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1.  Aberrant Hypermethylation in Primary and Sentinel Lymph Node Metastases in Pediatric Cutaneous Melanoma Patients 
The British Journal of Dermatology  2012;166(6):1319-1326.
Background
Debate on how to manage pediatric cutaneous melanoma patients continues; particularly in those with sentinel lymph node(SLN) metastases who are at higher risk of poor outcomes. Management is often based on adult algorithms, although differences in clinical outcomes between pediatric and adult patients suggests that melanoma in pediatric patients differs biologically. Yet, there are no molecular prognostic studies identifying these differences.
Objectives
We investigated the epigenetic(methylation) regulation of several tumor-related genes(TRGs) known to be significant in adult melanoma progression in histopathology(+) SLN metastases(n=17) and primary tumors(n=20) of pediatric melanoma patients to determine their clinical relevance.
Methods
AJCC Stage I-III(n=37) pediatric cutaneous melanoma patients(≤ 21 years at diagnosis) were analyzed. Gene promoter methylation of TRGs: RASSF1A, RARβ2, WIF1, and APC was evaluated.
Results
Hypermethylation of RASSF1A, RARβ2, WIF1, and APC in histopathology(+) SLNs was 29.4%(5/17), 25%(4/16), 25%(4/16), and 18.8%(3/16), respectively. When matched to adult cutaneous melanomas by Breslow thickness and ulceration, hypermethylation of all four TRGs in SLN(+) pediatric melanoma patients was equivalent to or less than in adults. With a median follow-up of 55 months, SLN(+) pediatric melanoma patients with hypermethylation of >1 TRGs versus ≤1 TRG had worse disease-free(p=0.02) and overall survival(p=0.02).
Conclusions
Differences in the methylation status of these TRGs in the SLN(+) pediatric and adult melanoma patients may account for why SLN(+) pediatric patients have different clinical outcomes. SLN biopsy should continue to be performed; within SLN(+) pediatric melanoma patients, hypermethylation of TRGs can be used to identify a subpopulation at highest risk for poor outcomes who warrant vigilant clinical follow-up.
doi:10.1111/j.1365-2133.2012.10867.x
PMCID: PMC3360819  PMID: 22293026
6.  Hepatic oxidative DNA damage is associated with increased risk for hepatocellular carcinoma in chronic hepatitis C 
British Journal of Cancer  2008;98(3):580-586.
Although the oxidative stress frequently occurs in patients with chronic hepatitis C, its role in future hepatocellular carcinoma (HCC) development is unknown. Hepatic 8-hydroxydeoxyguanosine (8-OHdG) was quantified using liver biopsy samples from 118 naïve patients who underwent liver biopsy from 1995 to 2001. The predictability of 8-OHdG for future HCC development and its relations to epidemiologic, biochemical and histological baseline characteristics were evaluated. During the follow-up period (mean was 6.7±3.3 years), HCC was identified in 36 patients (30.5%). Univariate analysis revealed that 16 variables, including 8-OHdG counts (65.2±20.2 vs 40.0±23.5 cells per 105 μm2, P<0.0001), were significantly different between patients with and without HCC. Cox proportional hazard analysis showed that the hepatic 8-OHdG (P=0.0058) and fibrosis (P=0.0181) were independent predicting factors of HCC. Remarkably, 8-OHdG levels were positively correlated with body and hepatic iron storage markers (vs ferritin, P<0.0001 vs hepatic iron score, P<0.0001). This study showed that oxidative DNA damage is associated with increased risk for HCC and hepatic 8-OHdG levels are useful as markers to identify the extreme high-risk subgroup. The strong correlation between hepatic DNA damage and iron overload suggests that the iron content may be a strong mediator of oxidative stress and iron reduction may reduce HCC incidence in patients with chronic hepatitis C.
doi:10.1038/sj.bjc.6604204
PMCID: PMC2243145  PMID: 18231107
oxidative stress; free radicals; 8-hydroxydeoxyguanosine; iron; hepatitis C virus; immunohistochemistry
7.  Cap polyposis: an inflammatory disorder or a spectrum of mucosal prolapse syndrome? 
Gut  2005;54(9):1342-1343.
doi:10.1136/gut.2005.073452
PMCID: PMC1774658  PMID: 16099801
Cap polyposis; inflammatory disorder; mucosal prolapse syndrome
8.  Type II (adult onset) citrullinaemia: clinical pictures and the therapeutic effect of liver transplantation 
OBJECTIVE—Adult onset type II citrullinemia is an inherited disorder of amino acid metabolism caused by a deficiency of liver specific argininosuccinate synthetase activity. Most of the patients with this disease were reported in Japan and therefore, this disease has not been well recognised outside this country. The detailed clinical pictures of the patients with type II citrullinaemia are reported and their outcomes after liver transplantation referred to.
