Intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic cystic neoplasm that is often invasive and metastatic, resulting in a poor prognosis. Few molecular alterations unique to IPMN are known. We performed whole-exome sequencing for a primary IPMN tissue, which uncovered somatic mutations in KCNF1, DYNC1H1, PGCP, STAB1, PTPRM, PRPF8, RNASE3, SPHKAP, MLXIPL, VPS13C, PRCC, GNAS, KRAS, RBM10, RNF43, DOCK2, and CENPF. We further analyzed GNAS mutations in archival cases of 118 IPMNs and 32 pancreatic ductal adenocarcinomas (PDAs), which revealed that 48 (40.7%) of the 118 IPMNs but none of the 32 PDAs harbored GNAS mutations. G-protein alpha-subunit encoded by GNAS and its downstream targets, phosphorylated substrates of protein kinase A, were evidently expressed in IPMN; the latter was associated with neoplastic grade. These results indicate that GNAS mutations are common and specific for IPMN, and activation of G-protein signaling appears to play a pivotal role in IPMN.
Prostaglandin D2 (PGD2), a major cyclooxygenase product in a variety of tissues and cells, readily undergoes dehydration to yield the bioactive cyclopentenone-type PGs of the J2-series, such as 15-deoxy-⌬ 12,14 -PGJ2 (15d-PGJ2). The observation that the level of 15d-PGJ2 increased in the tissue cells from patients with sporadic amyotrophic lateral sclerosis suggested that the formation of 15d-PGJ2 may be closely associated with neuronal cell death during chronic inflammatory processes. In vitro experiments using SH-SY5Y human neuroblastoma cells revealed that 15d-PGJ2 induced apoptotic cell death. An oligonucleotide microarray analysis demonstrated that, in addition to the heat shock-responsive and redox-responsive genes, the p53-responsive genes, such as gadd45, cyclin G1, and cathepsin D, were significantly up-regulated in the cells treated with 15d-PGJ2. Indeed, the 15d-PGJ2 induced accumulation and phosphorylation of p53, which was accompanied by a preferential redistribution of the p53 protein in the nuclei of the cells and by a time-dependent increase in p53 DNA binding activity, suggesting that p53 accumulated in response to the treatment with 15d-PGJ2 was functional. The 15d-PGJ2-induced accumulation of p53 resulted in the activation of a death-inducing caspase cascade mediated by Fas and the Fas ligand.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. Approximately 5-10% of ALS is familial. Superoxide dismutase 1 (SOD1) gene mutations are shown to be associated with about 20% of familial ALS (FALS) patients. The neuronal Lewy-body-like hyaline inclusion (LBHI) and astrocytic hyaline inclusion (Ast-HI) are morphological hallmarks of certain SOD1-linked FALS patients with SOD1 gene mutant and transgenic mice expressing human SOD1 with G85R mutation. From the detailed immunohistochemical analyses, the essential common protein of both inclusions is SOD1. Ultrastructurally, both inclusions consist of granule-coated fibrils 15-25 nm in diameter. Based on the immuno-electron microscopical finding that these abnormal granule-coated fibrils are positive for SOD1, the formation (or aggregation) of the abnormal fibrils containing SOD1 would be essential evidence in diseases caused by various SOD1 mutations. The granule-coated fibrils are also modified by advanced glycation end products (AGEs). The AGEs themselves are insoluble molecules with direct toxic effects on cells. AGE formation of SOD1 composing the granule-coated fibrils (probable AGE-modified mutant SOD1) may amplify their aggregation and produce a more marked toxicity.
Epidemiological studies suggest that the consumption of flavonoid-rich diets decreases the risk of cardiovascular diseases. However, the target sites of flavonoids underlying the protective mechanism in vivo are not known. Quercetin represents antioxidative/anti-inflammatory flavonoids widely distributed in the human diet. In this study, we raised a novel monoclonal antibody 14A2 targeting the quercetin-3-glucuronide (Q3GA), a major antioxidative quercetin metabolite in human plasma, and found that the activated macrophage might be a potential target of dietary flavonoids in the aorta. Immunohistochemical studies with monoclonal antibody 14A2 demonstrated that the positive staining specifically accumulates in human atherosclerotic lesions, but not in the normal aorta, and that the intense staining was primarily associated with the macrophage-derived foam cells. In vitro experiments with murine macrophage cell lines showed that the Q3GA was significantly taken up and deconjugated into the much more active aglycone, a part of which was further converted to the methylated form, in the activated macrophages. In addition, the mRNA expression of the class A scavenger receptor and CD36, which play an important role for the formation of foam cells, was suppressed by the treatment of Q3GA. These results suggest that injured/inflamed arteries with activated macrophages are the potential targets of the metabolites of dietary quercetin. Our data provide a new insight into the bioavailability of dietary flavonoids and the mechanism for the prevention of cardiovascular diseases.Flavonoids are widely distributed in plant foods and beverages and therefore are regularly ingested with the human diet. In 1936, Rusznyak and Szent-Gyoygi (1) found citrus flavonoids reduced capillary fragility and permeability in blood vessels. Thereafter, a large number of biological activities of flavonoids have been described which overall are believed to be beneficial for good health. Quercetin (3,3Ј,4Ј,5,7-pentahydroxyflavone) is a prime example of such a flavonoid and is bound to sugars in foods, mainly as -glycosides. The quercetin glycosides occur in broccoli, apples, and especially in onions, with an abundance as high as 0.25-0.5 g/kg (2). The average daily intake of the flavonoids subclasses in The Netherlands is 23 mg (calculated as aglycones) of which quercetin supplies 16 mg (3). Epidemiological evidence links diets rich in quercetin with decreased incidence of cardiovascular and neoplastic diseases (4 -9). Because oxidative stress has been implicated in the pathogenesis of these diseases, the bioavailability of quercetin and other flavonoids has been investigated in relation to their antioxidant activities in vivo. The antioxidant potential of quercetin is related to the number and position of the free hydroxyl groups in the molecule (10); therefore, the regioselectivity of conjugation of the hydroxyl groups can be expected to modulate the biological activity of quercetin. Upon ingestion with the diet, quercetin glycosides are rapidly ...
