurological features. Mapping to chromosome 10q22-24 (Nelen et al., 1996) led to the identification of PTEN in which

Clinical Characteristics of Heterozygous Carriers

Without difference in waist hip ratio. Fat free mass was lower but there was no significant difference in fat mass. The lack of significant differences between the IGF-1 levels of the two groups suggested that these effects are not mediated by circulating IGF-1.167 Heterozygous subjects also have a smaller thyroid volume compared to normal individuals but normal serum thyroid hormone levels.149

Postoperative hypocalcaemia

Hypocalcaemia is exceedingly common following both thyroidectomy and parathyroidectomy and if transient and minimal, requires no treatment. Despite clearly identifying all adjacent parathyroid glands or identifying all parathyroid glands at thyroid surgery, permanent hypoparathyroidism can still occur. Most experienced endocrine surgeons do not advocate ligation of the inferior thyroid artery laterally because of the risk of devas-cularising the parathyroid glands. Instead they recommend ligating the branches of the inferior artery medially on the thyroid capsule medial to the nerve, having identified the parathyroid glands clearly.

The Link Between Birth Weight and Later Health

While most clinical attention has been focused on premature and SGA babies, there is a complementary literature indicating that excessive fetal growth can present a different set of problems. With large-for-gestational age babies (LGA), there is a significant increase in obstetrical complications and need for caesarian delivery (Gregory et al, 1998). In addition, these infants are more likely to continue on the path toward obesity during childhood and adulthood, especially after diabetic pregnancies (Law et al, 1992). Longitudinal studies show they are predisposed to have poorer glucoregu-lation and to develop type 2 diabetes as adults. Here too, basic science studies in animals have provided considerable support for these associations and revealed several critical mediating pathways linking accentuated growth rates and later disease. For example, pregnant dams fed a high caloric diet will gestate offspring with a distinctive insulin response and altered pancreatic size and renal...

The Mixed Blessing of Antenatal Corticosteroids

For some expectant women threatening to deliver early, there have been up to 10 courses administered before birthing. When treatments are repeated or prolonged, studies in rodents, sheep, and monkeys have all found adverse effects, especially on sensitive brain regions like the hippocampus (Matthews, 2000 Uno et al, 1994). When extended over many days, antenatal corti-costeroids can retard fetal growth, suppress both maternal and fetal adrenal activity, decrease thyroid activity, and affect kidney functioning in ways that would pose a long-term risk for later hypertension (Coe and Lubach, 2005 French et al, 1999 Seckl et al, 2000). One further reason for these concerns is that when administered directly to the mother before delivery, both dexamethasone and betamethasone can readily bypass the placental enzyme 116-HSD2 and then can become sequestered in fetal circulation. While examining the impact of a standard 2-day course of maternal dexamethasone in the rhesus monkey, we found...

Functional development of oligodendrocytes

Oligodendrocyte differentiation is regulated by a variety of growth factors. PDGF-AA is the best characterized mitogen and survival factor for OPCs. Fibrob-last growth factor 2 (FGF2) is a mitogen for OPCs and inhibits their differentiation into oligodendrocytes, at least partly by maintaining expression of PDGFaR. Expression of FGF receptors is developmentally regulated in oligodendrocytes FGF-R1 increases as cells mature FGF-R2 is expressed throughout the lineage FGF-R3 is expressed transiently by premyelinating oligodendrocytes and is important in the initiation of myelination. Insulin-like growth factor I (IGF-I) is a survival factor for oligodendrocytes and with thyroid hormone promotes differentiation. The precise interactions of these trophic factors in vivo are unresolved. When OPCs reach their final destinations, contact with axons may be sufficient for survival and differentiation, under the influence of neuregulin-1 (NRG-1) and Notch Jagged signalling.

Chlorination by molecular chlorine

Liver, thyroid and kidney enzymes that 5 -deiodinate iodothyronines contain one mol of selenium mol, presumably present as selenocysteine F882 . Astrocyte type III iodothyronine deiodinase, which removes an iodine from the inner ring of triiodothyronine is also a selenoprotein J197 .

