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3 The HOG Signaling System

The HOG pathway (Fig. 2.1) is one of the best understood and most intensively studied MAPK systems. First, components (Hog1 and Pbs2) were identified in a genetic screen for osmosensitive mutants deficient in glycerol accumulation (Brewster et al., 1993). In parallel, inactivation of SLN1, encoding the single yeast sensor histidine kinase, was found to be lethal (Ota and Varshavsky, 1993). This lethality, which was later shown to be because of inappropriate overactivation of the Hog1 kinase, was suppressed by knockout of any of the genes SSK1, SSK2, PBS2, and HOG1, thereby defining a linear pathway from Sln1 to Hog1. In addition, overexpression of PTC1, PTP2, or PTP3 suppressed lethality of the sln1 mutant, defining those as negative elements of the pathway (Maeda et al., 1994; Posas and Saito, 1997; Posas et al., 1996). Finally, the observation that ssk1 as well as ssk2 ssk22 mutants were osmotolerant while deletion of PBS2 and HOG1 caused osmosensitivity prompted genetic screens employing synthetic enhancement that identified SHO1, STE20, and STE11 as encoding components of the Sho1 branch (Maeda et al., 1995). Identification of the pathway components and characterization of their order of function represent textbook examples of the power of both targeted and global yeast genetics approaches. In fact, forward genetics, suppressor mutation, multicopy suppression, synthetic enhancement, epistasis analysis, and yeast two hybrid screens were all employed in this context. Particular powerful genetic tools are mutations that activate signaling constitutively. Significant knowledge has emerged on the flow of information through the pathway and hence the mechanisms of signal transduction by combining the genetic tools with in vitro and in vivo protein interaction assays, as well as in vitro protein kinase assays (de Nadal et al., 2002; Hohmann, 2002; O'Rourke et al., 2002; Saito and Tatebayashi, 2004; Tatebayashi et al., 2006).

The HOG signaling system consists of two branches that converge on the MAPKK Pbs2, the Sln1, and the Sho1. Components of the Sho1 branch also take part in pseudohyphal development and mating in S. cerevisiae (O'Rourke and Herskowitz, 1998). In many fungi, it appears that the Sho1 module is not connected to Pbs2 and hence is not involved in osmotic responses (Furukawa et al., 2005; Krantz et al., 2006). This indicates that the Sho1 module might not primarily have a role in osmosensing but rather perceives signals related to cell shape and/or cell surface conditions, in accordance with the role in activation played by the cell polarity machinery. Sho1 is specifically located at sites of cell growth and does not appear to sense turgor changes (Reiser et al., 2000, 2003).

The Sho1 branch consists almost exclusively of proteins shared with the pseudohyphal development pathway and the pheromone response pathway. Signaling specificity seems to be assured by recruitment to scaffold proteins (Sho1, Opy2, Pbs2) and requires the Hog1 kinase. In hog1 mutants, exposure to osmotic stress causes activation of the pseudohyphal and pheromone response pathways and morphological aberrations (Davenport et al., 1999; O'Rourke and Herskowitz, 1998; Rep et al., 2000). The mechanism by which Hog1 prevents such cross talk has not yet been elucidated. Mechanisms involved in activation of the Sho1 branch following osmotic shock have been described in detail using constitutively active Stell and Sho1 mutants as well as protein interaction studies (Tatebayashi et al., 2006). As indicated earlier, the sensing mechanism of osmotic changes in the Sho1 branch is not understood at this point but must be closely related to Sho1 (Tatebayashi et al., 2006). The observation that Sho1 can be replaced by engineered proteins that recruit Pbs2 to the plasma membrane suggests that Sho1 does not function as a sensor itself (Raitt et al., 2000). Sho1 shows much less variation in size than in primary sequence (Krantz and Hohmann, 2006), indicating a structural rather than an enzymatic function.

Sln1 is a sensor histidine kinase related to bacterial twocomponent systems. Such proteins are widespread in fungi and plants (Catlett et al., 2003). Sln1 has a similar domain organization as the bacterial osmosensing histidine kinase EnvZ. Both proteins have two transmembrane domains at their N terminus, which are connected by a large extracellular loop, about 300 amino acids in yeasts. It is believed that the extracellular loop and the transmembrane domains sense turgor changes (Reiser et al., 2003), perhaps by responding to movements of the plasma membrane relative to the cell wall. The homodimer is likely regulated by a structural change, which is propagated from the extracellular sensing domain to the intracellular histidine kinase domain of Sln1 (Posas et al., 1996; Reiser et al., 2003). In S. cerevisiae the Sln1 histidine kinase is a negative regulator of the downstream MAPK cascade; deletion of SLN1 or inactivation of the kinase results in lethal Hog1 overactivation (Maeda et al., 1994). When active (i.e., under ambient conditions), the Sln1 histidine kinase crossphosphorylates within a dimer (Posas et al., 1996), and the phosphate group is transferred via the Sln1 receiver and response regulator domains as well as the Ypd1 phosphotransfer protein to the Ssk1 response regulator protein. Hyperosmotic shock causes inactivation of Sln1 kinase activity and dephosphorylation of Ssk1. This scenario is well supported by mutational analysis of all steps in the phosphorelay system (Posas et al., 1996). Unphosphorylated Ssk1 mediates activation of the redundant MAPKKKs Ssk2 and Ssk22, which in turn activate Pbs2.

The activity and the relative contribution of the two pathway branches to Hog1 kinase activity are usually measured in mutants that are blocked in either branch (Maeda et al., 1995; O'Rourke and Herskowitz, 2004). Whether such experiments reflect activity of the two branches in wildtype cells is presently unknown. It appears that the Sho1 branch has a higher stress threshold for activation (Maeda et al., 1995; O'Rourke and Herskowitz, 2004) and that it is insufficient to mediate maximal pathway activation alone (unpublished data).

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Alzheimer's Disease Collaborative Group. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nature Genet. 11: 219-222, 1995. [PubMed: 7550356] [Full Text: https://dx.doi.org/10.1038/ng1095-219%5D

Ataka, S., Tomiyama, T., Takuma, H., Yamashita, T., Shimada, H., Tsutada, T., Kawabata, K., Mori, H., Miki, T. A novel presenilin-1 mutation (leu85pro) in early-onset Alzheimer disease with spastic paraparesis. Arch. Neurol. 61: 1773-1776, 2004. [PubMed: 15534188] [Full Text: https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/archneur.61.11.1773%5D

Athan, E. S., Williamson, J., Ciappa, A., Santana, V., Romas, S. N., Lee, J. H., Rondon, H., Lantigua, R. A., Medrano, M., Torres, M., Arawaka, S., Rogaeva, E., and 10 others. A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. JAMA 286: 2257-2263, 2001. [PubMed: 11710891] [Full Text: https://jamanetwork.com/journals/jama/fullarticle/vol/286/pg/2257%5D

Bai, G., Chivatakarn, O., Bonanomi, D., Lettieri, K., Franco, L., Xia, C., Stein, E., Ma, L., Lewcock, J. W., Pfaff, S. L. Presenilin-dependent receptor processing is required for axon guidance. Cell 144: 106-118, 2011. [PubMed: 21215373] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(10)01375-9%5D

Bai, X., Yan, C., Yang, G., Lu, P., Ma, D., Sun, L., Zhou, R., Scheres, S. H. W., Shi, Y. An atomic structure of human gamma-secretase. Nature 525: 212-217, 2015. [PubMed: 26280335] [Full Text: https://doi.org/10.1038/nature14892%5D

Beck, J. A., Poulter, M., Campbell, T. A., Uphill, J. B., Adamson, G., Geddes, J. F., Revesz, T., Davis, M. B., Wood, N. W., Collinge, J., Tabrizi, S. J. Somatic and germline mosaicism in sporadic early-onset Alzheimer's disease. Hum. Molec. Genet. 13: 1219-1224, 2004. [PubMed: 15115757] [Full Text: https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddh134%5D

Beglopoulos, V., Sun, X., Saura, C. A., Lemere, C. A., Kim, R. D., Shen, J. Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice. J. Biol. Chem. 279: 46907-46914, 2004. [PubMed: 15345711] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=15345711%5D