Prostaglandin D 2 (PGD 2 ), a major cyclooxygenase product in a variety of tissues, readily undergoes dehydration to yield the cyclopentenone-type PGs of the J 2 series, such as 15-deoxy-⌬ 12,14 -PGJ 2 (15d-PGJ 2 ), which have been suggested to exert anti-inflammatory effects in vivo. Meanwhile, the mechanism of these effects is not well understood and the natural site and the extent of its production in vivo remain unclear. In the present study, we raised a monoclonal antibody specific to 15d-PGJ 2 and determined its production in inflammationrelated events. The monoclonal antibody (mAb11G2) was raised against the 15d-PGJ 2 -keyhole limpet hemocyanin conjugate and was found to recognize free 15d-PGJ 2 specifically. The presence of 15d-PGJ 2 in vivo was immunohistochemically verified in the cytoplasm of most of the foamy macrophages in human atherosclerotic plaques. In addition, the immunostaining of lipopolysaccharide-stimulated RAW264.7 macrophages with mAb11G2 demonstrated an enhanced intracellular accumulation of 15d-PGJ 2 , suggesting that the PGD 2 metabolic pathway, generating the anti-inflammatory PGs, is indeed utilized in the cells during inflammation. The activation of macrophages also resulted in the extracellular production of PGD 2 , which was associated with a significant increase in the extracellular 15d-PGJ 2 levels, and the extracellular 15d-PGJ 2 production was reproduced by incubating PGD 2 in a cell-free medium and in phosphate-buffered saline. Moreover, using a chiral high performance liquid chromatography method for separation of PGD 2 metabolites, we established a novel metabolic pathway, in which PGD 2 is converted to 15d-PGJ 2 via an albumin-independent mechanism.The prostaglandins (PGs) 1 are a family of structurally related molecules that are produced by cells in response to a variety of extrinsic stimuli and regulate cellular growth, differentiation, and homeostasis (1, 2). PGs are derived from fatty acids, primarily arachidonate, which are released from membrane phospholipids by the action of phospholipases. Arachidonate is first converted to an unstable endoperoxide intermediate by cyclooxygenases and subsequently converted to one of several related products, including PGD 2 , PGE 2 , PGF 2␣ , prostacyclin (PGI 2 ), and thromboxane A 2 , through the action of specific PG synthetases. PGD 2 , among them, is a major cyclooxygenase (COX) product in a variety of tissues and cells and has marked effects on a number of biological processes, including platelet aggregation, relaxation of vascular and nonvascular smooth muscles, and nerve cell functions (3). The PGs are physiologically present in body fluids in picomolar-to-nanomolar concentrations (4); however, arachidonate metabolism is highly increased under several pathological conditions, including hyperthermia, infection, and inflammation (5), and local PG concentrations in the micromolar range have been detected at sites of acute inflammation (6). In vitro, PGD 2 spontaneously converts into the cyclopentenone PGs of the J series, s...
Acinar cell carcinoma of the pancreas is a rare tumor with a poor prognosis. Compared to pancreatic ductal adenocarcinoma, its molecular features are poorly known. We studied a total of 11 acinar cell carcinomas, including 3 by exome and 4 by target sequencing. Exome sequencing revealed 65 nonsynonymous mutations and 22 indels with a mutation rate of 3.4 mutations/Mb per tumor, on average. By accounting for not only somatic but also germline mutations with loss of the wild-type allele, we identified recurrent mutations of BRCA2 and FAT genes. BRCA2 showed somatic or germline premature termination mutations, with loss of the wild-type allele in 3 of 7 tumors. FAT1, FAT3, and FAT4 showed somatic or germline missense mutations in 4 of 7 tumors. The germline FAT mutations were with loss of the wild-type allele. Loss of BRCA2 expression was observed in 5 of 11 tumors. One patient with a BRCA2-mutated tumor experienced complete remission of liver metastasis following cisplatinum chemotherapy. In conclusion, acinar cell carcinomas show a distinct mutation pattern and often harbor somatic or germline mutations of BRCA2 and FAT genes. This result may warrant assessment of BRCA2 abrogation in patients with the carcinoma to determine their sensitivity to chemotherapy.
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