Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Determination of serum alpha-fetoprotein is useful in the clinical management of liver cancer, but it has not been particularly helpful in the early diagnosis of this disease, since also non-neoplastic liver diseases may result in small increases of its serum concentration. To improve the clinical performance of this assay, we have previously developed an in vitro culture system, in which the expression of alpha-fetoprotein and albumin could be coordinately modulated by thyroid hormone. This system allowed large scale production and purification of native alpha-fetoprotein to be used as reference material. In addition, we synthesized and cloned in a bacterial expression vector a DNA sequence coding of human alpha-fetoprotein amino acid sequence 38-119. This alpha-fetoprotein sequence was chosen since it is the least homologous to albumin, being the amino acid sequence of the two proteins extremely similar with an overall identity of about 38%. Now we have obtained three hybridomas recognizing with high affinity and specificity both the recombinant fragment and native alpha-fetoprotein. These antibodies, which therefore recognize the native protein in the amino acid sequence 38-119, should allow the development of an immunoassay for alpha-fetoprotein with absolute selectivity versus albumin. This might result in more sensitive clinical determinations, avoiding the possibility of cross-reactions.
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PMID:Monoclonal antibodies recognizing a recombinant portion of human alpha-fetoprotein with antigenic selectivity versus albumin. 248 Apr 33

During chemical carcinogenesis by N-2-fluorenylacetamide, the hormonal status of female Sprague Dawley rats is largely modified. Thyroids present a modified activity which is evidenced by the histological study as well as T4 and T3 assays. In hypophysis, thyrotropic cells were found in an hyperactive state, a fact which is in agreement with the changes observed in thyroid follicles size and epithelial cells demonstrating an hyperactivity of thyroid glands. Despite this histological result, T4 serum level was lowered. T3 level was also decreased but to a lesser extent. We suggest that the low thyroid hormone level play a role in the relative protection of females versus males toward liver cancer induction by chemicals.
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PMID:Thyroid activity during hepatocarcinogenesis by N-2-fluorenylacetamide. 616 27

Thyroid adenoma is commonly associated with surgery and radiometabolic treatment; recently, according to previous successful reports, percutaneous ethanol injection therapy under sonographic guidance, has been introduced as an alternative. This technique has already been favourably used in the treatment of focal lesions, such as liver cancer and hyperparathyroidism. In our experience, we have treated with such therapy 69 patients affected by thyroid adenoma (55 females, 14 males; 28 pretoxic, 41 toxic). Ethanol (0.5-2.8 mL/mL nodular tissue) was injected, under sonographic guidance, in 4-9 sessions (1 weekly). Thyroid hormone profile was assessed during treatment and at 3 and 6 months follow-up. Apart from local transient pain in 21% sessions, two cases of pyrexia (38.5 degrees-1 day) and 3 cases of transient dysphonia, no relevant adverse effects were observed. A slight thyroid hormone increase was seen in both groups immediately following treatment. Six months after therapy a biochemical and clinical remission of hyperthyroidism was observed in 33 out of 41 toxic patients (80%); a significant increase of TSH levels was seen in both groups (p < 0.001). With follow-up, significant volume shrinkage (70-80% volume reduction--p < 0.0001) as well as structural alterations of the nodule, were consistently recorded at sonography, in both groups; a linear relationship (p < 0.0001) between pretreatment volume and volume reduction was found. At scintiscan functional activity of extranodular parenchyma was found in 75% of patients affected by pretoxic adenoma and in 63.1% of patients with toxic adenoma. These data confirm that percutaneous ethanol injection therapy is effective in obtaining functional ablation and in inducing remission of hyperthyroidism, when present; so it represents a valid and safe alternative to standard therapeutic tools of thyroid adenoma.
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PMID:[Treatment of hyperfunctioning thyroid adenoma: current trends]. 833 Apr 72

The morphological and morphometric characteristics of peroxisomes in normal human liver and the peroxisomal alterations in the liver of patients with acquired or congenital non-peroxisomal diseases are reviewed. Secondary peroxisomal changes are observed in steatosis, hepatitis and cirrhosis induced by various agents (viruses, alcohol, drugs, etc.), in cholestasis, in hepatomas, in extra-hepatic cancer with or without liver metastasis, in extrahepatic inflammatory processes, in metabolic disorders affecting metabolism of carbohydrates, lipids and lipoproteins, glycoproteins, amino acids, bilirubin or copper, and in altered thyroid hormone levels. They are recognized as a proliferation of peroxisomes (increased in number and to a lesser extent in surface density and volume density) often accompanied by a minor reduction in size (at most to 68% of the mean diameter in control livers) but very rarely by an increase in mean peroxisomal diameter, and as proliferation-related changes in shape (tails, gastruloid cisternae, funnel-like constrictions, elongation, protrusions) in at least a few of the peroxisomes. These secondary alterations of the peroxisomes are clearly distinguishable from the primary changes in peroxisomes observed in the liver of patients with congenital peroxisomal disorders.
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PMID:Secondary alterations of human hepatocellular peroxisomes. 905 51