Bertoli Avella, A. M., Teruel, B. M., Llibre Rodriguez, J. J., Gomez Viera, N., Borrajero Martinez, I., Severijnen, E. A., Joosse, M., van Duijn, C. M., Heredero Baute, L., Heutink, P. A novel presenilin 1 mutation (L174M) in a large Cuban family with early onset Alzheimer disease. Neurogenetics 4: 97-104, 2002. [PubMed: 12484344]

Borchelt, D. R., Thinakaran, G., Eckman, C. B., Lee, M. K., Davenport, F., Ratovitsky, T., Prada, C.-M., Kim, G., Seekins, S., Yager, D., Slunt, H. H., Wang, R., Seeger, M., Levey, A. I., Gandy, S. E., Copeland, N. G., Jenkins, N. A., Price, D. L., Younkin, S. G, Sisodia, S. S. Familial Alzheimer's disease-linked presenilin 1 variants elevate A-beta-1-42/1-40 ratio in vitro and in vivo. Neuron 17: 1005-1013, 1996. [PubMed: 8938131] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0896-6273(00)80230-5%5D

Bruni, A. C., Bernardi, L., Colao, R., Rubino, E., Smirne, N., Frangipane, F., Terni, B., Curcio, S. A. M., Mirabelli, M., Clodomiro, A., Di Lorenzo, R., Maletta, R., and 23 others. Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation. Neurology 74: 798-806, 2010. [PubMed: 20164095] [Full Text: http://www.neurology.org/cgi/pmidlookup?view=long&pmid=20164095%5D

Buckler, A. J., Chang, D. D., Graw, S. L., Brook, J. D., Haber, D. A., Sharp, P. A., Housman, D. E. Exon amplification: a strategy to isolate mammalian genes based on RNA splicing. Proc. Nat. Acad. Sci. 88: 4005-4009, 1991. [PubMed: 1850845] [Full Text: http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1850845%5D

Cai, D., Netzer, W. J., Zhong, M., Lin, Y., Du, G., Frohman, M., Foster, D. A., Sisodia, S. S., Xu, H., Gorelick, F. S., Greengard, P. Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation. Proc. Nat. Acad. Sci. 103: 1941-1946, 2006. [PubMed: 16449386] [Full Text: http://www.pnas.org/cgi/pmidlookup?view=long&pmid=16449386%5D

Cai, D., Zhong, M., Wang, R., Netzer, W. J., Shields, D., Zheng, H., Sisodia, S. S., Foster, D. A., Gorelick, F. S., Xu, H., Greengard, P. Phospholipase D1 corrects impaired beta-APP trafficking and neurite outgrowth in familial Alzheimer's disease-linked presenilin-1 mutant neurons. Proc. Nat. Acad. Sci. 103: 1936-1940, 2006. [PubMed: 16449385] [Full Text: http://www.pnas.org/cgi/pmidlookup?view=long&pmid=16449385%5D

Chau, D.-M., Crump, C. J., Villa, J. C., Scheinberg, D. A., Li, Y.-M. Familial Alzheimer disease presenilin-1 mutations alter the active site conformation of gamma-secretase. J. Biol. Chem. 287: 17288-17296, 2012. [PubMed: 22461631] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=22461631%5D

Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., Johnson-Wood, K., Lee, M., Seubert, P., Davis, A., Kholodenko, D., Motter, R., Sherrington, R., Perry, B., Yao, H., Strome, R., Lieberburg, I., Rommens, J., Kim. S., Schenk, D., Fraser, P., St George Hyslop, P., Selkoe, D. J. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nature Med. 3: 67-72, 1997. [PubMed: 8986743]

Clark, R. F., Hutton, M., Talbot, C., Wragg, M., Lendon, C., Busfield, F., Han, S. W., Perez-Tur, J., Adams, M., Fuldner, R., Roberts, G., Karran, E., Hardy, J., Goate, A. The role of presenilin 1 in the genetics of Alzheimer's disease. Cold Spring Harbor Symp. Quant. Biol. 61: 551-558, 1996. [PubMed: 9246481] [Full Text: http://symposium.cshlp.org/cgi/pmidlookup?view=long&pmid=9246481%5D

Crook, R., Verkkoniemi, A., Perez-Tur, J., Mehta N., Baker, M., Houlden, H., Farrer, M., Hutton, M., Lincoln, S., Hardy, J., Gwinn, K., Somer, M., Paetau, A., Kalimo, H., Ylikoski, R., Poyhonen, M., Kucera, S., Haltia, M. A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nature Med. 4: 452-455, 1998. [PubMed: 9546792]

Cruts, M., Van Broeckhoven, C. Presenilin mutations in Alzheimer's disease. Hum. Mutat. 11: 183-190, 1998. [PubMed: 9521418] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1998)11:33.0.CO;2-J%5D

Cruts, M., van Duijn, C. M., Backhovens, H., Van den Broeck, M., Wehnert, A., Serneels, S., Sherrington, R., Hutton, M., Hardy, J., St George-Hyslop, P. H., Hofman, A., Van Broeckhoven, C. Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum. Molec. Genet. 7: 43-51, 1998. [PubMed: 9384602]

Davis, J. A., Naruse, S., Chen, H., Eckman, C., Younkin, S., Price, D. L., Borchelt, D. R., Sisodia, S. S., Wong, P. C. An Alzheimer's disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos. Neuron 20: 603-609, 1998. [PubMed: 9539132] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0896-6273(00)80998-8%5D

De Jonghe, C., Cruts, M., Rogaeva, E. A., Tysoe, C., Singleton, A., Vanderstichele, H., Meschino, W., Dermaut, B., Vanderhoeven, I., Backhovens, H., Vanmechelen, E., Morris, C. M., Hardy, J., Rubinsztein, D. C., St George-Hyslop, P. H., Van Broeckhoven, C. Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer's disease by increased A-beta-42 secretion. Hum. Molec. Genet. 8: 1529-1540, 1999. [PubMed: 10401002]

De Strooper, B., Annaert, W., Cupers, P., Saftig, P., Craessaerts, K., Mumm, J. S., Schroeter, E. H., Schrijvers, V., Wolfe, M. S., Ray, W. J., Goate, A., Kopan, R. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398: 518-522, 1999. [PubMed: 10206645] [Full Text: https://doi.org/10.1038/19083%5D

De Strooper, B., Saftig, P., Craessaerts, K., Vanderstichele, H., Guhde, G., Annaert, W., Von Figura, K., Van Leuven, F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391: 387-390, 1998. [PubMed: 9450754] [Full Text: https://doi.org/10.1038/34910%5D

De Strooper, B. Aph-1, Pen-2, and nicastrin with presenilin generate an active gamma-secretase complex. Neuron 38: 9-12, 2003. [PubMed: 12691659] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0896627303002058%5D

Dermaut, B., Cruts, M., Slooter, A. J. C., Van Gestel, S., De Jonghe, C., Vanderstichele, H., Vanmechelen, E., Breteler, M. M., Hofman, A., van Duijn, C. M., Van Broeckhoven, C. The glu318-to-gly substitution in presenilin 1 is not causally related to Alzheimer disease. (Letter) Am. J. Hum. Genet. 64: 290-292, 1999. [PubMed: 9915968] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61682-6%5D

Dermaut, B., Kumar-Singh, S., Engelborghs, S., Theuns, J., Rademakers, R., Saerens, J., Pickut, B. A., Peeters, K., van den Broeck, M., Vennekens, K., Claes, S., Cruts, M., Cras, P., Martin, J.-J., Van Broeckhoven, C., De Deyn, P. P. A novel presenilin 1 mutation associated with Pick's disease but not beta-amyloid plaques. Ann. Neurol. 55: 617-626, 2004. [PubMed: 15122701] [Full Text: https://doi.org/10.1002/ana.20083%5D

Devi, G., Fotiou, A., Jyrinji, D., Tycko, B., DeArmand, S., Rogaeva, E., Song, Y.-Q., Medieros, H., Liang, Y., Orlacchio, A., Williamson, J., St George-Hyslop, P., Mayeux, R. Novel presenilin 1 mutations associated with early onset of dementia in a family with both early-onset and late-onset Alzheimer disease. Arch. Neurol. 57: 1454-1457, 2000. [PubMed: 11030797] [Full Text: https://jamanetwork.com/journals/jamaneurology/fullarticle/vol/57/pg/1454%5D