METHODS—Ten patients with this disease were evaluated. Seven of them underwent liver transplants using a graft obtained from a healthy family member.
RESULTS—There were six men and four women; the age of onset of encephalopathy ranged from 17 to 51 years. The initial symptom in nine patients was sudden onset disturbance of consciousness, and one patient had long been regarded as having a chronic progressive psychotic illness. High concentrations of plasma citrulline and ammonia were commonly seen on admission. Although brain CT or MRI lacked any consistent findings, the EEG was abnormal in all patients, showing diffuse slow waves. Additionally, in five patients chronic pancreatitis preceded the onset of encephalopathy. After liver transplantation the metabolic abnormalities, including abnormal plasma concentrations of citrulline and ammonia, were immediately corrected and all neuropsychic symptoms soon disappeared, except for impaired cognitive function in one patient. Six out of these seven patients returned to their previous social lives, including work.
CONCLUSIONS—The clinical concept of adult onset type II citrullinaemia coincides well with the range of hepatic encephalopathy, and liver transplantation is a very promising therapeutic approach.


doi:10.1136/jnnp.71.5.663
PMCID: PMC1737600  PMID: 11606680
9.  Golgi Vesiculation and Lysosome Dispersion in Cells Lacking Cytoplasmic Dynein  
The Journal of Cell Biology  1998;141(1):51-59.
Cytoplasmic dynein, a minus end–directed, microtubule-based motor protein, is thought to drive the movement of membranous organelles and chromosomes. It is a massive complex that consists of multiple polypeptides. Among these polypeptides, the cytoplasmic dynein heavy chain (cDHC) constitutes the major part of this complex. To elucidate the function of cytoplasmic dynein, we have produced mice lacking cDHC by gene targeting. cDHC−/− embryos were indistinguishable from cDHC+/−or cDHC+/+ littermates at the blastocyst stage. However, no cDHC−/− embryos were found at 8.5 d postcoitum. When cDHC−/− blastocysts were cultured in vitro, they showed interesting phenotypes. First, the Golgi complex became highly vesiculated and distributed throughout the cytoplasm. Second, endosomes and lysosomes were not concentrated near the nucleus but were distributed evenly throughout the cytoplasm. Interestingly, the Golgi “fragments” and lysosomes were still found to be attached to microtubules.
These results show that cDHC is essential for the formation and positioning of the Golgi complex. Moreover, cDHC is required for cell proliferation and proper distribution of endosomes and lysosomes. However, molecules other than cDHC might mediate attachment of the Golgi complex and endosomes/lysosomes to microtubules.
PMCID: PMC2132725  PMID: 9531547
10.  Immunohistochemical detection of imidazolone, a novel advanced glycation end product, in kidneys and aortas of diabetic patients. 
Journal of Clinical Investigation  1997;99(6):1272-1280.
To investigate the role of the Maillard reaction in the pathogenesis of diabetic complications, we produced several clones of monoclonal antibodies against advanced glycation end products (AGEs) by immunizing mice with AGE-modified keyhole limpet hemocyanin, and found that one clone (AG-1) of the anti-AGE antibodies reacted specifically with imidazolones A and B, novel AGEs. Thus, the imidazolones, which are the reaction products of the guanidino group of arginine with 3-deoxyglucosone (3-DG), a reactive intermediate of the Maillard reaction, were found to be common epitopes of AGE-modified proteins produced in vitro. We determined the erythrocyte levels of imidazolone in diabetic patients using ELISA with the monoclonal anti-imidazolone antibody. The imidazolone levels in the erythrocytes of diabetic patients were found to be significantly increased as compared with those of healthy subjects. Then we studied the localization of imidazolone in the kidneys and aortas obtained from diabetic patients by immunohistochemistry using the antibody. Specific imidazolone immunoreactivity was detected in nodular lesions and expanded mesangial matrix of glomeruli, and renal arteries in an advanced stage of diabetic nephropathy, as well as in atherosclerotic lesions of aortas. This study first demonstrates the localization of imidazolone in the characteristic lesions of diabetic nephropathy and atherosclerosis. These results, taken together with a recent demonstration of increased serum 3-DG levels in diabetes, strongly suggest that imidazolone produced by 3-DG may contribute to the progression of long-term diabetic complications such as nephropathy and atherosclerosis.
