Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic haemochromatosis is characterised by an inappropriately high rate of iron absorption by the small intestine. The disease is transmitted as an autosomal recessive condition. The gene frequency in the Caucasian population is approximately 1 in 20 and the disease frequency is 1 in 400. Excessive iron deposition occurs in the liver, pancreas, heart, pituitary and joints and hepatic iron concentrations above approximately 400 mumol/g dry weight are always associated with fibrosis and usually with cirrhosis and progressive liver failure. Accurate diagnosis depends upon the demonstration of elevated hepatic iron stores. An hepatic iron index [hepatic iron concentration (in mumol/g dry weight) divided by patient age] of greater than 2.0 distinguishes homozygous subjects from the other conditions in which slight increases in hepatic iron concentration may occur, e.g. in a subject heterozygous for haemochromatosis or alcoholic liver disease. If cirrhosis is present, patients are at a high risk of developing hepatocellular carcinoma. Therefore, they should undergo regular abdominal ultrasound and alpha-fetoprotein estimation. In the absence of cirrhosis, phlebotomy restores life expectancy to normal. Venesection should be continued until all excess iron stores are removed as judged by failure of a rise in haemoglobin concentration on cessation of phlebotomy. Screening of first degree relatives should commence from a young age (e.g. 10 years). If serum ferritin or transferrin saturation are abnormal, liver biopsy should be undertaken. HLA typing of the family allows for the identification of those siblings who are most likely to develop the disease. Secondary iron overload is often multifactorial in origin. Iron chelation therapy with subcutaneous deferoxamine (desferrioxamine) should only commence after careful consideration of the potential benefits in each individual patient.
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PMID:Current concepts in rational therapy for haemochromatosis. 171 64

Iron is essential for life, but iron overload is toxic and potentially fatal. The liver is a major site of iron storage and is particularly susceptible to injury from iron overload, especially when (as in primary hemochromatosis) the iron accumulates in hepatocytes. Iron can be taken up by the liver in several forms and by several pathways including: (1) receptor-mediated endocytosis of diferric or monoferric transferrin or ferritin, (2) reduction and carrier-facilitated internalization of iron from transferrin without internalization of the protein moiety of transferrin, (3) electrogenic uptake of low molecular weight, non-protein bound forms of iron, and (4) uptake of heme from heme-albumin, heme-hemopexin, or hemoglobin-haptoglobin complexes. Normally, pathway 2 is probably the major one for uptake of iron by hepatocytes. Iron is stored in the liver in the cores of ferritin shells and as hemosiderin, an insoluble product derived from iron-rich ferritin. Iron in hepatocytes stimulates translation of ferritin mRNA and represses transcription of DNA for transferrin and transferrin receptors. The major pathologic effects of chronic hepatic iron overload are: (1) fibrosis and cirrhosis, (2) porphyria cutanea tarda, and (3) hepatocellular carcinoma. Although precise pathogenetic mechanisms remain unknown, iron probably produces these and other toxic effects by increasing oxidative stress and lysosomal lability. Vigorous efforts at diagnosis and treatment of iron overload are essential since the pathologic effects of iron are totally preventable by early vigorous iron removal and prevention of iron re-accumulation.
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PMID:Iron and the liver. 184 76

A cell line, HuH-33 was cultured in vitro from a patient with hepatocellular carcinoma. This cell line has been in continuous culture over 12 month period with slow growth potential. HuH-33 was composed spindle-or polygonal-shaped cells as a major population. Chromosome number of the cells were widely distributed even in the primary culture. HuH-33 was transplantable into nude mice and secreted alpha-fetoprotein, albumin, beta 2 microglobulin, ferritin and tissue polypeptide antigen.
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PMID:[Tissue culture course of a human hepatoma cell line]. 196 86

Synthesis of the iron-storage protein ferritin is thought to be regulated at the translational level by the cytosolic content of chelatable iron. This response to iron is regulated by the iron-modulated binding to ferritin mRNAs of a repressor protein, the iron regulatory element-binding protein. From measurements made in a cell-free system, regulation of the iron regulatory element-binding protein has been recently suggested to involve direct interaction with hemin. The following observations on the synthesis of ferritin and of heme oxygenase (HO), the heme-degrading enzyme, in rat fibroblasts or hepatoma cells lead us to conclude that chelatable iron is a direct physiological regulator of ferritin synthesis in intact cells: (i) the inhibitor of heme degradation, tin mesoporphyrin IX, reduces the ability of exogenous hemin to induce ferritin synthesis but enhances HO synthesis; (ii) the iron chelator desferal suppresses the ability of hemin to induce synthesis of ferritin but not of HO; (iii) the heme synthesis inhibitor succinylacetone does not block iron induction of ferritin synthesis; (iv) there is no apparent relationship between the ability of various metalloporphyrins to inactivate the iron regulatory element-binding protein in cell-free extracts and their capacity to induce ferritin synthesis in intact cells; (v) administered inorganic iron significantly induces the synthesis of ferritin but not of HO; (vi) addition of delta-aminolevulinic acid to stimulate heme synthesis represses the ability of inorganic iron to induce ferritin synthesis while activating HO synthesis. Taken together, our results demonstrate that (i) release of iron by HO plays an essential role in the induction of ferritin synthesis by heme and (ii) chelatable iron can regulate ferritin synthesis independently of heme formation.
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PMID:Regulation of ferritin and heme oxygenase synthesis in rat fibroblasts by different forms of iron. 199 60