Dineley, K. T., Xia, X., Bui, D., Sweatt, J. D., Zheng, H. Accelerated plaque accumulation, associative learning deficits, and up-regulation of alpha-7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins. J. Biol. Chem. 277: 22768-22780, 2002. [PubMed: 11912199] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11912199%5D

Dolzhanskaya, N., Gonzalez, M. A., Sperziani, F., Stefl, S., Messing, J., Wen, G. Y., Alexov, E., Zuchner, S., Velinov, M. A novel p.Leu(381)Phe mutation in presenilin 1 is associated with very early onset and unusually fast progressing dementia as well as lysosomal inclusions typically seen in Kufs disease. J. Alzheimers Dis. 39: 23-27, 2014. [PubMed: 24121961] [Full Text: https://content.iospress.com/openurl?genre=article&id=doi:10.3233/JAD-131340%5D

Donoviel, D. B., Hadjantonakis, A.-K., Ikeda, M., Zheng, H., St George Hyslop, P., Bernstein, A. Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev. 13: 2801-2810, 1999. [PubMed: 10557208] [Full Text: http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=10557208%5D

Duff, K., Eckman, C., Zehr, C., Yu, X, Prada, C.-M., Perez-tur, J., Hutton, M., Buee, L., Harigaya, Y., Yager, D., Morgan, D., Gordon, M. N., Holcomb, L., Refolo, L., Zenk, B., Hardy, J., Youndkin, S. Increased amyloid-beta-42(43) in brains of mice expressing mutant presenilin 1. Nature 383: 710-713, 1996. [PubMed: 8878479] [Full Text: https://doi.org/10.1038/383710a0%5D

Esselens, C., Oorschot, V., Baert, V., Raemaekers, T., Spittaels, K., Serneels, L., Zheng, H., Saftig, P., De Strooper, B., Klumperman, J., Annaert, W. Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway. J. Cell Biol. 166: 1041-1054, 2004. [PubMed: 15452145] [Full Text: http://jcb.rupress.org/cgi/pmidlookup?view=long&pmid=15452145%5D

Feng, R., Rampon, C., Tang, Y.-P., Shrom, D., Jin, J., Kyin, M., Sopher, B., Miller, M. W., Ware, C. B., Martin, G. M., Kim, S. H., Langdon, R. B., Sisodia, S. S., Tsien, J. Z. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron 32: 911-926, 2001. Note: Erratum: Neuron 33: 313 only, 2002. [PubMed: 11738035] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0896-6273(01)00523-2%5D

Fox, N. C., Kennedy, A. M., Harvey, R. J., Lantos, P. L., Roques, P. K., Collinge, J., Hardy, J., Hutton, M., Stevens, J. M., Warrington, E. K., Rossor, M. N. Clinicopathological features of familial Alzheimer's disease associated with the M139V mutation in the presenilin 1 gene: pedigree but not mutation specific age at onset provides evidence for a further genetic factor. Brain 120: 491-501, 1997. [PubMed: 9126060]

Francis, R., McGrath, G., Zhang, J., Ruddy, D. A., Sym, M., Apfeld, J., Nicoll, M., Maxwell, M., Hai, B., Ellis, M. C., Parks, A. L., Xu, W., Li, J., Gurney, M., Myers, R. L., Himes, C. S., Hiebsch, R., Ruble, C., Nye, J. S., Curtis, D. aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of beta-APP, and presenilin protein accumulation. Dev. Cell 3: 85-97, 2002. [PubMed: 12110170] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S1534-5807(02)00189-2%5D

Ganguly, A., Feldman, R. M. R., Guo, M. Ubiquilin antagonizes presenilin and promotes neurodegeneration in Drosophila. Hum. Molec. Genet. 17: 293-302, 2008. [PubMed: 17947293] [Full Text: https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddm305%5D

Georgakopoulos, A., Marambaud, P., Efthimiopoulos, S., Shioi, J., Cui, W., Li, H.-C., Schutte, M., Gordon, R., Holstein, G. R., Martinelli, G., Mehta, P., Friedrich, V. L., Jr., Robakis, N. K. Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system and is recruited to intercellular and synaptic contacts. Molec. Cell 4: 893-902, 1999. [PubMed: 10635315] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S1097-2765(00)80219-1%5D

Godbolt, A. K., Beck, J. A., Collinge, J., Garrard, P., Warren, J. D., Fox, N. C., Rossor, M. N. A presenilin 1 R278I mutation presenting with language impairment. Neurology 63: 1702-1704, 2004. [PubMed: 15534260] [Full Text: http://www.neurology.org/cgi/pmidlookup?view=long&pmid=15534260%5D

Goldman, J. S., Johnson, J. K., McElligott, K., Suchowersky, O., Miller, B. L., Van Deerlin, V. M. Presenilin 1 Glu318Gly polymorphism: interpret with caution. Arch. Neurol. 62: 1624-1627, 2005. [PubMed: 16216949] [Full Text: https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/archneur.62.10.1624%5D

Grilli, M., Diodato, E., Lozza, G., Brusa, R., Casarini, M., Uberti, D., Rozmahel, R., Westaway, D., St George-Hyslop, P., Memo, M., Ongini, E. Presenilin-1 regulates the neuronal threshold to excitotoxicity both physiologically and pathologically. Proc. Nat. Acad. Sci. 97: 12822-12827, 2000. [PubMed: 11070093] [Full Text: http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11070093%5D

Guo, M., Hong, E. J., Fernandes, J., Zipursky, S. L., Hay, B. A. A reporter for amyloid precursor protein gamma-secretase activity in Drosophila. Hum. Molec. Genet. 12: 2669-2678, 2003. [PubMed: 12944419] [Full Text: https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddg292%5D

Gustafson, L., Brun, A., Englund, E., Hagnell, O., Nilsson, K., Stensmyr, M., Ohlin, A.-K., Abrahamson, M. A 50-year perspective of a family with chromosome-14-linked Alzheimer's disease. Hum. Genet. 102: 253-257, 1998. [PubMed: 9544835]

Halliday, G. M., Song, Y. J. C., Lepar, G., Brooks, W. S., Kwok, J. B., Kersaitis, C., Gregory, G., Shepherd, C. E., Rahimi, F., Schofield, P. R., Kril, J. J. Pick bodies in a family with presenilin-1 Alzheimer's disease. Ann. Neurol. 57: 139-143, 2005. [PubMed: 15622541] [Full Text: https://doi.org/10.1002/ana.20366%5D

Handler, M., Yang, X., Shen, J. Presenilin-1 regulates neuronal differentiation during neurogenesis. Development 127: 2593-2606, 2000. [PubMed: 10821758] [Full Text: http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=10821758%5D

Hartmann, D. From Alzheimer's disease to skin tumors: the catenin connection. Proc. Nat. Acad. Sci. 98: 10522-10523, 2001. [PubMed: 11553799] [Full Text: http://www.pnas.org/cgi/pmidlookup?view=long&pmid=11553799%5D

Harvey, R. J., Ellison, D., Hardy, J., Hutton, M., Roques, P. K., Collinge, J., Fox, N. C., Rossor, M. N. Chromosome 14 familial Alzheimer's disease: the clinical and neuropathological characteristics of a family with a leucine-to-serine (L250S) substitution at codon 250 of the presenilin 1 gene. J. Neurol. Neurosurg. Psychiat. 64: 44-49, 1998. [PubMed: 9436726] [Full Text: http://jnnp.bmj.com/cgi/pmidlookup?view=long&pmid=9436726%5D

Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, T.-C., Gelpi, E., Halle, A., Korte, M., Latz, E., Golenbock, D. T. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493: 674-678, 2013. [PubMed: 23254930] [Full Text: https://doi.org/10.1038/nature11729%5D

Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., Cole, G. Correlative memory deficits, A-beta elevation, and amyloid plaques in transgenic mice. Science 274: 99-103, 1996. [PubMed: 8810256] [Full Text: http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=8810256%5D