Children Of Centenarians

Health histories of a nationwide sample of centenarian offspring (n 176) and controls (n 166). The controls consisted of offspring whose parents were born in the same years as the centenarians but at least one of whom died at age 73, the average life expectancy for that birth cohort. The average age at death of the other parent was 77 years, the same as the spouses of the centenarians. Centenarian offspring were found to have a 56 reduced relative prevalence of heart disease, a 66 reduced relative prevalence of hypertension, and a 59 reduced relative prevalence of diabetes in multi-variate analyses that controlled for age, gender, years of education, annual income, IADL score, ethnicity, marital status, exercise, smoking, and alcohol use. There were no significant differences in the prevalence of a number of other age-related diseases including cancer, stroke, dementia, osteoporosis, cataracts, glaucoma, macular degeneration, depression, Parkinson's disease, thyroid disease, and COPD....

Metabolism Energy Expenditure

Adults with long-standing GH-deficiency have reduced whole body resting energy expenditure (REE), with lower values than predicted for age, sex, height, and weight (46). GH replacement in GH-deficiency results in rapid and large increases in REE (10,47,48). Because REE is largely dependant on LBM metabolic activity, much of this increase is attributable to the observed increase in LBM associated with GH replacement. However, when changes in REE are expressed per LBM these rises are still significant, indicating that direct increases in cellular metabolism are responsible for some of the increased REE (10). GH treatment of the GH-deficient adult results in an increase in circulating tri-iodothyronine (T3) levels, both in patients on thyroxine replacement and those with normal thyroid function (49), indicating that GH is a physiological regulator of thyroid function, in particular the peripheral conversion of thyroxine (T4) to T3. This effect on T4 metabolism probably accounts for some...

Activation of Protein Kinases in Human Cancer

Chromosomal translocations can activate protooncogenes, either by linking the protooncogene to a more powerful or inappropriately regulated promoter or by generating a gene fusion linking the protooncogene product to a heterologous protein. In the latter case, activation can occur either by deletion of an autoinhibitory domain or because the fusion partner provides an activating function, such as dimerization or localization to a novel intracellular compartment. Fusions of receptor or non-receptor tyrosine kinases to heterologous proteins are observed in a variety of cancers and leukemias. Examples include the Tel-PDGFRP fusion in chronic myelomonocytic leukemia 41 , the ZNF198-FGFR1 fusion in certain forms of acute myelogenous leukemia 42 , and a variety of fusions involving TrkA, Met, or Ret in papillary thyroid carcinomas 43 (for a complete listing, see Table 1 in Blume-Jensen and Hunter 6 ).

Dissection Of The Central Compartment

Figure 4-54 The right superior thyroid artery crosses inferomedially toward the thyroid gland. CA, carotid artery st, superior thyroid artery oh, omohyoid muscle sh, sternohyoid muscle. Figure 4-54 The right superior thyroid artery crosses inferomedially toward the thyroid gland. CA, carotid artery st, superior thyroid artery oh, omohyoid muscle sh, sternohyoid muscle. For some tumor locations the central compartment must be included in the dissection. This is the case of tumors of the thyroid gland, subglottic lesions, and some hypopharyngeal cancers. In some cases, it is also important to remove the lymph nodes in the anterior superior mediastinum along with the dissection of the central compartment. Figure 4-55 Anatomical boundaries of the central compartment of the neck. CA, carotid artery IJ, internal jugular vein hb, hyoid bone sn, suprasternal notch tg, thyroid gland. Figure 4-55 Anatomical boundaries of the central compartment of the neck. CA, carotid artery IJ, internal...

Oxidations and reductions of substituent side chains and nonaromatic ring systems without altering chain length

Beef adrenal enzyme is inhibited by the anti-thyroid agents methimazole and propylthiouracil, by thiouracil and 2-mercaptoimidazole A19l8 . Thioureas inhibit by several mechanisms and both inhibit noncompetitively relative to substrate, but the former is a mixed type inhibitor with respect to ascorbate, and Cu2+ does not reverse the inhibition. Inhibition by is noncompetitive relative to ascorbate, and inhibition is reversed by Cu2+ A797 . Catalase protects against denaturation, and diethylpyrocarbamate, a histidine-binding compound, inactivates it. It is inhibited by diethyldithiocarbamate A1097 . Incubation with cysteine inactivates it irreversibly. Although the mechanism has not been identified A800 , reduction of disulphide bridges possibly followed by bonding with cysteine may occur. It is not stimulated by N-ethylmaleimide A3375 .