The effects of 131-labelled antiferritin polyclonal antibody for the treatment of established hepatocellular carcinoma (HC-04) in athymic nude mice were evaluated. 131I-labelled antiferritin antibody localised specifically to a subcutaneous tumour with a mean of 8.1% of the infused dose per gram of tumour at 24 h after infusion when the experiment was started 15 days after inoculation and with a mean of about 6.5% of the infused dose per gram of tumour when the experiment was started 30 days after tumour transplantation. The concentrations of 131I-antiferritin antibody in tumour delivered a mean of 1994 cGy to tumour following infusion of 500 microCi of radiolabelled antiferritin antibody in the early group and a mean of 1600 cGy in the late group. Treatment with 500 microCi led to regression of the tumour in 55% of animals in the early group and 44% in the late group. In contrast, unlabelled antiferritin and 131I-labelled IgG failed to exert any significant effect on tumour growth. The transplanted tumours in the early groups of animals had relatively higher concentration of ferritin than those in the late group. There was accelerated inhibition of tumour growth and prolonged survival in animals in the early group compared with those in the late group.
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PMID:Radioimmunotherapy of human hepatocellular carcinoma xenografts with 131I-labelled antiferritin antibody. 202 33

Chemical analysis of ascitic fluid may be helpful in determining the underlying disease. We discuss the diagnostic accuracy of the common and newer chemical parameters (protein, LDH, lactate, glucose, cholesterol, triglycerides, phospholipids, fibronectin, albumin gradient [value of serum minus value of ascites], ferritin, tumor markers, immunomodulators, leukocytes, bacterial and cytologic examinations). We also review the pathogenesis and clinical findings of the most frequent ascites forms (benign hepatic, infective, malignant ascites, ascites associated with liver metastases or hepatocellular carcinoma, cardiac and pancreatic ascites) and the most important diagnosis criteria. In the malignant ascites a high cholesterol, a narrow albumin gradient or a high ferritin value have high diagnostic accuracy, but diagnosis is by the finding of malignant cells. For the diagnosis of infective ascites, bacteriology is mandatory even though the results are negative in most cases, particularly in spontaneous bacterial peritonitis where diagnosis has to be established clinically, by a low pH or by a high leukocyte count. Benign hepatic ascites is diagnosed by demonstrating an underlying chronic liver disease and laboratory examinations of the peritoneal fluid to exclude other causes. The laboratory tests in ascites associated with liver metastases or with hepatocellular carcinoma were similar to those in benign hepatic ascites and the two ascites forms must be separated by other clinical and technical findings. Pancreatic ascites can easily be distinguished from the other forms by the high amylase and lipase content.
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PMID:[Laboratory chemical analysis in ascites]. 203 10

This review starts with a description of certain features of mammalian ferritins and their DNA and RNA structures relevant to translational control of ferritin synthesis. Although the amino acid sequences of the two ferritin subunits (H and L) diverge in about 50% of the coding region, their five alpha-helices and the exon sizes of their genes are compatible with the proposition that they diverged from a single ancestral gene. Of particular note is their long 5'-untranslated regions (5'UTRs) which include a 28-nucleotide sequence almost completely identical in the H- and L-subunits of a range of species. This motif near the cap region of the 5'-UTR, which forms a specific stem-loop structure, provides for regulation of the translation of H- and L-ferritin mRNAs. When intracellular levels of chelatable iron are not in excess, a large reserve of H- and L-mRNAs is present in the cell sap, restrained from translation by a protein with an Mr of about 90-100,000 which binds to the stem-loop structure. When excess iron floods the cytosol, this protein/RNA complex appears to dissociate and the 40S ribosome subunit is now able to initiate ferritin protein synthesis so that the dormant mRNAs become active and are transferred to the polyribosomes. The mechanism whereby the binding protein is regulated in response to iron is currently under investigation. The regulatory protein occurs in the cell sap and is present in several interchangeable forms which appear to differ in the redox state of specific sulphydryls within the protein. Under some circumstances, the abundance of these forms appears to be altered by intracellular iron status. It is unclear how iron influences binding of the regulatory protein to ferritin mRNA. Some investigators consider that iron binds in the form of heme to the regulatory protein, for which they offer in vitro evidence. We have examined the role of heme versus inorganic chelatable iron in the regulation of ferritin and heme oxygenase synthesis in rat fibroblasts and hepatoma cells. By manipulating the flow of iron between the intracellular chelatable iron and heme iron pools we have concluded that chelatable iron can act as a regulator of ferritin synthesis in a manner which is independent of heme formation. This conclusion does not exclude a role for heme in some specialized cell types.
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PMID:Translational regulation of ferritin synthesis by iron. 213 57