Hull, M., Fiebich, B. L., Dykierek, P., Schmidtke, K., Nitzsche, E., Orszagh, M., Deuschl, G., Moser, E., Schumacher, M., Lucking, C., Berger, M., Bauer, J. Early-onset Alzheimer's disease due to mutations of the presenilin-1 gene on chromosome 14: a 7-year follow-up of a patient with a mutation at codon 139. Europ. Arch. Psychiat. Clin. Neurosci. 248: 123-129, 1998. [PubMed: 9728730]

Ikeuchi, T., Sisodia, S. S. The notch ligands, delta-1 and jagged-2, are substrates for presenilin-dependent 'gamma-secretase' cleavage. J. Biol. Chem. 278: 7751-7754, 2003. [PubMed: 12551931] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=12551931%5D

Ishikawa, A., Piao, Y.-S., Miyashita, A., Kuwano, R., Onodera, O., Ohtake, H., Suzuki, M., Nishizawa, M., Takahashi, H. A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease. Ann. Neurol. 57: 429-434, 2005. [PubMed: 15732120] [Full Text: https://doi.org/10.1002/ana.20393%5D

Jankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Copeland, N. G., Lee, M. K., Younkin, L. H., Wagner, S. L., Younkin, S. G., Borchelt, D. R. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum. Molec. Genet. 13: 159-170, 2004. [PubMed: 14645205] [Full Text: https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddh019%5D

Jarrett, J. T., Berger, E. P., Lansbury, P. T. The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry 32: 4693-4697, 1993. [PubMed: 8490014]

Johnson, K. A., Lopera, F., Jones, K., Becker, A., Sperling, R., Hilson, J., Londono, J., Siegert, I., Arcos, M., Moreno, S., Madrigal, L., Ossa, J., Pineda, N., Ardila, A., Roselli, M., Albert, M. S., Kosik, K. S., Rios, A. Presenilin-1-associated abnormalities in regional cerebral perfusion. Neurology 56: 1545-1551, 2001. [PubMed: 11402113] [Full Text: http://www.neurology.org/cgi/pmidlookup?view=long&pmid=11402113%5D

Jorgensen, P., Bus, C., Pallisgaard, N., Bryder, M., Jorgensen, A. L. Familial Alzheimer's disease co-segregates with a met146ile substitution in presenilin-1. Clin. Genet. 50: 281-286, 1996. [PubMed: 9007311] [Full Text: https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=1996&volume=50&issue=5&spage=281%5D

Kaether, C., Capell, A., Edbauer, D., Winkler, E., Novak, B., Steiner, H., Haass, C. The presenilin C-terminus is required for ER-retention, nicastrin-binding and gamma-secretase activity. EMBO J. 23: 4738-4748, 2004. [PubMed: 15549135] [Full Text: http://emboj.embopress.org/cgi/pmidlookup?view=long&pmid=15549135%5D

Kamal, A., Almenar-Queralt, A., LeBlanc, J. F., Roberts, E. A., Goldstein, L. S. B. Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature 414: 643-648, 2001. [PubMed: 11740561] [Full Text: https://doi.org/10.1038/414643a%5D

Kamal, A., Stokin, G. B., Yang, Z., Xia, C., Goldstein, L. S. Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron 28: 449-459, 2000. [PubMed: 11144355] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0896-6273(00)00124-0%5D

Kang, D. E., Soriano, S., Xia, X., Eberhart, C. G., De Strooper, B., Zheng, H., Koo, E. H. Presenilin couples the paired phosphorylation of beta-catenin independent of Axin: implications for beta-catenin activation in tumorigenesis. Cell 110: 751-762, 2002. [PubMed: 12297048] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0092867402009704%5D

Katayama, T., Imaizumi, K., Honda, A., Yoneda, T., Kudo, T., Takeda, M., Mori, K., Rozmahel, R., Fraser, P., St. George-Hyslop, P., Tohyama, M. Disturbed activation of endoplasmic reticulum stress transducers by familial Alzheimer's disease-linked presenilin-1 mutations. J. Biol. Chem. 276: 43446-43454, 2001. [PubMed: 11551913] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11551913%5D

Kauwe, J. S. K., Jacquart, S., Chakraverty, S., Wang, J., Mayo, K., Fagan, A. M., Holtzman, D. M., Morris, J. C., Goate, A. M. Extreme cerebrospinal fluid amyloid-beta levels identify family with late-onset Alzheimer's disease presenilin 1 mutation. Ann. Neurol. 61: 446-453, 2007. [PubMed: 17366635] [Full Text: https://doi.org/10.1002/ana.21099%5D

Kopan, R., Goate, A. A common enzyme connects Notch signaling and Alzheimer's disease. Genes Dev. 14: 2799-2806, 2000. [PubMed: 11090127] [Full Text: http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=11090127%5D

Kosik, K. S., Munoz, C., Lopez, L., Arcila, M. L., Garcia, G., Madrigal, L., Moreno, S., Rios Romenets, S., Lopez, H., Gutierrez, M., Langbaum, J. B., Cho, W., Suliman, S., Tariot, P., Ho, C., Reiman, E. M., Lopera, F. Homozygosity of the autosomal dominant Alzheimer disease presenilin 1 E280A mutation. Neurology 84: 206-208, 2015. [PubMed: 25471389] [Full Text: http://www.neurology.org/cgi/pmidlookup?view=long&pmid=25471389%5D

Kounnas, M. Z., Danks, A. M., Cheng, S., Tyree, C., Ackerman, E., Zhang, X., Ahn, K., Nguyen, P., Comer, D., Mao, L., Yu, C., Pleynet, D., and 9 others. Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease. Neuron 67: 769-780, 2010. [PubMed: 20826309] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0896-6273(10)00628-8%5D

Kovacs, D. M., Fausett, H. J., Page, K. J., Kim, T.-W., Moir, R. D., Merriam, D. E., Hollister, R. D., Hallmark, O. G., Mancini, R., Felsenstein, K. M., Hyman, B. T., Tanzi, R. E., Wasco, W. Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nature Med. 2: 224-229, 1996. [PubMed: 8574969]

Kumar-Singh, S., Theuns, J., Van Broeck, B., Pirici, D., Vennekens, K., Corsmit, E., Cruts, M., Dermaut, B., Wang, R., Van Broeckhoven, C. Mean age-of-onset of familial Alzheimer disease caused by presenilin mutations correlates with both increased A-beta-42 and decreased A-beta-40. Hum. Mutat. 27: 686-695, 2006. [PubMed: 16752394] [Full Text: https://doi.org/10.1002/humu.20336%5D

Kwok, J. B. J., Halliday, G. M., Brooks, W. S., Dolios, G., Laudon, H., Murayama, O., Hallupp, M., Badenhop, R. F., Vickers, J., Wang, R., Naslund, J., Takashima, A., Gandy, S. E., Schofield, P. R. Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with non-cored plaques and no neuritic dystrophy. J. Biol. Chem. 278: 6748-6754, 2003. [PubMed: 12493737] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=12493737%5D

Kwok, J. B. J., Taddei, K., Hallupp, M., Fisher, C., Brooks, W. S., Broe, G. A., Hardy, J., Fulham, M. J., Nicholson, G. A., Stell, R., St. George Hyslop, P. H., Fraser, P. E., and 6 others. Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport 8: 1537-1542, 1997. [PubMed: 9172170] [Full Text: http://Insights.ovid.com/pubmed?pmid=9172170%5D

Lambert, J.-C., Mann, D. M. A., Harris, J. M., Chartier-Harlin, M.-C., Cumming, A., Coates, J., Lemmon, H., StClair, D., Iwatsubo, T., Lendon, C. The -48 C/T polymorphism in the presenilin 1 promoter is associated with an increased risk of developing Alzheimer's disease and an increased A-beta load in brain. J. Med. Genet. 38: 353-355, 2001. [PubMed: 11389157] [Full Text: http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=11389157%5D

Landman, N., Jeong, S. Y., Shin, S. Y., Voronov, S. V., Serban, G., Kang, M. S., Park, M. K., Di Paolo, G., Chung, S., Kim, T.-W. Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism. Proc. Nat. Acad. Sci. 103: 19524-19529, 2006. [PubMed: 17158800] [Full Text: http://www.pnas.org/cgi/pmidlookup?view=long&pmid=17158800%5D