Genetic abnormalities downstream of notch signal activation

The SEL1L gene is located at I4q31 and this locus harbours a number of genes, notably the thyroid stimulating hormone (TSH) receptor gene. Significantly, a gene residing at this locus encodes a 230 kDa protein, which seems to be capable of binding the cell cycle regulatory Rb protein as well as the TSH receptor. The Rb protein could be regulating cellular response to TSH via the Rb-interacting protein (KH Chang et al., 1997). It is not known at present whether Rb affects the transcription of other genes in the locus including SEL1L. A gene whose expression is related to the myelination of the CNS (Ono et al., 1999) and genes belonging to the fibulin family are also present at the locus.

Marginal Zone BCell Lymphoma MZL

The lymphomas of marginal zone B-cell type occur in extranodal sites as well as lymph nodes 36 . Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is a relatively common low-grade lymphoid neoplasm of the gastrointestinal tract, and morphologically similar lymphomas occur in other mucosa-associated sites, such as the bronchial tree and ocular adnexa. Translocations involving the BCL2 gene may be seen in MZL, but genes other than IGH are often associated as partners in these chromosomal abnormalities. Different translocations may be seen preferentially in lesions from different sites. For example, a t(11 18)(q21 q21) translocation is most frequently found in gastric or pulmonary tumors, while a t(14 18)(q32 q21) translocation is more likely to be found in neoplasms involving ocular adnexa or salivary gland. A t(3 14)(p14.1 q32) translocation may occur in tumors of the thyroid, ocular adnexa, or skin. Distinguishing MZL from MCL (mantle cell...

Interaction with Corepressors

Ski was first identified as a viral oncogene (v-Ski) from the Sloan-Kettering avian retrovirus that transforms chicken embryonic fibroblasts (Liu et al., 2001b Luo, 2004). SnoN is a member of the Ski proto-oncogene family. In addition to being an oncogene, SnoN appears to act as a tumor suppressor, at least in certain cells (Liu et al., 2001b Luo, 2004). Ski and SnoN directly binds to the N-CoR and mSin3A that form a complex with HDAC (Luo et al., 1999 Nomura et al., 1999). In addition, Ski has been shown to be able to bind directly to the corepressors HIPK2 and MeCP2 (Kokura et al., 2001 Harada et al., 2003). Ski is also required for transcriptional repression by several other proteins, including the Mad, the thyroid hormone receptor-(3, Rb protein and the Gli3 repressor (Liu et al., 2001b Luo, 2004). Thus, Ski appears to be an integral part of the transcriptional repression machinery.

Cathepsin D in cancer

The expression of cathepsins D and B has been studied with great enthusiasm and much effort has been directed to relating cathepsin levels to histopathological and clinical features of tumours. This is illustrated by a broad spectrum of human tumours where cathepsin D has been found to be over-expressed or abnormally processed or secreted. Early studies and also more recent investigations with human neoplasms have shown an enhanced cathepsin D expression in hepatomas (Maguchi et al., 1988), thyroid dysplasias and carcinomas (Sinadinovic et al., 1989 Metaye et al., 1993), melanomas (Tsushima etal., 1989), gynaecological malignancies (Galtier de Reureetal., 1992 Nazeer etal., 1994 Scambia et al., 1995), gastric tumours (Matsuo et al, 1996) and carcinoma of the prostate (Kuczyk et al, 1994 Makar et al, 1994), bladder (Nakata et al., It follows from the somewhat equivocal nature of the evidence concerning the involvement of cathepsin D in cancer invasion that its association with cancer...