Scarcity of donor livers is a major obstacle to the general application of hepatocytes for the development of bioartificial liver assist devices as well as intracorporeal engraftment of hepatocytes for the treatment of inherited metabolic diseases. The number of hepatocytes that can be transplanted into the liver safely in a single sitting also limits the utility of this procedure. These limitations could be addressed by providing preferential proliferative advantage to the transplanted cells. Studies using transgenic mouse recipients or donors have indicated that massive repopulation of the host liver by engrafted hepatocytes requires that the transplanted cells are subjected to a proliferative stimulus to which the host hepatocytes cannot respond. Prevention of host hepatocyte proliferation has been achieved by treatment with a plant alkaloid, retrorsine. Because retrorsine is carcinogenic, we have evaluated preparative irradiation for this purpose. The proliferative stimulus may consist of the loss of hepatic mass (e.g., partial hepatectomy, reperfusion injury or induction of Fas-mediated apoptosis by gene transfer) or administration of stimulants of hepatocellular mitosis (e.g., growth factors or thyroid hormone). Potential applications of these preparative manipulations of the host liver include the treatment of inherited metabolic disorders by transplantation of allogeneic hepatocytes, hepatocyte-mediated ex vivo gene therapy, rescuing liver cancer patients from radiation-induced liver damage, and expansion of human hepatocytes in animal livers.
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PMID:Amplification of engrafted hepatocytes by preparative manipulation of the host liver. 1149 72

BACKGROUND: The metabolic inhibitor rotenone inhibits hepatocellular proliferation and the incidence of liver cancer resulting from exposure to the PPARalpha agonist Wy-14,643, via unknown mechanisms. Since the absence of thyroid hormones diminishes hepatomegaly, an early biomarker for the hepatocarcinogenicity induced by PPARalpha agonists, this study was undertaken to investigate whether rotenone might interference with the ability of Wy-14,643 to alter the animal thyroid status. METHODS: Male B6C3F1 mice were given Wy-14,643 (100 ppm), rotenone (600 ppm) or a mixture of both, in the feed for 7 days. Bromodeoxyuridine (BrDU), marker of cell replication, was delivered through subcutaneously implanted osmotic mini-pumps. At the end of the experiment, sera were collected and corticosterone and thyroid hormone levels were measured by solid-phase radioimmunoassay kits. In addition, liver tissue samples were stained immunohistochemically for BrDU to determine percentages of labeled cells. Further, cell surface area was determined from images generated by a Zeiss Axioplan microscope equipped with a plan Neofluar x40 0.75 na objective. Tracings of individual hepatocyte perimeters were then analyzed and cell-surface areas were calculated using MicroMeasure FL-4000. RESULTS: Wy-14,643 caused a significant increase in liver weights, hepatocyte BrDU labeling index (LI), and hepatocyte surface area. In animals which received both Wy-14,643 and rotenone simultaneously, all of these effects were significantly less pronounced compared with mice that received Wy-14,643 alone. Rotenone alone decreased liver weights, LI and surface area. The Free Thyroid Index (FTI), which provides an accurate reflection of the animal's thyroid status, was 5.0 +/- 0.3 in control mice. In animals exposed to rotenone, these values decreased to 2.0 +/- 0.9, but in animals which received Wy-14,643, levels increased significantly to 7.7 +/- 0.9. FTI values decreased to 3.4 +/- 0.8 in mice receiving both rotenone and Wy-14,643. CONCLUSION: A strong correlation was observed between the animal thyroid status and both, hepatocyte proliferation (r2 = 0.62), and hepatocyte surface area (r2 = 0.83). These results support the hypothesis that the thyroid status of the animal plays a role in PPARalpha-induced hepatocellular proliferation and liver cell enlargement. Both these events are known to contribute to the expression of liver cancer in response to the activation of PPARalpha.
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PMID:Correlation between thyroid hormone status and hepatic hyperplasia and hypertrophy caused by the peroxisome proliferator-activated receptor alpha agonist Wy-14,643. 1515 75

The objective of this study was to identify genes regulated by thyroid hormone (T(3)) mediated by its receptor (TR) and associated with tumorigenesis. The gene encoding aldo-keto reductase family 1, member B1 (AKR1B1), as previously identified by c-DNA microarray, is known to be up-regulated by T(3) treatment. Enzyme AKR1B1 was elevated roughly 3-fold in HepG2-TRalpha1 cells at the protein level and 4.6-fold increase at the mRNA level after 48 h T(3) treatment. Similar findings were obtained from thyroidectomized rats after T(3) application. To identify and localize the critical TR element (TRE), series deletion of the promoter mutant were constructed and electrophoretic mobility shift assays were carried out. The TRE on the AKR1B1 promoter was localized to the -1099/-1028 region. Further, this study demonstrated that AKR1B1 over-expression in some types of hepatocellular carcinomas (HCCs) is TR-dependent and might play a crucial role in the development of HCC. Thus, T(3) regulates AKR1B1 gene expression via a TRE-dependant mechanism and associates liver cancer.
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PMID:Regulation of AKR1B1 by thyroid hormone and its receptors. 1942 79