PMCID: PMC507942  PMID: 9077536
11.  Roles of endothelin-1 and nitric oxide in the mechanism for ethanol-induced vasoconstriction in rat liver. 
Journal of Clinical Investigation  1993;91(4):1337-1342.
This study was designed to investigate the mechanism for ethanol-induced hepatic vasoconstriction in isolated perfused rat liver. Upon initiation of ethanol infusion into the portal vein at concentrations ranging from 25 to 100 mM, portal pressure began to increase in a concentration-dependent manner and reached maximal levels in 2-5 min (initial phase), followed by a gradual decrease over the period of ethanol infusion (escape phenomenon). Endothelin-1 antiserum significantly inhibited this ethanol-induced hepatic vasoconstriction by 45-80%. Cessation of infusion of endothelin-1 antiserum was followed by a subsequent increase in portal pressure. On the other hand, when a nitric oxide synthesis inhibitor, NG-monomethyl-L-arginine (L-NMMA), was infused into the portal vein simultaneously with ethanol, the initial phase of the response of portal pressure to ethanol was not altered and the peak values of portal pressure remained unchanged. However, after the peak increase in portal pressure, the rate of decrease was less than in the absence of L-NMMA. Thus, L-NMMA diminished the escape phenomenon and sustained the vasoconstriction. This study supports the hypothesis that two endothelium-derived vasoactive factors, endothelin-1 and nitric oxide, regulate hepatic vascular tone in the presence of ethanol.
PMCID: PMC288104  PMID: 8473486
12.  CT-assisted stereotactic brain biopsy: value of intraoperative frozen section diagnosis. 
In 100 recent CT-guided brain biopsies, the value of intraoperative histologic examination using frozen section technique was evaluated. In 87 of these cases, the biopsy was performed stereotactically. In the remaining 13 cases, a CT-guided free hand technique was used. Of the 100 biopsies performed, adequate tissue for histopathologic diagnosis was obtained in 97, and in three the biopsy was nondiagnostic. In 61 procedures the initial biopsy specimen was adequate for diagnosis. Two specimens were required in 25 and in the remaining cases it was necessary to obtain three to four biopsy specimens before a definitive diagnosis could be made. Ultimately, the histologic diagnosis was made on frozen section examination in 93 of the cases. The lesions identified were neoplastic disease in 83 cases, vascular disease in seven, infectious disease in five, demyelinating disease in one, and radiation necrosis in one. Comparison between the frozen section diagnosis and the final diagnosis based on the permanent sections revealed that they matched in 89 cases (92%). Of the 83 cases of neoplasms the exact grade of malignancy was determined by frozen section to make a final diagnosis revealed that even if the specimen volume was less than 2 mm3, the biopsy was generally successful. The disadvantages of the small sample size obtained through needle biopsy are best overcome by careful targeting and assessment of sample quality by intraoperative frozen section examinations, which will give the definitive diagnosis in most of the cases without paraffin-embedded sections.
Images
PMCID: PMC1032857  PMID: 3283295
13.  Infantile spongy degeneration of the central nervous system associated with glycogen storage and markedly fatty liver1 
The clinical, biochemical, and pathological features of an unusual expression of infantile spongy degeneration of the central white matter are presented with emphasis on neuropathological observations. The topographical distribution of the spongy change along with the observed defect in myelination were such as to suggest an arrest in development of the white matter in late foetal life. Of additional interest, in the present case, is the observed deposition of glycogen in the brain, heart, and liver along with a markedly fatty liver. Our findings are compared with those in other cases of so-called spongy degeneration, as well as with certain of the aminoacidurias and, as a consequence, we wish to suggest that the basic pathogenetic factor probably lies in a disturbance of the biochemical energy supply system rather than in a disorder of myelin lipid metabolism per se.
Images
PMCID: PMC493956  PMID: 4503011

Results 1-14 (14)