Neuroendocrine Systems

Most neuroendocrine axes are regulated by the hypothalamic-pituitary unit, i.e., the hypothalamic-pituitary-adrenal (HPA) axis, the hypothalamic-pituitary-thyroid axis, the hypothalamic-pituitary-gonadal axis, the hypothalamic-pituitary-prolactin system, and the hypothalamic-pituitary-growth hormone axis. The sympatho-adrenal-medullary system with its hormones epinephrine and nore-pinephrine (see Section 5) and pancreatic insulin secretion (see Section 6) are further major neuroendocrine systems, while some tissues such as adipose tissues and the digestive tract also possess neuroendocrine properties (Druce et al, 2004 Kershaw and Flier, 2004). Corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone stimulate the release of a further set of glandotropic hormones ( hormones regulating a remote endocrine target gland) into the general circulation. Their binding to specific endocrine cells in the anterior pituitary induces the...

The Hypothalamic PituitaryGrowth Hormone Axis

The release of GH (also referred to as soma-totropin) is stimulated by neurons from the arcuate nucleus containing GH-releasing factor and inhibited by neurons from the periventricular nucleus containing GH-inhibiting factor. Further neurotransmitters, neuropeptides, and hormones affect GH release, such as dopamine, TRH, neuropeptide Y, sex hormones, glucocorticoid hormones, and thyroid hormones. Additionally, food-related substances such as free fatty acids, glucose, and amino acids alter GH regulation, as do alterations in caloric intake, physical activity, and stress. GH stimulates the production of hepatic insulin-like-growth factor -1 (IGF-1). In concert with IGF-1 both hormones regulate growth, somatic development, and cell metabolism (Laron, 2002). Gonadal steroids distinctively modulate GH-IGF-1 actions in a sex-specific way (Meinhardt and Ho, 2006).

Molecular Biology of Estrogen Receptors a and p

Expression cloning of the human ER using monoclonal ER antibodies provided the first full-length sequence of ERa.32,33 In common with the other members of the steroid thyroid hormone receptor family of nuclear receptors, ERa has six main structural and functional domains (A-F) a variable or regulatory domain containing a transcriptional activation function (A B), a DNA-binding domain (C), a hinge region (D), a ligand-binding domain (E), and a region that plays a role in distinguishing agonists vs. antagonists (F) (Fig. 14.1). Functions for these regions were initially proposed based on the coded amino acid sequence and hydrophobicity analyses of these sequences. In vitro site mutagene-sis assays, deletion mutation studies, and domain swapping experiments have confirmed functional roles for these domains.34-36 A portion of the N-terminal regulatory domain, amino acids 41-150 known as activation function-1 (AF-1), is associated with modulation of transcriptional activity. This domain...

Alteration of Estrogen Receptor Interaction with Coregulator Proteins

The corepressors silencing mediator of retinoid and thyroid receptors (SMRT) and nuclear receptor-corepressor (N-CoR) bind to ER in the absence of ligand and silence transcription. Unlike coactivators that have intrinsic his-tone acetylase activity, one of the functions of corepressors is to recruit a complex of proteins having histone deacetylase activity, to repress gene expression by maintaining chromatin in a more condensed state.37,99 The inhibitory potency of antiestrogens is enhanced by recruitment of other coregulators, including an ER-selective repressor of ER activity in addition to SMRT and N-CoR.102-104 Corepressor expression is reduced in some tamoxifen-resistant breast cancers.104

Biological Functions of Rb and E2F

Besides apoptosis, mouse models confirm many of the additional biological functions ascribed to Rb and E2F (reviewed in Classon and Harlow, 2002 Liu et al, 2004). The best characterized of the pocket protein knockout animals are Rb deficient mice. Rb heterozygous mice show a similar phenotype to heterozygous humans except that instead of developing retinoblastomas, Rb+ - mice develop pituitary and thyroid tumors (Jacks et al, 1992). The incidence of these tumors can be decreased by eliminating E2F 1, suggesting that the ability of Rb to suppress tumors is due to its inhibition of activating E2Fs. Rb null mice die at embryonic day 13.5 and show ectopic S phases, extensive neuronal apoptosis, and defects in the differentiation of muscle and red blood cells, among other tissues. However, many of these defects appear not to be cell autonomous but may instead be due to hypoxia since the Rb- - placenta and red blood cell development are abnormal (Wu et al, 2003). In contrast, pi07 or pi30...