To investigate the effects of iron supplementation on hepatoma cell growth, cells from a human hepatoma cell line, PLC/PRF/5, were grown in RPMI 1640 supplemented with 0, 10 and 20 micrograms/ml of FeSO4 and harvested weekly. At the end of 6 wk culture, cell mass measured 9.6, 14.7 and 13.2 gm, respectively. Amounts of ferritin from these cell masses were 0 (undetectable), 0.89 and 2.27 micrograms/gm of cells. To study the effects of iron deprivation of hepatoma cells, three human hepatoma cell lines (PLC/PRF/5, Hep G2 and Hep 3B) were incubated in tissue culture medium mixed with graded amounts of an iron-chelating agent, desferoxamine, for 48 to 96 hr at 37 degrees C with 5% CO2. Over 50% cell death in PLC/PRF/5 cells and 30% to 50% cell death in Hep G2 and Hep 3B cells were observed 48 to 72 hr after exposure to desferoxamine. Addition of ferric citrate partially reversed the cytotoxic effect of desferoxamine. On the other hand, viability of control cells, human diploid cell line (WI 38), was not affected by desferoxamine. Even after 96 hr exposure to desferoxamine, cell death was only 2% to 4%. These results suggest that (a) iron enhances tumor cell growth, (b) iron induces increased ferritin synthesis by tumor cells in vitro and (c) iron depletion causes tumor cell death but has little effect on normal human diploid cells. These findings should be considered when designing treatment of patients with hepatoma. Iron oversupply in patients with cancer might enhance tumor growth and adversely affect cancer therapy. Iron chelation with desferoxamine might have a place in the treatment of patients with hepatoma in conjunction with other anticancer agents.
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PMID:Effect of iron and desferoxamine on cell growth and in vitro ferritin synthesis in human hepatoma cell lines. 215 79

During the period 1978-1987, 255 patients with pathologically proven hepatocellular carcinoma (HCC) were assessed to be unresectable by laparotomy. Of them 155 had their tumors chiefly confined in the right or left lobe. Second stage resection was performed in 26 (16.8%) after marked reduction of the tumor by combination treatment with hepatic artery ligation (HAL) + hepatic artery infusion chemotherapy (HAI) + multifractionated radiotherapy (MFD) with linear accelerator, or radioimmunotherapy using 131I-anti human HCC ferritin antibody (131I-FtAb), which yielded the highest second stage resection rate (29.8%, 14/47) as compared to HAL + HAI or HAL + cryosurgery (16.9%, 12/71), HAL or HAI (0%, 0/37) alone. The 3 year survival rate of the 26 patients with second stage resection was 74.3%, comparable with those of small HCC resection (82.7%, n = 111) and radical resection of large HCC (56.1%, n = 122) in the same period. Experimental study using nude mice bearing human HCC also showed the superiority of triple (MFD or 131I-FtAb + Cisplatin PDD + mixed bacterial vaccine MBV) versus double (MFD or 131I-FtAb + PDD, or MFD or 131I-FtAb + MBV) and double versus single treatment modality. Both experimental and clinical data indicated that immunosuppression after radiotherapy was prevented by adjuvant immunotherapy (MBV). Thus, this treatment model provides an opportunity for resection or even cure in a part of patients with unresectable HCC confined in one lobe.
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PMID:[Multimodality treatment and two-stage resection for unresectable hepatocellular carcinoma--experimental and clinical studies]. 216 21

Paraffin sections of livers from 20 patients with hepatocellular carcinoma were examined by a method using peroxidase antiperoxidase for the detection of alpha-fetoprotein, carcinoembryonic antigen, and ferritin. Ferritin was detected in 70% of the cases, alpha-fetoprotein was in 50% and carcinoembryonic antigen in 30%. The incidence of the detection of these antigens was in accordance with the incidence of these antigens in the sera of patients with hepatocellular carcinoma. Moreover, these antigens were mainly expressed in the well differentiated type of hepatocellular carcinoma by the Edmondson's criteria. Our results also revealed that different antigens were usually present in different tumor cells, although some cells displayed two or more antigens simultaneously. These findings suggest that hepatocellular carcinoma cells are functionally heterogeneous, even if they appear histologically monomorphic.
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PMID:Immunohistochemical detection of alpha-fetoprotein, carcinoembryonic antigen, and ferritin in formalin-paraffin sections from hepatocellular carcinoma. 241 56


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