Laudon, H., Hansson, E. M., Melen, K., Bergman, A., Farmery, M. R., Winblad, B., Lendahl, U., von Heijne, G., Naslund, J. A nine-transmembrane domain topology for presenilin 1. J. Biol. Chem. 280: 35352-35360, 2005. [PubMed: 16046406] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=16046406%5D

Lazarov, O., Robinson, J., Tang, Y.-P., Hairston, I. S., Korade-Mirnics, Z., Lee, V. M.-Y., Hersh, L. B., Sapolsky, R. M., Mirnics, K., Sisodia, S. S. Environmental enrichment reduces A-beta levels and amyloid deposition in transgenic mice. Cell 120: 701-713, 2005. [PubMed: 15766532] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(05)00089-9%5D

Lee, S.-F., Shah, S., Li, H., Yu, C., Han, W., Yu, G. Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch. J. Biol. Chem. 277: 45013-45019, 2002. [PubMed: 12297508] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=12297508%5D

Leissring, M. A., Akbari, Y., Fanger, C. M., Cahalin, M. D., Mattson, M. P., LaFerla, F. M. Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J. Cell Biol. 149: 793-797, 2000. [PubMed: 10811821] [Full Text: http://jcb.rupress.org/cgi/pmidlookup?view=long&pmid=10811821%5D

Lemere, C. A., Lopera, F., Kosik, K. S., Lendon, C. L., Ossa, J., Saido, T. C., Yamaguchi, H., Ruiz, A., Martinez, A., Madrigal, L., Hincapie, L., Arango, J. C., Anthony, D. C., Koo, E. H., Goate, A. M., Selkoe, D. J., Arango, J. C. The E280A presenilin 1 Alzheimer mutation produces increased A-beta-42 deposition and severe cerebellar pathology. Nature Med. 2: 1146-1150, 1996. [PubMed: 8837617]

Lewis, P. A., Perez-Tur, J., Golde, T. E., Hardy, J. The presenilin 1 C92S mutation increases A-beta-42 production. Biochem. Biophys. Res. Commun. 277: 261-263, 2000. [PubMed: 11027672] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(00)93646-5%5D

Li, D., Parks, S. B., Kushner, J. D., Nauman, D., Burgess, D., Ludwigsen, S., Partain, J., Nixon, R. R., Allen, C. N., Irwin, R. P., Jakobs, P. M., Litt, M., Hershberger, R. E. Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am. J. Hum. Genet. 79: 1030-1039, 2006. [PubMed: 17186461] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63465-X%5D

Li, J., Xu, M., Zhou, H., Ma, J., Potter, H. Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation. Cell 90: 917-927, 1997. [PubMed: 9298903] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(00)80356-6%5D

Li, Y.-M., Xu, M., Lai, M.-T., Huang, Q., Castro, J. L., DiMuzio-Mower, J., Harrison, T., Lellis, C., Nadin, A., Neduvelil, J. G., Register, R. B., Sardana, M. K., Shearman, M. S., Smith, A. L., Shi, X.-P., Yin, K.-C., Shafer, J. A., Gardell, S. J. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405: 689-694, 2000. [PubMed: 10864326] [Full Text: https://doi.org/10.1038/35015085%5D

Lleo, A., Berezovska, O., Herl, L., Raju, S., Deng, A., Bacskai, B. J., Frosch, M. P., Irizarry, M., Hyman, B. T. Nonsteroidal anti-inflammatory drugs lower A-beta-42 and change presenilin 1 conformation. Nature Med. 10: 1065-1066, 2004. [PubMed: 15448688] [Full Text: https://dx.doi.org/10.1038/nm1112%5D

Lopera, F., Ardilla, A., Martinez, A., Madrigal, L., Arango-Viana, J. C., Lemere, C. A., Arango-Lasprilla, J. C., Hincapie, L., Arcos-Burgos, M., Ossa, J. E., Behrens, I. M., Norton, J., Lendon, C., Goate, A. M., Ruiz-Linares, A., Rosselli, M., Kosik, K. S. Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA 277: 793-799, 1997. [PubMed: 9052708] [Full Text: https://jamanetwork.com/journals/jama/fullarticle/vol/277/pg/793%5D

Lu, P., Bai, X., Ma, D., Xie, T., Yan, C., Sun, L., Yang, G., Zhao, Y., Zhou, R., Scheres, S. H. W., Shi, Y. Three-dimensional structure of human gamma-secretase. Nature 512: 166-170, 2014. [PubMed: 25043039] [Full Text: https://doi.org/10.1038/nature13567%5D

Marambaud, P., Wen, P. H., Dutt, A., Shioi, J., Takeshima, A., Siman, R., Robakis, N. K. A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 114: 635-645, 2003. [PubMed: 13678586] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0092867403006512%5D

Matsubara-Tsutsui, M., Yasuda, M., Yamagata, H., Nomura, T., Taguchi, K., Kohara, K., Miyoshi, K., Miki, T. Molecular evidence of presenilin 1 mutation in familial early onset dementia. Am. J. Med. Genet. 114: 292-298, 2002. [PubMed: 11920851] [Full Text: https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0148-7299&date=2002&volume=114&issue=3&spage=292%5D

Mercken, M., Takahashi, H., Honda, T., Sato, K., Murayama, M., Nakazato, Y., Noguchi, K., Imahori, K., Takashima, A. Characterization of human presenilin 1 using N-terminal specific monoclonal antibodies: evidence that Alzheimer mutations affect proteolytic processing. FEBS Lett. 389: 297-303, 1996. [PubMed: 8766720] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/0014-5793(96)00608-4%5D

Moehlmann, T., Winkler, E., Xia, X., Edbauer, D., Murrell, J., Capell, A., Kaether, C., Zheng, H., Ghetti, B., Haass, C., Steiner, H. Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on A-beta(42) production. Proc. Nat. Acad. Sci. 99: 8025-8030, 2002. [PubMed: 12048239] [Full Text: http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12048239%5D

Moonis, M., Swearer, J. M., Dayaw, M. P. E., St. George-Hyslop, P., Rogaeva, E., Kawarai, T., Pollen, D. A. Familial Alzheimer disease: decreases in CSF amyloid-beta-42 levels precede cognitive decline. Neurology 65: 323-325, 2005. [PubMed: 16043812] [Full Text: http://www.neurology.org/cgi/pmidlookup?view=long&pmid=16043812%5D

Morelli, L., Prat, M. I., Levy, E., Mangone, C. A., Castano, E. M. Presenilin 1 met146leu variant due to an A-T transversion in an early-onset familial Alzheimer's disease pedigree from Argentina. Clin. Genet. 53: 469-473, 1998. [PubMed: 9712537] [Full Text: https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9163&date=1998&volume=53&issue=6&spage=469%5D

Moretti, P., Lieberman, A. P., Wilde, E. A., Giordani, B. I., Kluin, K. J., Koeppe, R. A., Minoshima, S., Kuhl, D. E., Seltzer, W. K., Foster, N. L. Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis. Neurology 62: 1865-1868, 2004. [PubMed: 15159497] [Full Text: http://www.neurology.org/cgi/pmidlookup?view=long&pmid=15159497%5D

Morgan, D., Diamond, D. M., Gottschall, P. E., Ugen, K. E., Dickey, C., Hardy, J., Duff, K., Jantzen, P., DiCarlo, G., Wilcock, D., Connor, K., Hatcher, J., Hope, C., Gordon, M., Arendash, G. W. A-beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 408: 982-985, 2000. Note: Erratum Nature 412: 660 only, 2001. [PubMed: 11140686] [Full Text: https://doi.org/10.1038/35050116%5D

Murrell, J., Ghetti, B., Cochran, E., Macias-Islas, M. A., Medina, L., Varpetian, A., Cummings, J. L., Mendez, M. F., Kawas, C., Chui, H., Ringman, J. M. The A431E mutation in PSEN1 causing familial Alzheimer's disease originating in Jalisco state, Mexico: an additional fifteen families. (Letter) Neurogenetics 7: 277-279, 2006. [PubMed: 16897084] [Full Text: https://dx.doi.org/10.1007/s10048-006-0053-1%5D

