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

US-guided puncture is the simplest and most popular method in the RFA treatment for HCC. However, depending on the location of tumors, it is often difficult to detect them by US. We report here the utility of CT-guided RFA for the treatment of HCC. We performed CT-guided RFA for 27 nodules in 21 patients with HCC from July 1999 to June, 2001. We used the LeVeen Needle Electrode made by Boston Company and the Cool-tip type electrode made by Radionics Company. We judged the effects of the treatment by dynamic CT within 7 days after RFA. We were able to accomplish the treatment for all patients with the exception of one case who developed severe pain during RFA. We experienced transient increases of AST/ALT in a few cases, subcutaneous emphysema in one case, pleural effusion and ascites in two cases, but conservative treatments were effective for all cases. US-guided puncture was especially useful for the treatment of the tumors localized below the diaphragm that were hardly detectable by US.
 ...
PMID:[Usefulness of CT-guided RFA for hepatocellular carcinoma]. 1170 86

Alpha(1)-antitrypsin functions as a "mousetrap" to inhibit its target proteinase, neutrophil elastase. The common severe Z deficiency variant (Glu(342)-->Lys) destabilizes the mousetrap to allow a sequential protein-protein interaction between the reactive-centre loop of one molecule and beta-sheet A of another. These loop-sheet polymers accumulate within hepatocytes to form inclusion bodies that are associated with juvenile cirrhosis and hepatocellular carcinoma. The lack of circulating protein predisposes the Z alpha(1)-antitrypsin homozygote to emphysema. Loop-sheet polymerization is now recognized to underlie deficiency variants of other members of the serine proteinase inhibitor (serpin) superfamily, i.e. antithrombin, C1 esterase inhibitor and alpha(1)-antichymotrypsin, which are associated with thrombosis, angio-oedema and emphysema respectively. Moreover, we have shown recently that the same process in a neuron-specific protein, neuroserpin, underlies a novel inclusion-body dementia, known as familial encephalopathy with neuroserpin inclusion bodies. Our understanding of the structural basis of polymerization has allowed the development of strategies to prevent the aberrant protein-protein interaction in vitro. This must now be achieved in vivo if we are to treat the associated clinical syndromes.
 ...
PMID:Hypersensitive mousetraps, alpha1-antitrypsin deficiency and dementia. 1202 31

Invasive carcinoma originates from the epithelial cells lining the lumen of an organ. It is often preceded by metaplasia, dysplasia or carcinoma in situ. The purpose of this review is to suggest that this disease of the epithelium may be, in part, the result of underlying tissue-based disorganization. Human cancer is frequently associated with pre-existing tissue disease. For example, hepatocellular carcinoma usually occurs in patients with a macronodular cirrhotic liver. Most lung cancers arise among patients with chronic lung disease (bronchitis, emphysema, and chronic infection). Mechanical forces appear to play a major role in regulating normal and cancer cell growth. The loss of cell polarity by neoplastic cells, coupled to an otherwise normal growth rate is enough to explain the cancer star-shaped pattern. By changing the plane of cell division, tumor cells may escape physical constraints from surrounding cells and divide. Loss of cell polarity and the resulting cell proliferation appears to be a consequence of either tissue-based disorganization (chronic inflammation, fibrosis) or of direct carcinogenic insult. The multiple mutations frequently described in cancer may be, in part, secondary to physical stress and not primary events. Several animal and clinical trials have shown that tissue disruption (i.e. radiation-induced fibrosis or liver cirrhosis) can be successfully treated. It is possible that treatment targeted at tissue disruption would delay or reduce cancer incidence regardless of the precise biological mechanism of carcinogenesis.
 ...
PMID:Cancer: the role of extracellular disease. 1202 30

