Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis is an energy-requiring mechanism of cell death which is a physiological event in organ morphogenesis, clone selection of lymphoid cells and cell turnover, but also occurs in many pathological conditions. It is under genetic control, bcl-2 being the major apoptosis suppressing gene, while p53 and c-myc are apoptosis promoting genes. Other factors, such as the Fas/Fas1 system, the caspases cascade, cytokines and enzymes also play a role in determining apoptosis. The term apoptosis was introduced by Kerr to describe this type of death in ischaemic rat liver, and the same Councilman bodies are now considered an example of apoptotic death. Virus-infected hepatocytes bear Fas receptors and apoptosis is induced by binding to the Fas ligand which is expressed by activated T cells; this action is probably mediated by enzymes of the caspase family and/or by granzyme B. The Fas/Fas1 system is also involved in apoptosis occurring in chronic non suppurative destructive cholangitis, in transplant rejection and in other liver diseases, including neoplasms; in the latter Bcl-2 protein and mutations of p53 also seem to play an important role. Cytokines are also frequently involved. Toxins like alcohol probably induce apoptosis by producing active oxidants. Whether aging enhances apopstosis in liver is still controversial. Although many molecular mechanisms have been suggested to be involved the switch on/off of apoptosis is still poorly understood and will be a matter of further investigations.
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PMID:Liver and apoptosis. 1009 Nov 8

To evaluate whether it is useful for diagnosis to detect K-ras and p53 mutations in biopsy specimens and bile of biliary tract lesions, 12 cholangiocarcinomas (CC), eight cases of cholangitis, seven gallbladder carcinomas (GBC), seven gallbladder cholesterol polyps, four cases of adenomyomatosis of the gallbladder and five cases of cholecystitis were examined. K-ras and p53 mutations in bile were detected by a two-step polymerase chain reaction (PCR) and nested PCR-single-strand conformation polymorphism (SSCP) analysis. In addition, p53 protein expression in biopsy specimens from CC were examined by immunostaining. K-ras mutations at codon 12 were detected in 50% of CC and 57.1% of GBC in both biopsy specimens and bile. The incidence of p53 mutations was 33.3% in CC and 42.9% in GBC. p53 protein overexpression was observed in 60% CC biopsy specimens. In contrast, K-ras and p53 abnormalities were not detected in any non-neoplastic biliary tract lesion. K-ras and p53 mutations in biliary tract cancers showed the same mutation patterns in spite of differences in the collection methods used between bile and biopsy specimens or surgically resected tissue. Genetic analysis of K-ras and p53 mutations in biopsy specimens and bile may be useful for the diagnosis of biliary tract cancers, although it may be effectively limited to patients with advanced disease.
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PMID:K-ras codon 12 and p53 mutations in biopsy specimens and bile from biliary tract cancers. 1022 22

The diagnosis of biliary disease, namely malignant disorders, is frequently hampered by the inconclusive cytology. We investigated prospectively the frequency of molecular changes in p53 and ras compared with cytology in patients with primary or secondary hepato-biliary disease. We investigated 118 consecutive patients, aged 24-89 with the following clinical diagnoses: choledocho/cholecystolithiasis (28), cholangiocellular carcinoma (21), gall bladder tumor (8), liver metastasis (3), autoimmune disease (8), chronic pancreatitis (16), pancreatic carcinoma (11), papillary disease (4), hepatic cirrhosis (6), cholangitis (2), anomalies (2), and normal (9). Bile was aspirated during routine endoscopic retrograde cholangio pancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC). DNA was prepared freshly from a native aliquot. p53 mutations were detected by polymerase chain reaction (PCR) for exons 5 through 8 followed by TGGE. PCR for ras mutations was performed as RFLP-PCR with sequencing. In four cases, mutations in p53 could be found in exons 6 and 7. Twenty-two samples showed ras mutations; ras mutations were found in choledocholithiasis (4/28), bile duct (5/21), gall bladder (3/8) and pancreatic (1/11) carcinoma, liver metastasis (3/3), ulcerative colitis (2/3), PSC (1/2), and chronic pancreatitis (1/16). Cytology was clearly positive in seven cases, suspicious in three other, inconclusive in six, and negative in the rest. The molecular analysis resulted in a sensitivity of 33% and specificity of 87%, respectively, for the diagnosis of a malignant condition. PCR for p53 and ras mutations may aid the diagnosis of primary and secondary (metastatic) hepatobiliary disease if a malignant condition of the bile ducts and the liver is suspected and cytology is inconclusive or negative. However, the incidence of p53 and ras mutations in bile seems less frequent than in other malignant conditions of the gastrointestinal tract and the pancreas and lower than in tissue, leaving a poor sensitivity and specificity. Nevertheless, the presence of a p53 and/or ras mutation per se supports a clinical suspicion of malignancy, even when the conventional cytology is negative or inconclusive.
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PMID:Low frequency of p53 and ras mutations in bile of patients with hepato-biliary disease: a prospective study in more than 100 patients. 1126 52