The ras oncogene in tumorigenesis

E.g. carcinomas of the colon, pancreas, lung thyroid, lymphomas and myeloproliferative disorders. Although attempts have been made to assess the clinical significance of ras activation, there is no incontrovertible evidence of its association with disease stage or recurrence, although some studies have suggested that it may serve as a marker related to the malignant potential of tumours (Harada et al., 1992), Ras mutation appears to be an infrequent event in bronchioalveolar adenocarcinoma (Rusch et al., 1992) and of little clinical relevance in lung adenocarcinoma (Rodenhuis and Slebos, 1992). Gulbis and Galand (1993) have critically examined the question of whether ras protein expression can be regarded as a criterion of malignancy. Their study reveals that an insufficiency of information makes it difficult to determine whether ras expression can serve as a marker in tissues of the colon, lung, bladder, ovary, and neural and odontogenic tissues and their corresponding neoplastic...

Androgen Receptor Structure And Function

The AR is a member of the superfamily of nuclear transcription factors, which consists of more than 300 members across vertebrates, arthropods, and nematodes and includes receptors for steroid hormones, vitamin D, retinoic acids, and thyroid hormones, as well as a number of orphan receptors for which no ligand has yet been identified.1 Specifically, the AR is a member of the class III NR family, including receptors for estrogen (ER), progestin, glucocorticoids (GR), mineralocorticoids (MR), and the orphan estrogen-related receptors, which represent the terminal derivatives of cholesterol biosynthesis.3 Like many other NRs e.g., GRs, progesterone receptors (PRs), and ERs , the AR contains a ligand-dependent activation function (AF-2) in helix 12 of the ligand-binding domain (LBD), which interacts predominantly with LxxLL motifs of the p160 coactivators. A key functional role for AF-2 is to recruit, in a ligand-dependent manner, chromatin-remodeling factors, which may bridge or...

Recruitment of Cofactors

Formed by AF-2 residues in the LBD via a set of conserved LxxLL-like motifs termed NR boxes.54 The p160 coactivators enhance steroid receptor transcriptional activity by actively recruiting secondary coactivators, such as p300 cAMP response element binding protein (CBP) and p300 CBP-associated factor (PCAF), resulting in chromatin remodeling via targeted histone acetylation and stable assembly of the preinitiation transcriptional complex, leading to enhanced rates of transcription initiation by RNA polymerase II.53 In contrast, corepressors such as the related proteins silencing mediator of retinoic and thyroid hormone receptors (SMRT) and NR-corepressor (N-CoR) are thought to interact with only the apo-LBD of the steroid receptors. However, recent studies in our laboratories (Buchanan, Coetzee, and Tilley, unpublished data) suggest that SMRT may interact with multiple domains of the AR by ligand-dependent and ligand-independent mechanisms and may play an important role in AR...

Microsatellite Instability

For MSI analysis, at least five repeated sequences should be tested for example, the following loci containing tetra- and pentanucleotide polymorphic tandem repeat sequences CD4 (12p13), a (TTTTC) repeat located in the 5' nontranscribed region of the T cell surface antigen gene VWA31 (12p12-pter), an (AGAT) repeat in intron 40 of the von Willebrand factor gene Fes FPS (15q25-qter), an (ATTT) repeat in intron 5 of the c-fes proto-oncogene TPOX (2p23-pter), an (AATG) repeat in intron 10 of the thyroid peroxidase gene p53 (17p13), an (AAAAT) repeat in the first intron of the TP53 gene.

Alexander Mason Steven Toms and Aleck Hercbergs

Conventional multimodailty therapies have not altered the dismal prognosis of glioblastoma which has prompted alternative investigational approaches utilising biological modifiers of response.We review here interferon alpha (IFN-a) and beta (IFN-P), interleukin-2 (IL-2), tumor necrosis factor-a TNF, interleukin 4 (IL-4) , monoclonal antibodies to EGFR, EGFRvIII and radiolabeled anti-tenascin monoclonal antibody. A current novel approach is exploitation of some of the biological consequences of thyroid hormone deprivation on tumor biology. In a preliminary Phase I II trial significant improvement in survival and tumor regression rates in recurrent high grade glioma patients were observed following propylthiouracil induced mild (chemical) hypothyroidism combined with high dose tamoxifen.The background to this approach is reviewed.