The peroxisome proliferator-activated receptor alpha (PPARalpha, or NR1C1) is a nuclear hormone receptor activated by a structurally diverse array of synthetic chemicals known as peroxisome proliferators. Endogenous activation of PPARalpha in liver has also been observed in certain gene knockout mouse models of lipid metabolism, implying the existence of enzymes that either generate (synthesize) or degrade endogenous PPARalpha agonists. For example, substrates involved in fatty acid oxidation can function as PPARalpha ligands. PPARalpha serves as a xenobiotic and lipid sensor to regulate energy combustion, hepatic steatosis, lipoprotein synthesis, inflammation and liver cancer. Mainly, PPARalpha modulates the activities of all three fatty acid oxidation systems, namely mitochondrial and peroxisomal beta-oxidation and microsomal omega-oxidation, and thus plays a key role in energy expenditure. Sustained activation of PPARalpha by either exogenous or endogenous agonists leads to the development of hepatocellular carcinoma resulting from sustained oxidative and possibly endoplasmic reticulum stress and liver cell proliferation. PPARalpha requires transcription coactivator PPAR-binding protein (PBP)/mediator subunit 1(MED1) for its transcriptional activity.
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PMID:PPARalpha: energy combustion, hypolipidemia, inflammation and cancer. 2041 53

Deiodinases constitute a group of thioredoxin fold-containing selenoenzymes that play an important function in thyroid hormone homeostasis and control of thyroid hormone action. There are three known deiodinases: D1 and D2 activate the pro-hormone thyroxine (T4) to T3, the most active form of thyroid hormone, while D3 inactivates thyroid hormone and terminates T3 action. A number of studies indicate that deiodinase expression is altered in several types of cancers, suggesting that (i) they may represent a useful cancer marker and/or (ii) could play a role in modulating cell proliferation - in different settings thyroid hormone modulates cell proliferation. For example, although D2 is minimally expressed in human and rodent skeletal muscle, its expression level in rhabdomyosarcoma (RMS)-13 cells is threefold to fourfold higher. In basal cell carcinoma (BCC) cells, sonic hedgehog (Shh)-induced cell proliferation is accompanied by induction of D3 and inactivation of D2. Interestingly a fivefold reduction in the growth of BCC in nude mice was observed if D3 expression was knocked down. A decrease in D1 activity has been described in renal clear cell carcinoma, primary liver cancer, lung cancer, and some pituitary tumors, while in breast cancer cells and tissue there is an increase in D1 activity. Furthermore D1 mRNA and activity were found to be decreased in papillary thyroid cancer while D1 and D2 activities were significantly higher in follicular thyroid cancer tissue, in follicular adenoma, and in anaplastic thyroid cancer. It is conceivable that understanding how deiodinase dysregulation in tumor cells affect thyroid hormone signaling and possibly interfere with tumor progression could lead to new antineoplastic approaches.
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PMID:Thyroid hormone deiodinases and cancer. 2267 19

Thousands of untested chemicals in the environment require efficient characterization of carcinogenic potential in humans. A proposed solution is rapid testing of chemicals using in vitro high-throughput screening (HTS) assays for targets in pathways linked to disease processes to build models for priority setting and further testing. We describe a model for predicting rodent carcinogenicity based on HTS data from 292 chemicals tested in 672 assays mapping to 455 genes. All data come from the EPA ToxCast project. The model was trained on a subset of 232 chemicals with in vivo rodent carcinogenicity data in the Toxicity Reference Database (ToxRefDB). Individual HTS assays strongly associated with rodent cancers in ToxRefDB were linked to genes, pathways, and hallmark processes documented to be involved in tumor biology and cancer progression. Rodent liver cancer endpoints were linked to well-documented pathways such as peroxisome proliferator-activated receptor signaling and TP53 and novel targets such as PDE5A and PLAUR. Cancer hallmark genes associated with rodent thyroid tumors were found to be linked to human thyroid tumors and autoimmune thyroid disease. A model was developed in which these genes/pathways function as hypothetical enhancers or promoters of rat thyroid tumors, acting secondary to the key initiating event of thyroid hormone disruption. A simple scoring function was generated to identify chemicals with significant in vitro evidence that was predictive of in vivo carcinogenicity in different rat tissues and organs. This scoring function was applied to an external test set of 33 compounds with carcinogenicity classifications from the EPA's Office of Pesticide Programs and successfully (p = 0.024) differentiated between chemicals classified as "possible"/"probable"/"likely" carcinogens and those designated as "not likely" or with "evidence of noncarcinogenicity." This model represents a chemical carcinogenicity prioritization tool supporting targeted testing and functional validation of cancer pathways.
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PMID:In vitro perturbations of targets in cancer hallmark processes predict rodent chemical carcinogenesis. 2302 76


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