The purpose of this review is to evaluate our current knowledge of the embryologic etiology of pancreaticobiliary maljunction (PBM), its diagnosis, clinical aspects, and treatment, and to clarify the mechanisms of PBM involvement in carcinogenesis. Although the embryologic etiology of PBM still awaits clarification, an arrest of the migration of the common duct of the biliary and pancreatic ducts inwards in the duodenal wall has hitherto been speculated to result in a long common channel in PBM. However, we propose the hypothesis that the etiology of PBM is caused by a disturbance in the embryonic connections (misarrangement) of the choledochopancreatic duct system in the extremely early embryo. That is, PBM is an anomaly caused by a misarrangement whereby the terminal bile duct joins with a branch of the ventral pancreatic duct system, including the main pancreatic duct. PBM is frequently associated with congenital bile duct cyst (CCBD). However, these two anomalies are thought to have different embryonic etiologies. The diagnostic criteria for PBM are the radiological and anatomical detection of the extramural location of the junction of the pancreatic and biliary ducts in the duodenal wall. However, in PBM patients with a short common duct (less than 1 cm in length), detection of the extramural location is difficult. The clinical features of PBM are intermittent abdominal pain, with or without elevation of pancreatic enzyme levels; and obstructive jaundice, with or without acute pancreatitis, while the clinical features of PBM patients with CCBD are primary bile duct stone and acute cholangitis. The optimum approach for the treatment of PBM is the prevention of the reciprocal reflux of bile and pancreatic juice in the pancreas and the bile duct system. To achieve these aims, the surgical approach is most effective, and complete biliary diversion procedures with bile duct resection (for example, choledochoduodenostomy or choledochojejunostomy of the Roux-en-Y type) are most useful. Recently, it has been recognized that the development of biliary ductal carcinoma is associated with PBM. That is, the development of gallbladder cancer occurs frequently in PBM patients without CCBD, and bile duct cancer originating from the cyst wall also occurs in PBM patients with CCBD. It is speculated that the pathogenesis of the bile duct or gallbladder cancer in PBM patients involves the reciprocal reflux of bile and pancreatic juice. Investigations of epithelial cell proliferation in the gallbladder of PBM patients, and of K- ras mutations and p53 suppressor gene mutations, loss of heterozygosity of p53, and overexpression of the p53 gene product in gallbladder cancer and noncancerous lesions in PBM patients have been carried out in various laboratories around the world. The results support the conclusion that PBM is a high risk factor for the development of bile duct carcinoma.
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PMID:Recent advances in pancreaticobiliary maljunction. 1202 97

We report a case of distal common bile duct adenoma presenting with acute cholangitis. A 47-year-old woman suffered from right upper abdominal pain with persistent fever for 4 days. Abdominal ultrasonography showed mild dilatation of common bile duct and bilateral intrahepatic ducts. Endoscopic retrograde cholangiopancreatography disclosed a fixed filling defect in the distal common bile duct. Transpapillary biopsy and brush cytology was performed after sphincterotomy. The biopsy specimen showed adenomatous change with dysplasia and negative stain for p53. No significant regional lymph node enlargement was found on computed tomography. The patient subsequently received exploratory laparotomy and sphincteroplasty with excision of the distal common bile duct tumor. Finally, the tumor was diagnosed as common bile duct tubular adenoma with moderate nuclear dysplasia. Postoperatively, the patient had an uneventful course and has been well at follow-up for 8 months. We encountered a rare case of common bile duct adenoma in which malignant change was hard to rule out. We propose that sphincterotomy with biopsy is crucial before operation and p53 immunohistochemical staining is valuable for determining whether or not malignant change occurs in this borderline tumor.
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PMID:Acute cholangitis secondary to a common bile duct adenoma. 1284 56