Modeling Human Disease through Targeted Overexpression

This pituitary hormone belongs to a family of glycoprotein hormones that include thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG). Members of this family are heterodimers containing a common a subunit and a unique (3 subunit. LH and FSH are secreted into the circulation as distinct pulses that ultimately regulate gametogenesis and gonadal steroidogenesis. The secreted pulses of LH and FSH derive from identical pulses of GnRH secreted from the hypothalamus. Although LH and FSH stimulated production of estrogen and androgens from the gonads, these sex steroids also feed back at the level of both the hypothalamus and the pituitary to limit secretion of additional LH.

Akt signalling in cancer growth and invasion

The induction of apoptosis by staurosporine as well as by etoposide, both well-established mitochondrial apoptotic stimuli, is accompanied by marked activation of Akt prior to the onset of apoptosis, and the resultant overexpression of Akt indeed greatly delays apoptosis (Tang et. al., 2001). It is to be expected that deregulation of the restraint on apoptosis would lead to tumour expansion and this has turned out to be the case. Akt is over-expressed in cancers of the thyroid (Ringel et al., 2001). Akt is said to be constitutively active in non-small cell lung carcinoma cells lines (Brognard etal., 2001). Its activation occurs upon exposure of breast cancer cell lines to oestrogen, irrespective of their ER status (Tsai et al., 2001). Zinda et al. (2001) found no differences in Akt RNA expression of normal and tumour tissues derived from lung, breast, prostate and colon. However, one ought to take cognisance of the possibility that there might yet be differences in protein expression...

On The Physiological Role Of Igfi And Igfii

The IGF molecules appear to regulate cell proliferation in both epithelial and mesenchymal tissues. They act as a non-tissue-specific permissive mitogen, required for optimal proliferative responses to highly tissue-specific trophic factors such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) or thyroid-stimulating hormone (TSH). They consequently perform the function of a general progression factor for cells previously stimulated by a more specific competent factor (81). This has been formally demonstrated using cells derived from mice with a targeted disruption of the IGF-1R genes (IGF-lR . These cells do not grow in serumfree medium supplemented with growth factors that sustain the same type of cells derived from wild type littermates (82).

Inhibitors of Type2 Serine Threonine Phosphatases

Sequence, first identified in the transcription factor NFAT (nuclear factor of activated T cells), a PP2B substrate. These include CAIN, MCIP, and the product of the disease gene associated with Down's syndrome, the thyroid hormone-inducible protein ZAKI-4. Over-expression of these proteins suppresses PP2B functions consistent with their actions as PP2B inhibitors. PP2B also binds to immunophilins that in turn bind the immunosuppressive drugs cyclosporin and FK506 to inhibit calcineurin activity. Experimental evidence suggests that some immunophilins bind PP2B in the absence of drugs and may regulate its phosphatase activity.

Production of Plasma Proteins

Plasma albumin and most of the plasma globulins (with the exception of immunoglobulins, or antibodies) are produced by the liver. Albumin constitutes about 70 of the total plasma protein and contributes most to the colloid osmotic pressure of the blood (chapter 14). The globulins produced by the liver have a wide variety of functions, including transport of cholesterol and triglycerides, transport of steroid and thyroid hormones, inhibition of trypsin activity, and blood clotting. Clotting factors I (fibrinogen), II (prothrombin), III, V, VII, IX, and XI, as well as angiotensinogen, are all produced by the liver.

Mechanism of transduction of signals by

Can one formulate a putative mechanism by which Akt might activate specific transcription factors that might be associated with specific cellular properties characterising the development of cancer At least three isoforms of Akt have been identified. There seems to be no differential expression between the Akt 1, 2 and 3, and it is uncertain if they are differentially expressed between normal and neoplastic tissues. Whilst Ringel et cil. (2001) found them over-expressed in thyroid carcinomas as compared with corresponding normal tissue, Zinda et al. (2001) encountered no significant differences in their investigations, which included normal and cancers of the colon, lung, breast and the prostate. It should be noted however that EGF might activate a specific isoform of Akt (Okano et al., 2001).