Ni, C.-Y., Murphy, M. P., Golde, T. E., Carpenter, G. Gamma-secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294: 2179-2181, 2001. [PubMed: 11679632] [Full Text: http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=11679632%5D

Nielsen, A. L., Holm, I. E., Johansen, M., Bonven, B., Jorgensen, P., Jorgensen, A. L. A new splice variant of glial fibrillary acidic protein, GFAP-epsilon, interacts with the presenilin proteins. J. Biol. Chem. 277: 29983-29991, 2002. [PubMed: 12058025] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=12058025%5D

Nornes, S., Newman, M., Verdile, G., Wells, S., Stoick-Cooper, C. L., Tucker, B., Frederich-Sleptsova, I., Martins, R., Lardelli, M. Interference with splicing of presenilin transcripts has potent dominant negative effects on presenilin activity. Hum. Molec. Genet. 17: 402-412, 2008. [PubMed: 17981814] [Full Text: https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddm317%5D

Norton, J. B., Cairns, N. J., Chakraverty, S., Wang, J., Levitch, D., Galvin, J. E., Goate, A. Presenilin-1 G217R mutation linked to Alzheimer disease with cotton wool plaques. Neurology 73: 480-482, 2009. [PubMed: 19667325] [Full Text: http://www.neurology.org/cgi/pmidlookup?view=long&pmid=19667325%5D

O'Riordan, S., McMonagle, P., Janssen, J. C., Fox, N. C., Farrell, M., Collinge, J., Rossor, M. N., Hutchinson, M. Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities. Neurology 59: 1108-1110, 2002. [PubMed: 12370477] [Full Text: http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12370477%5D

Page, K., Hollister, R., Tanzi, R. E., Hyman, B. T. In situ hybridization analysis of presenilin 1 mRNA in Alzheimer disease and in lesioned rat brain. Proc. Nat. Acad. Sci. 93: 14020-14024, 1996. [PubMed: 8943053] [Full Text: http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8943053%5D

Parimoo, S., Patanjali, S. R., Shukla, H., Chaplin, D. D., Weissman, S. M. cDNA selection: efficient PCR approach for the selection of cDNAs encoded in large chromosomal DNA fragments. Proc. Nat. Acad. Sci. 88: 9623-9627, 1991. [PubMed: 1946377] [Full Text: http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1946377%5D

Pasternak, S. H., Bagshaw, R. D., Guiral, M., Zhang, S., Ackerley, C. A., Pak, B. J., Callahan, J. W., Mahuran, D. J. Presenilin-1, nicastrin, amyloid precursor protein, and gamma-secretase activity are co-localized in the lysosomal membrane. J. Biol. Chem. 278: 26687-26694, 2003. [PubMed: 12736250] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=12736250%5D

Pastor, P., Roe, C. M., Villegas, A., Bedoya, G., Chakraverty, S., Garcia, G., Tirado, V., Norton, J., Rios, S., Martinez, M., Kosik, K. S., Lopera, F., Goate, A. M. Apolipoprotein E-epsilon-4 modifies Alzheimer's disease onset in an E280A PS1 kindred. Ann. Neurol. 54: 163-169, 2003. [PubMed: 12891668] [Full Text: https://doi.org/10.1002/ana.10636%5D

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The potential therapeutic benefits of HESC research provide strong grounds in favor of the research. If looked at from a strictly consequentialist perspective, its almost certainly the case that the potential health benefits from the research outweigh the loss of embryos involved and whatever suffering results from that loss for persons who want to protect embryos. However, most of those who oppose the research argue that the constraints against killing innocent persons to promote social utility apply to human embryos. Thus, as long as we accept non-consequentialist constraints on killing persons, those supporting HESC research must respond to the claim that those constraints apply to human embryos.

In its most basic form, the central argument supporting the claim that it is unethical to destroy human embryos goes as follows: It is morally impermissible to intentionally kill innocent human beings; the human embryo is an innocent human being; therefore it is morally impermissible to intentionally kill the human embryo. It is worth noting that this argument, if sound, would not suffice to show that all or even most HESC research is impermissible, since most investigators engaged in HESC research do not participate in the derivation of HESCs but instead use cell lines that researchers who performed the derivation have made available. To show that researchers who use but do not derive HESCs participate in an immoral activity, one would further need to establish their complicity in the destruction of embryos. We will consider this issue in section 2. But for the moment, let us address the argument that it is unethical to destroy human embryos.

A premise of the argument against killing embryos is that human embryos are human beings. The issue of when a human being begins to exist is, however, a contested one. The standard view of those who oppose HESC research is that a human being begins to exist with the emergence of the one-cell zygote at fertilization. At this stage, human embryos are said to be whole living member[s] of the species homo sapiens [which] possess the epigenetic primordia for self-directed growth into adulthood, with their determinateness and identity fully intact (George & Gomez-Lobo 2002, 258). This view is sometimes challenged on the grounds that monozygotic twinning is possible until around days 1415 of an embryos development (Smith & Brogaard 2003). An individual who is an identical twin cannot be numerically identical to the one-cell zygote, since both twins bear the same relationship to the zygote, and numerical identity must satisfy transitivity. That is, if the zygote, A, divides into two genetically identical cell groups that give rise to identical twins B and C, B and C cannot be the same individual as A because they are not numerically identical with each other. This shows that not all persons can correctly assert that they began their life as a zygote. However, it does not follow that the zygote is not a human being, or that it has not individuated. This would follow only if one held that a condition of an entitys status as an individual human being is that it be impossible for it to cease to exist by dividing into two or more entities. But this seems implausible. Consider cases in which we imagine adult humans undergoing fission (for example, along the lines of Parfits thought experiments, where each half of the brain is implanted into a different body) (Parfit 1984). The prospect of our going out of existence through fission does not pose a threat to our current status as distinct human persons. Likewise, one might argue, the fact that a zygote may divide does not create problems for the view that the zygote is a distinct human being.

There are, however, other grounds on which some have sought to reject that the early human embryo is a human being. According to one view, the cells that comprise the early embryo are a bundle of homogeneous cells that exist in the same membrane but do not form a human organism because the cells do not function in a coordinated way to regulate and preserve a single life (Smith & Brogaard 2003, McMahan 2002). While each of the cells is alive, they only become parts of a human organism when there is substantial cell differentiation and coordination, which occurs around day-16 after fertilization. Thus, on this account, disaggregating the cells of the 5-day embryo to derive HESCs does not entail the destruction of a human being.

This account is subject to dispute on empirical grounds. That there is some intercellular coordination in the zygote is revealed by the fact that the development of the early embryo requires that some cells become part of the trophoblast while others become part of the inner cell mass. Without some coordination between the cells, there would be nothing to prevent all cells from differentiating in the same direction (Damschen, Gomez-Lobo and Schonecker 2006). The question remains, though, whether this degree of cellular interaction is sufficient to render the early human embryo a human being. Just how much intercellular coordination must exist for a group of cells to constitute a human organism cannot be resolved by scientific facts about the embryo, but is instead an open metaphysical question (McMahan 2007a).

Suppose that the 5-day human embryo is a human being. On the standard argument against HESC research, membership in the species Homo sapiens confers on the embryo a right not to be killed. This view is grounded in the assumption that human beings have the same moral status (at least with respect to possessing this right) at all stages of their lives.

Some accept that the human embryo is a human being but argue that the human embryo does not have the moral status requisite for a right to life. There is reason to think that species membership is not the property that determines a beings moral status. We have all been presented with the relevant thought experiments, courtesy of Disney, Orwell, Kafka, and countless science fiction works. The results seem clear: we regard mice, pigs, insects, aliens, and so on, as having the moral status of persons in those possible worlds in which they exhibit the psychological and cognitive traits that we normally associate with mature human beings. This suggests that it is some higher-order mental capacity (or capacities) that grounds the right to life. While there is no consensus about the capacities that are necessary for the right to life, some of the capacities that have been proposed include reasoning, self-awareness, and agency (Kuhse & Singer 1992, Tooley 1983, Warren 1973).