Cholangiocarcinomas are malignant tumors of the intra- or extrahepatic biliary tract. An increasing incidence of cholangiocarcinomas has been documented. This increase might be only apparent, due to the progress in investigation and changes in tumor codification. The major clinical sign of cholangiocarcinomas is obstructive jaundice, which is persistent and progressive. Biological tumor markers are nonspecific: an increased serum level of carcinoembryonic antigen is relevant when associated with an increased level of CA 19-9 or CA-125. K-ras mutation and aberrant expression of p53 are present in one third of intrahepatic cholangiocarcinomas. The firstline imaging investigation is ultrasonography, which always detects dilatation of the bile ducts, but more rarely the tumor itself. Classically, endoscopic retrograde cholangiopancreatography (ERCP), the "gold standard" investigation in case of obstructive jaundice, has been performed following ultrasonography. The actual recommendations, based on grade B and C evidences, are to start investigations with ultrasonography and to continue with noninvasive methods: MRI/MRCP or spiral CT, whenever a malignant obstructive jaundice is suspected. Invasive cholangiography (ERCP, PTC) should be reserved for tissue diagnosis or therapeutic decompression when cholangitis is present, or for stent insertion in unresectable tumors. If MRI, CT or cholangiography do not exclude resectability, hepatic arteriography and portal vein evaluation should be performed preoperatively. All patients who do not have unequivocal cholangiographic and angiographic signs of unresectability should undergo surgery, in order to benefit of a possible tumor resection. The radical surgical procedures relieve the obstruction and jaundice by resecting the tumor. The palliative (surgical or endoscopic) procedures cure the jaundice, but do not remove the tumor. Prognosis of cholangiocarcinomas is dismal, although five-year survival rates for these tumors have improved due progress in surgery and adjuvant oncological therapy.
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PMID:Cholangiocarcinoma: risk factors, diagnosis and management. 1552 94

Primary biliary cirrhosis (PBC) is histologically characterized by chronic nonsuppurative destructive cholangitis (CNSDC) and the progressive loss of intrahepatic small bile ducts. Cellular immune mechanisms involving T-cell reaction are thought to be significantly involved in the formation of CNSDC and bile duct loss. In inflamed portal tracts of PBC, CD4+ T cells of Th1 type expressing IFN-gamma or CXCR3 are aggregated and more commonly detected around injured bile ducts than Th2-type CD4+ T cells expressing IL-4 or CCR4, indicating that Th1-dominant cellular immunity plays a more-prominent role in recruitment of memory T-cell subsets in PBC and may be responsible for the progressive bile duct damage. Biliary epithelial apoptosis is demonstrated to be a major pathogenic process of bile duct loss in PBC. In CNSDC, several biliary apoptotic cells, an aberrant expression of Fas antigen (proapoptotic molecule) and decreased expression of bcl-2 and mcl-1 (antiapoptotic molecules) are found, although interlobular bile ducts express bcl-2 and mcl-2 but lack Fas. In addition, the upregulation of WAF1 and p53 related to biliary apoptosis is found in biliary epithelial cells of PBC, which may be due to cell senescence in response to genotoxic damage such as oxidative stress. Several steps and mechanisms during induction and progression of cholangitis and biliary apoptosis followed by bile duct loss are now being proposed in PBC, but future analysis of an etiopathogenesis to explain the characteristic histopathogenesis of PBC is required.
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PMID:Molecular mechanisms of cholangiopathy in primary biliary cirrhosis. 1682 Nov 41