alpha(1)-Antitrypsin is a member of the serine proteinase inhibitor (serpin) superfamily and a potent inhibitor of neutrophil elastase. The most important deficiency variant of alpha(1)-antitrypsin arises from the Z mutation (Glu342Lys). This mutation perturbs the protein's tertiary structure to promote a precise, sequential intermolecular linkage that results in polymer formation. These polymers accumulate within the endoplasmic reticulum of the hepatocyte forming inclusion bodies that are associated with neonatal hepatitis, juvenile cirrhosis and adult hepatocellular carcinoma. The resultant secretory defect leads to plasma deficiency of alpha(1)-antitrypsin. This exposes lung tissue to uncontrolled proteolytic attack from neutrophil elastase, culminating in alveolar destruction. Thus, the Z alpha(1)-antitrypsin homozygote is predisposed to developing early onset basal, panacinar emphysema. In this review, we summarise the current understanding of the pathobiology of alpha(1)-antitrypsin deficiency and the associated liver cirrhosis and emphysema. We show how this knowledge has led to the development of novel therapeutic approaches to treat this condition.
 ...
PMID:Alpha(1)-antitrypsin deficiency, liver disease and emphysema. 1267 69

Alpha-1-antitrypsin (alpha(1)-antitrypsin) is the archetypal member of the serine proteinase inhibitor or serpin superfamily. The most common severe deficiency variant is the Z allele, which results in the accumulation of mutant protein within hepatocytes. This 'protein overload' causes neonatal hepatitis, cirrhosis and hepatocellular carcinoma. The lack of circulating plasma alpha(1)-antitrypsin results in early-onset panlobular emphysema. The mechanism underlying the deficiency of Z alpha(1)-antitrypsin is due to an aberrant conformational transition within the protein and the formation of chains of polymers that tangle within the secretory pathway of hepatocytes. This mechanism also underlies the plasma deficiency of other members of the serpin superfamily to cause a class of diseases called the serpinopathies. Specifically mutant alleles of antithrombin, C1-inhibitor and alpha(1)-antichymotrypsin have been reported that favour the spontaneous formation of polymers and the retention of protein within hepatocytes. The consequent lack of plasma antithrombin, C1-inhibitor and alpha(1)-antichymotrypsin results in thrombosis, angio-oedema and emphysema, respectively. Moreover, the polymerisation of mutants of neuroserpin results in the retention of polymers within neurones to cause the inclusion body dementia, familial encephalopathy with neuroserpin inclusion bodies or FENIB. We review here the genetic and molecular basis and clinical features of alpha(1)-antitrypsin deficiency, and show how this provides a platform to understand the other serpinopathies.
 ...
PMID:Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies. 1469 55

Alpha-1-antitrypsin (AT) deficiency was first described in the late 1960s in patients with severe pulmonary emphysema. The recognition of AT deficiency as a cause of emphysema then led to what is still the prevailing theory for the pathogenesis of emphysema, the protease-antiprotease theory. Soon it was found that AT deficiency accounted for a significant number of cases of neonatal liver disease that were previously categorized as idiopathic. We now know that AT deficiency is the most common genetic cause of neonatal liver disease and the most frequent diagnosis necessitating liver transplantation. It has also been shown to cause chronic liver disease, cryptogenic cirrhosis, and hepatocellular carcinoma in adults never previously known to have liver disease in infancy or childhood. Observations indicate that genetic traits unlinked to the AT gene or environmental factors predispose to or protect AT-deficient individuals from liver disease.
 ...
PMID:Alpha-1-antitrypsin deficiency: diagnosis and treatment. 1546 58

Alpha1-ATD is the most common metabolic liver disease in children for which liver transplantation is performed and, in adults, is associated with cirrhosis, hepatocellular carcinoma, and emphysema. It appears that only a proportion of patients with the deficiency develop clinical manifestations of this disease. Moreover, recent characterization of specific cellular and physiologic events have provided the basis for future potential therapeutic interventions.
 ...
PMID:Liver disease associated with alpha1-antitrypsin deficiency. 1556 52