The main difficulty for those who appeal to such mental capacities as the touchstone for the right to life is that early human infants lack these capacities, and do so to a greater degree than many of the nonhuman animals that most deem it acceptable to kill (Marquis 2002). This presents a challenge for those who hold that the non-consequentialist constraints on killing human children and adults apply to early human infants. Some reject that these constraints apply to infants, and allow that there may be circumstances where it is permissible to sacrifice infants for the greater good (McMahan 2007b). Others argue that, while infants do not have the intrinsic properties that ground a right to life, we should nonetheless treat them as if they have a right to life in order to promote love and concern towards them, as these attitudes have good consequences for the persons they will become (Benn 1973, Strong 1997).

Some claim that we can reconcile the ascription of a right to life to all humans with the view that higher order mental capacities ground the right to life by distinguishing between two senses of mental capacities: immediately exercisable capacities and basic natural capacities. (George and Gomez-Lobo 2002, 260). According to this view, an individuals immediately exercisable capacity for higher mental functions is the actualization of natural capacities for higher mental functions that exist at the embryonic stage of life. Human embryos have a rational nature, but that nature is not fully realized until individuals are able to exercise their capacity to reason. The difference between these types of capacity is said to be a difference between degrees of development along a continuum. There is merely a quantitative difference between the mental capacities of embryos, fetuses, infants, children, and adults (as well as among infants, children, and adults). And this difference, so the argument runs, cannot justify treating some of these individuals with moral respect while denying it to others.

Given that a human embryo cannot reason at all, the claim that it has a rational nature has struck some as tantamount to asserting that it has the potential to become an individual that can engage in reasoning (Sagan & Singer 2007). But an entitys having this potential does not logically entail that it has the same status as beings that have realized some or all of their potential (Feinberg 1986). Moreover, with the advent of cloning technologies, the range of entities that we can now identify as potential persons arguably creates problems for those who place great moral weight on the embryos potential. A single somatic cell or HESC can in principle (though not yet in practice) develop into a mature human being under the right conditionsthat is, where the cells nucleus is transferred into an enucleated egg, the new egg is electrically stimulated to create an embryo, and the embryo is transferred to a womans uterus and brought to term. If the basis for protecting embryos is that they have the potential to become reasoning beings, then, some argue, we have reason to ascribe a high moral status to the trillions of cells that share this potential and to assist as many of these cells as we reasonably can to realize their potential (Sagan & Singer 2007, Savulescu 1999). Because this is a stance that we can expect nearly everyone to reject, its not clear that opponents of HESC research can effectively ground their position in the human embryos potential.

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Prof. Brian Catchpole – Our People – About – Royal …

Posted: March 14, 2019 at 10:43 am

Brians research interests centre around canine immunology and immunogenetics in relation to susceptibility to immune-mediated diseases and response to vaccination. Brian is currentlyinvestigating canine endocrine disease, more specifically working to understand the pathogenesis of diabetes mellitus, hypothyroidism and hypoadrenocorticism in dogs.

Brianis also involved in a studycharacterising canine innate immune response genes to determine whether these are involved in susceptibility to various disease syndromes (including anal furunculosis and inflammatory bowel disease). Alongside this, Brian is also examining the genetics of vaccine responses in dogs; how immune response genes can influence the response to vaccination and how immunosenescence impacts on the immune response as dogs get older.

Addisons disease (hypoadrenocorticism) is an autoimmune condition that occurs in dogs when the immune system attacks and destroys the adrenal gland, leading to a deficiency of steroid hormones.

We are interested in the genetics and autoimmune response in canine Addisons disease and have identified autoantibodies in the blood that react to proteins in the adrenal gland. We are interested in carrying out further research into this disease, to measure these autoantibodies, to see whether they can be used as part of diagnostic testing and potentially to identify dogs that have an autoimmune reaction, before they develop clinical signs. We are keen to recruit dogs that are undergoing blood sampling as part of diagnostic testing for Addisons disease or who are being monitored for their response to steroid replacement therapy.

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1: Dutton LC, Dudhia J, Catchpole B, Hodgkiss-Geere H, Werling D, Connolly DJ.Cardiosphere-derived cells suppress allogeneic lymphocytes by production of PGE2acting via the EP4 receptor. Sci Rep. 2018 Sep 6;8(1):13351. doi:10.1038/s41598-018-31569-1. PubMed PMID: 30190508; PubMed Central PMCID:PMC6127326.

2: Boag AM, Christie MR, McLaughlin KA, Syme HM, Graham P, Catchpole B. Alongitudinal study of autoantibodies against cytochrome P450 side-chain cleavageenzyme in dogs (Canis lupus familiaris) affected with hypoadrenocorticism(Addison's disease). Vet Immunol Immunopathol. 2018 Aug;202:41-45. doi:10.1016/j.vetimm.2018.05.013. Epub 2018 May 26. PubMed PMID: 30078597.

3: Soutter F, Martorell S, Solano-Gallego L, Catchpole B. Inconsistent MHC classII association in Beagles experimentally infected with Leishmania infantum. VetJ. 2018 May;235:9-15. doi: 10.1016/j.tvjl.2018.03.001. Epub 2018 Mar 7. PubMedPMID: 29704945.

4: Holder A, Jones G, Soutter F, Palmer DB, Aspinall R, Catchpole B.Polymorphisms in the canine IL7R 3'UTR are associated with thymic output inLabrador retriever dogs and influence post-transcriptional regulation by microRNA185. Dev Comp Immunol. 2018 Apr;81:244-251. doi: 10.1016/j.dci.2017.12.008. Epub2017 Dec 14. PubMed PMID: 29247721.

5: Holder A, Mirczuk SM, Fowkes RC, Palmer DB, Aspinall R, Catchpole B.Perturbation of the T cell receptor repertoire occurs with increasing age indogs. Dev Comp Immunol. 2018 Feb;79:150-157. doi: 10.1016/j.dci.2017.10.020. Epub2017 Oct 28. PubMed PMID: 29103899; PubMed Central PMCID: PMC5711257.

6: Dutton LC, Church SAV, Hodgkiss-Geere H, Catchpole B, Huggins A, Dudhia J,Connolly DJ. Cryopreservation of canine cardiosphere-derived cells: Implicationsfor clinical application. Cytometry A. 2018 Jan;93(1):115-124. doi:10.1002/cyto.a.23186. Epub 2017 Aug 22. PubMed PMID: 28834400.

7: O'Kell AL, Wasserfall C, Catchpole B, Davison LJ, Hess RS, Kushner JA,Atkinson MA. Comparative Pathogenesis of Autoimmune Diabetes in Humans, NOD Mice,and Canines: Has a Valuable Animal Model of Type 1 Diabetes Been Overlooked?Diabetes. 2017 Jun;66(6):1443-1452. doi: 10.2337/db16-1551. PubMed PMID:28533295; PubMed Central PMCID: PMC5440022.

8: Davison LJ, Holder A, Catchpole B, O'Callaghan CA. The Canine POMC Gene,Obesity in Labrador Retrievers and Susceptibility to Diabetes Mellitus. J VetIntern Med. 2017 Mar;31(2):343-348. doi: 10.1111/jvim.14636. Epub 2017 Feb 8.Erratum in: J Vet Intern Med. 2017 Jul;31(4):1362. PubMed PMID: 28176381; PubMedCentral PMCID: PMC5354034.

9: Scudder CJ, Niessen SJ, Catchpole B, Fowkes RC, Church DB, Forcada Y. Felinehypersomatotropism and acromegaly tumorigenesis: a potential role for the AIPgene. Domest Anim Endocrinol. 2017 Apr;59:134-139. doi:10.1016/j.domaniend.2016.11.005. Epub 2016 Dec 8. PubMed PMID: 28119176.

10: Peiravan A, Allenspach K, Boag AM, Soutter F, Holder A, Catchpole B, KennedyLJ, Werling D, Procoli F. Single nucleotide polymorphisms in majorhistocompatibility class II haplotypes are associated with potential resistanceto inflammatory bowel disease in German shepherd dogs. Vet Immunol Immunopathol.2016 Dec;182:101-105. doi: 10.1016/j.vetimm.2016.10.012. Epub 2016 Oct 22. PubMedPMID: 27863539.