Potential Adverse Experiences

The definition of appropriate treatment populations depends in part upon the balance of specific benefits and risks. A preliminary report indicates that a low plasma level of IGF-1 may correlate with increased mortality in patients over 70 yr old (52), suggesting a potential benefit in treatments which elevate IGF-1. However, just as thyroid hormone replacement can worsen the prognosis of patients with low-T3 syndrome, a recent study of high-dose GH treatment in critical illness, a state of GH resistance, showed a worse outcome in the GH treatment group (53). This is a somewhat different situation from the reduced GH secretion seen in aging, but it raises caution about the potential risks in reversing changes that may be in part adaptive.

Cowdens Syndrome Definition

Cowden syndrome (CS), also known as multiple hamartoma syndrome or Cowden disease, was first described by Lloyd and Dennis in 1963 (1) as a multisystem disorder with characteristic mucocutaneous lesions and abnormalities of the breast, thyroid, and gastrointestinal tract. They named the disorder after their first patient, Rachel Cowden, who died due to breast cancer. CS is a rare genetic disorder with an autosomal-dominant pattern of inheritance and variable expressivity. Characteristic lesions present in nearly all patients with CS include trichilemmomas on the face, acral keratoses on the hands, and oral papillomas of the mouth. Benign and malignant neoplasms of the breast and thyroid occur in up to two-thirds of patients. Intestinal tract hamartomatous polyps are seen in more than one-half of patients (2).

Chromosomal translocation in synovial sarcomas

A translocation t(X 18) (pll.2 qll.2) occurs consistently in synovial sarcomas. Several genes are located at the breakpoints in this translocation. They are SYT occurring on chromosome 18, and members of the testis cancer antigen SSX gene family, namely SSX1, SSX2 and SSX4 on the X-chromosome. The SSX genes are normally expressed in the testis and the thyroid. Of the SSX homologues, SSX J, SSX2 and SSX4 are frequently expressed in human neoplasms. SSX3 is not usually detected. Furthermore, SSX expression is found in many forms of cancer including breast cancer, colorectal cancer, head and neck tumours, melanoma and in lymphomas. No expression of the SSX genes is detectable in leukaemias, thyroid cancers, and seminomas (Tureci et al., 1998).

Role Of The Igf Axis In Tumour Formation And Growth

Further evidence was obtained in vivo. Activation of H-ras is a frequent event for tumour initiation in thyroid follicular cells (161-162) however, in vivo induction of H-ras mutations by thyroid injection of retroviruses carrying a mutated ras, yields formation of few tumours. If the mitogenic activity of the gland is increased by stimulation with thyroid-stimulating hormone besides with the introduction of ras mutations, the number of thyroid tumours is greatly enhanced (161, 163). These observations were explained by assuming that initial mutations leading to oncogene activation are not sufficient to induce cell proliferation at low primary mitogen levels. If clonal expansion of the oncogene-transformed cell occurs due to the influence of a physiological stimulus, however, new mutations may then take place, leading to a selective advantage for tumour growth. Later evidence indicated that growth factor signals, in particular those from the IGF-1R, are required for efficient tumour...

Secondary Malignancies

A similar study by Travis and colleagues evaluated 28,843 patients with a history of testicular cancer between 1935 to 1993 from 16 different tumor registries in North America and Europe.36 There were 1,406 cancers (excluding contralateral testicular cancer) and an RR of 1.43. In this cohort, 64 leukemias were identified, with a fourfold risk overall and an 11- to 15-fold increase when associated with chemotherapy. Acute nonlymphoblastic and lymphoblastic leukemias were both identified and also found to be associated with radiation therapy. The risk of solid tumors was noted to be increased, especially after 20 years, in a 3,330-patient cohort, with an RR of 1.54. Excess cancers of the bladder, stomach, and pancreas were mainly associated with radiotherapy. Other cancers with an increased incidence were colon cancer, rectal cancer, melanoma, prostate cancer, kidney cancer, thyroid cancer, and sarcomas. Further to this, Jacob-sen and colleagues found that of 6,187 men with testicular...