Alpha-1 antitrypsin deficiency is an inherited disease affecting the lung and liver. The typical pulmonary manifestation is chronic obstructive pulmonary disease and emphysema. Severe chronic obstructive pulmonary disease may occur in young adulthood, and terminal respiratory insufficiency causes premature death in many patients. In the liver, alpha-1 antitrypsin deficiency may manifest as benign neonatal hepatitis syndrome; a small percentage of adults develop liver fibrosis, with progression to cirrhosis and hepatocellular carcinoma. The alpha-1 antitrypsin molecule is a serine protease inhibitor that is predominantly produced in the liver. Its most important physiologic functions are the protection of pulmonary tissue from aggressive proteolytic enzymes and regulation of pulmonary immune processes. Diagnosis of alpha-1 antitrypsin deficiency can be established by measurement of the serum alpha-1 antitrypsin concentration or by genetic analysis. Treatment is similar to the usual treatment for patients with chronic obstructive pulmonary disease. A further option is substitution therapy with human alpha-1 antitrypsin. The targets of treatment are the prevention of the accelerated decline of pulmonary function, reduction of lung infections, and improvements in exercise capacity.
 ...
PMID:Alpha-1 antitrypsin deficiency: pathogenesis, clinical presentation, diagnosis, and treatment. 1850 Dec 15

Alpha(1)-antitrypsin (alpha(1)AT), the most abundant proteinase inhibitor circulating in the blood, protects extracellular matrix proteins of the lung against proteolytic destruction by neutrophil elastase. alpha(1)AT deficiency predisposes patients to emphysema, juvenile cirrhosis and hepatocellular carcinoma. Over 90% of clinical cases of severe alpha(1)AT deficiency are caused by the Z variant (E342K) of alpha(1)AT. The presence of the Z mutation results in misfolding and polymerization of alpha(1)AT. Due to its inherent propensity to polymerize there are no reported cases of recombinant Z alpha(1)AT production. This has created a major impediment to studying the effect of the Z mutation on alpha(1)AT. Here we report our attempts to produce recombinant Z alpha(1)AT using both Escherichia coli and Pichia pastoris as host systems. Using a range of expression vectors in E. coli we were unable to produce soluble active Z alpha(1)AT. Cytosolic expression of the Z alpha(1)AT gene in P. pastoris was successful. Monomeric and active recombinant Z alpha(1)AT was purified from the yeast cytosol using affinity chromatography and anion exchange chromatography. Biochemical analyses demonstrated that the recombinant Z alpha(1)AT has identical properties to its native counterpart purified from plasma of patients homozygous for the Z allele. A recombinant source of pathological Z alpha(1)AT will increase the chances of elucidating the mechanism of its polymerization and thus the development of therapeutic strategies.
 ...
PMID:Expression, purification and characterization of recombinant Z alpha(1)-antitrypsin--the most common cause of alpha(1)-antitrypsin deficiency. 1955 63

The serpinopathies encompass a large number of diseases caused by inappropriate conformational change and self-association (polymerization) of a serpin (serine proteinase inhibitor) molecule. The most common serpinopathy is alpha(1)-antitrypsin (alpha(1)AT) deficiency, which is associated with an increased risk for liver cirrhosis, hepatocellular carcinoma and early-onset emphysema. The Z variant of alpha(1)AT, which accounts for 95% of all cases of alpha(1)AT deficiency, polymerizes during synthesis and after secretion. Here, we show using intrinsic and extrinsic fluorescence probes that Z alpha(1)AT exists in a non-native conformation. We examined the thermodynamic stability by transverse urea gradient gel electrophoresis, thermal denaturation and equilibrium guanidine hydrochloride unfolding and found that, despite structural differences between the two proteins, wild-type alpha(1)AT and Z alpha(1)AT display similar unfolding pathways and thermodynamic stabilities. Far-UV circular dichroism and bis-ANS (4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid, dipotassium salt) fluorescence suggest that the intermediate ensembles formed during unfolding of wild-type alpha(1)AT and Z alpha(1)AT are characterized by similar structural features. Kinetic analysis of the unfolding transition showed that Z alpha(1)AT unfolds at least 1.5-fold faster than the wild type. The biological implications of these data are discussed.
 ...
PMID:Kinetic instability of the serpin Z alpha1-antitrypsin promotes aggregation. 1994 4


<< Previous 1 2 3 4 Next >>