Congenital choledochal cyst is occasionally complicated by carcinomatous transformation, mostly adenocarcinoma. Adenosquamous carcinoma arising in a congenital choledochal cyst is very rare. The author herein reports an adenosquamous carcinoma arising in congenital choledochal cyst associated with pancreatico-biliary maljunction. A 34-year-old man with congenital choledochal cyst and recurrent cholangitis had been followed up, and was admitted to hospital to undergo testing for cancer. Imaging modalities including computed tomography, magnetic resonance imaging and endoscopic retrograde cholangiography showed an elevated lesion in the choledochal cyst. Because clinical cytology of bile indicated malignant cells, pancreatico-duodenectomy, cholecystectomy, and resection of the choledochal cyst were performed. Grossly, the choledochal cyst was type I, and its size was 8 x 10 cm. Anomalous pancreatico-biliary ductal union was recognized. An elevated lesion was recognized in the choledochal cyst. Histologically, the lesion was composed of a squamous cell carcinoma element and an adenocarcinoma element; a gradual transition was recognized between the two. The squamous cell carcinoma element contained microcytic cells with mucins. On immunohistochemistry the adenocarcinoma element and microcytic cells were positive for CEA, but the squamous cell carcinoma element was negative for CEA. Both elements were positive for CA19-9. Ki-67 labeling was 53% in the adenocarcinoma element and 48% in the squamous cell carcinoma element. p53 protein was negative in both elements. At the time of writing, the patient was alive after 25 months without recurrence or metastasis. The present case is the second case of adenosquamous carcinoma arising in congenital choledochal cyst in the English-language literature.
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PMID:Adenosquamous carcinoma in a congenital choledochal cyst associated with pancreatico-biliary maljunction. 1956 12

Autoimmune pancreatitis (AIP) (also called IgG4-related sclerosing pancreatitis (IgG4-SP)) and IgG4-related sclerosing cholangitis (IgG4-SC) are frequently associated with each other. It is generally believed that association of these diseases with pancreatobiliary malignancy is, however, rare. Here, we report on the case of a patient with AIP whose biliary cytology revealed severely atypical cells. Surgically resected specimens from this patient showed typical AIP with IgG4-SC, as well as a mildly elevated lesion in the common bile duct with varying degrees of cellular atypia. In addition, the atypical cells tested positive for the mucin-core protein, MUC5AC and p53 overexpression. These findings led us to diagnose the common bile duct lesion as biliary intraepithelial neoplasia (BilIN, mainly BilIN-1/2). Recently, associations between K-ras mutations and pancreatobiliary carcinoma have been reported in patients with AIP. This case, therefore, provides important new insight into the potential association of AIP and/or IgG4-SC with malignancy (or precursor lesions) of the pancreatobiliary system.
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PMID:Autoimmune pancreatitis and biliary intraepithelial neoplasia of the common bile duct: a case with diagnostically challenging but pathogenetically significant association. 2179 Aug 63

Ursodeoxycholic acid (UDCA) is a steroid bile acid approved for primary biliary cirrhosis (PBC). UDCA is reported to have "hepato-protective properties". Yet, UDCA has "unanticipated" toxicity, pronounced by more than double number of deaths, and eligibility for liver transplantation compared to the control group in 28 mg/kg/day in primary sclerosing cholangitis, necessitating trial halt in North America. UDCA is associated with increase in hepatocellular carcinoma in PBC especially when it fails to achieve biochemical response (10 and 15 years incidence of 9% and 20% respectively). "Unanticipated" UDCA toxicity includes hepatitis, pruritus, cholangitis, ascites, vanishing bile duct syndrome, liver cell failure, death, severe watery diarrhea, pneumonia, dysuria, immune-suppression, mutagenic effects and withdrawal syndrome upon sudden halt. UDCA inhibits DNA repair, co-enzyme A, cyclic AMP, p53, phagocytosis, and inhibits induction of nitric oxide synthatase. It is genotoxic, exerts aneugenic activity, and arrests apoptosis even after cellular phosphatidylserine externalization. UDCA toxicity is related to its interference with drug detoxification, being hydrophilic and anti-apoptotic, has a long half-life, has transcriptional mutational abilities, down-regulates cellular functions, has a very narrow difference between the recommended (13 mg/kg/day) and toxic dose (28 mg/kg/day), and it typically transforms into lithocholic acid that induces DNA strand breakage, it is uniquely co-mutagenic, and promotes cell transformation. UDCA beyond PBC is unjustified.
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PMID:Molecular mechanisms of ursodeoxycholic acid toxicity & side effects: ursodeoxycholic acid freezes regeneration & induces hibernation mode. 2294 41


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