Cancer In Werner Syndrome

WS patients are at increased risk of developing cancer (Goto et al., 1996 Monnat, 2001 Monnat, 2002). The elevated risk of neoplasia in WS patients is of particular biological interest. As discussed later, neoplasia may be an expression of important mechanistic links between WRN function in vivo, genome stability assurance, and the limitation of cell proliferation defects. The elevated risk of neoplasia in WS is selective in that only a small subset of neoplasms are clearly elevated in incidence as compared with general population controls (see Table 80.2). The following neoplasms, in order of decreasing frequency, have been observed most often in WS patients and occur at higher or much higher frequency than in normal population controls soft tissue sarcomas, thyroid carcinoma, meningioma, malignant melanoma, malignant or preneoplastic hematologic disease, and osteosarcoma. Many other neoplasms, including common adult epithelial malignancies, have been observed in WS patients....

Cooperation and Competition Between Couptf and HNF4

COUP-TF (chicken ovalbumin upstream promoter-transcription factor) and HNF-4 were both frequently called orphan members of the steroid thyroid receptor super-family and exhibit ubiquitous and liver-enriched tissue distribution, respectively (Ki-mura et al., 1993). COUP-TFs strongly inhibit transcriptional activation mediated by nuclear hormone receptors, including HNF-4. COUP-TFs repress HNF-4-dependent gene expression by competition with HNF-4 for common binding sites found in several regulatory regions (Kimura et al., 1993 Ktistaki and Talianidis, 1997b). In contrast, promoters such as the HNF-1 promoter, which are recognized by HNF-4 but not by COUP-TFs, are activated by COUP-TFI and COUP-TFII in conjunction with HNF-4 more than 100-fold above basal levels, as opposed to about 8-fold activation by HNF-4 alone (Ktistaki and Talianidis, 1997b). This enhancement was strictly dependent on an intact HNF-4 E domain. In-vitro and in vivo evidence suggests that COUP-TFs enhance HNF-4...

PolyQ Diseases as Transcriptionopathies

Polyq Disease

AR androgen receptor, CA150 coactivator 150, CBP cyclic AMP response element binding protein, CtBP C-terminal binding protein, Crx cone-rod homeobox containing gene, htt huntingtin, HYP-B htt-yeast partner, mSin3a mammalian Sin3 protein-A, MTG8 myeloid translocation gene on 8q22, NCoR nuclear receptor corepressor NF-kB nuclear factor-KB, P CAF p300 CBP-associated factor, REST NRSF repressor element-1 transcription factor neuron restrictive silencer factor, SMRT silencing mediator of retinoid and thyroid hormone receptors, Spl specificity protein-1, TAF4 TBP-associated factor 4, TAF10 TBP-associated factor 10

Pernicious Anemia As A Subset Of Megaloblastic Anemias

Intrinsic factor is the single most important ingredient to the absorption of vitamin B12 and subsequent delivery of vitamin B12 to the circulation. When problems with intrinsic factor develop, the condition is called pernicious anemia. Drs. George Minot and William Murphy of Boston were awarded the Nobel Prize in 1934 for their discovery that ingestion of liver successfully treated patients with pernicious anemia. Several factors may account for the lack of intrinsic factor in the stomach, including physical factors such as partial or whole gastrectomy, or genetic and immune factors. Whatever the cause, either intrinsic factor is not being secreted or it is being blocked or neutralized in some fashion. Atrophic gastritis may occur in which gastric secretions are diminished and therefore intrinsic factor fails to be secreted. The reasons for this remain unclear but age may play a role.5 Immune factors may arise that cause antibodies to be produced against intrinsic factor, thyroid...

KISS1GPR54 and Cancer

In fact, the mechanism of metastasis suppression induced by kisspeptin is still uncertain. It is not entirely clear if kisspeptins binding to GPR54 is required for this function, since most studies were performed in cells that had experimentally elevated GPR54 expression, exposed to variable exogenous doses of kisspeptins, which could be either pharmacologic or physiologic.40 KISS1 mRNA expression have been evaluated in several tumor types, including melanoma, breast cancer, follicular, and papillary carcinoma of the thyroid, superficial, and invasive bladder neoplasms, esophageal squamous cell carcinoma, gastric cancer, and hepatocellular carcinoma.40 In general, loss or reduction of KISS1 expression was inversely correlated with tumor progression, metastatic potential, and survival.40

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