11: Holder A, Mella S, Palmer DB, Aspinall R, Catchpole B. An Age-AssociatedDecline in Thymic Output Differs in Dog Breeds According to Their Longevity. PLoSOne. 2016 Nov 8;11(11):e0165968. doi: 10.1371/journal.pone.0165968. eCollection2016. PubMed PMID: 27824893; PubMed Central PMCID: PMC5100965.

12: Boag AM, Christie MR, McLaughlin KA, Syme HM, Graham P, Catchpole B.Autoantibodies against Cytochrome P450 Side-Chain Cleavage Enzyme in Dogs (Canislupus familiaris) Affected with Hypoadrenocorticism (Addison's Disease). PLoSOne. 2015 Nov 30;10(11):e0143458. doi: 10.1371/journal.pone.0143458. eCollection2015. PubMed PMID: 26618927; PubMed Central PMCID: PMC4664467.

13: Threlfall AJ, Boag AM, Soutter F, Glanemann B, Syme HM, Catchpole B. Analysisof DLA-DQB1 and polymorphisms in CTLA4 in Cocker spaniels affected withimmune-mediated haemolytic anaemia. Canine Genet Epidemiol. 2015 Jun 9;2:8. doi:10.1186/s40575-015-0020-y. eCollection 2015. PubMed PMID: 26401336; PubMedCentral PMCID: PMC4579385.

14: Holder AL, Kennedy LJ, Ollier WE, Catchpole B. Breed differences indevelopment of anti-insulin antibodies in diabetic dogs and investigation of therole of dog leukocyte antigen (DLA) genes. Vet Immunol Immunopathol. 2015 Oct15;167(3-4):130-8. doi: 10.1016/j.vetimm.2015.07.014. Epub 2015 Aug 2. PubMedPMID: 26272177.

15: Boag AM, Catchpole B. A review of the genetics of hypoadrenocorticism. TopCompanion Anim Med. 2014 Dec;29(4):96-101. doi: 10.1053/j.tcam.2015.01.001. Epub2015 Jan 5. Review. PubMed PMID: 25813849.

16: Killick DR, Stell AJ, Catchpole B. Immunotherapy for canine cancer--is ittime to go back to the future? J Small Anim Pract. 2015 Apr;56(4):229-41. doi:10.1111/jsap.12336. Epub 2015 Feb 23. Review. PubMed PMID: 25704119.

17: Soutter F, Kennedy LJ, Ollier WE, Solano-Gallego L, Catchpole B. Restricteddog leucocyte antigen (DLA) class II haplotypes and genotypes in Beagles. Vet J.2015 Mar;203(3):345-7. doi: 10.1016/j.tvjl.2014.12.032. Epub 2015 Jan 5. PubMedPMID: 25634081; PubMed Central PMCID: PMC4366010.

18: Adams JP, Holder AL, Catchpole B. Recombinant canine single chain insulinanalogues: insulin receptor binding capacity and ability to stimulate glucoseuptake. Vet J. 2014 Dec;202(3):436-42. doi: 10.1016/j.tvjl.2014.09.027. Epub 2014Oct 5. PubMed PMID: 25457265.

19: Short AD, Catchpole B, Boag AM, Kennedy LJ, Massey J, Rothwell S, HenthornPS, Littman MP, Husebye E, Ollier B. Putative candidate genes for caninehypoadrenocorticism (Addison's disease) in multiple dog breeds. Vet Rec. 2014 Nov1;175(17):430. doi: 10.1136/vr.102160. Epub 2014 Aug 14. PubMed PMID: 25124887.

20: Kathrani A, Lee H, White C, Catchpole B, Murphy A, German A, Werling D,Allenspach K. Association between nucleotide oligomerisation domain two (Nod2)gene polymorphisms and canine inflammatory bowel disease. Vet ImmunolImmunopathol. 2014 Sep 15;161(1-2):32-41. doi: 10.1016/j.vetimm.2014.06.003. Epub2014 Jun 26. PubMed PMID: 25017709.

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OMIM Entry – * 104311 – PRESENILIN 1; PSEN1

Posted: March 8, 2019 at 6:43 am

Cruts, M., Van Broeckhoven, C. Presenilin mutations in Alzheimer's disease. Hum. Mutat. 11: 183-190, 1998. [PubMed: 9521418] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1998)11:3<183::AID-HUMU1>3.0.CO;2-J]

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OMIM Entry - * 104311 - PRESENILIN 1; PSEN1

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Learn Zone – VetCompass – Royal Veterinary College, RVC

Posted: January 27, 2019 at 9:40 am

Veterinary Epidemiology in Practice - The VetCompass Programme

Dr. Dan O'Neill (VetCompass, RVC)

In this e-lecture, recorded as part of the VET Talks series hosted by the RVC, Dr Dan O'Neill gives an overview of practice-based veterinary epidemiological research and describes the important role of VetCompass in pushing the boundaries of this exciting new field.

Dr. Dan O'Neill (VetCompass, RVC) & Dr. Katy Evans (University of Nottingham) British Small Animal Veterinary Association Annual Congress, 2015

This talk was delivered at BSAVA Congress 2015 and addresses the importance of generating high quality evidence to inform decision-making for the improvement of canine welfare. Dr. Dan ONeill and Dr. Katy Evans discuss the importance of evidence-based veterinary advice when aiming to improve dog health at a population level, highlighting how large-scale, ongoing health surveillance projects such as VetCompass are vital in providing relevant, representative findings for practical use by clinicians.

This audio recording is shared by kind permission of the UK Kennel Club.

Dr. Dan O'Neill (VetCompass, RVC) & Aimee Llewellyn (Geneticist & Health Information Manager, UK Kennel Club)British Small Animal Veterinary Association Annual Congress, 2015

This talk was delivered as part of the first ever BSAVA lecture stream on Practical aspects of dog breeding. Dr. Dan ONeill and Aimee Llewellyn (of the Royal Veterinary College & UK Kennel Club respectively) presented information on the practical approaches veterinary practices can take to improve the advice they give to breeder clients. Bothspeakers emphasised the vital role that veterinary practitioners can play in improving dog health at a population level and highlighted the importance of large-scale, ongoing health surveillance projects such as VetCompass.

This audio recording is shared by kind permission of the UK Kennel Club.

Discussinghowwe canuse the information contained in veterinary clinical records to better understand pain-related welfare in companion animals

A short video about VetCompass with examples of evidence generated, with musical accompaniment (no speaker)

Information on the expected lifespan and causes of death in dogs in England based on a VetCompass Programme study

Find out how common epilepsy is in dogs and which breeds are affected

McGreevy, PD, Wilson BJ, Mansfield, CS.Church DB, Brodbelt DC, Dhand, N,Soares Magalhaes, RJ and O'Neill DG. (2018)Canine Genetics and Epidemiology

O'Neill DG, Baral L, Church DB, Brodbelt DC and Packer RMA (2018) Canine Genetics and Epidemiology 5:3.

O'Neill DG, Darwent EC, Church DB and Brodbelt DC (2017) Canine Genetics and Epidemiology 4:15

O'Neill DG, Yin Seah W, Church DB and Brodbelt DC (2017) Canine Genetics and Epidemiology 4:13

O'Neill DG, Coulson NR, Church DB and Brodbelt DC (2017) Canine Genetics and Epidemiology 4:7

O'Neill DG, Darwent EC, Church DB andBrodbelt DC (2016) Canine Genetics and Epidemiology, 3(1):1-12.

Summers JF, ONeill DG, Church DB, Thomson PC, McGreevy PD and Brodbelt DC. (2015) Canine Genetics and Epidemiology.

Boyd, C., Jarvis, S., McGreevy, P., Heath, S., Church, D., Brodbelt, D., and O'Neill, DG. (2018)Animal Welfare

Conroy, M., O'Neill, DG., Boag, A., Church, DB., and Brodbelt, DC. (2018). Journal of Small Animal Practice.

McDonald JL, Cleasby LR, Brodblet DC, Church DB and O'Neill DG (2017) Journal of Small Animal Practice DOI: 10.1111/jsap.12716, n/a-n/a. (Early view)

O'Neill DG, Church DB, McGreevy PD, Thomson PC, Brodbelt DC (2014) Veterinary Journal.

O'Neill DG, Church DB, McGreevy PD, Thomson PC, Brodbelt DC (2014) Journal of Feline Medicine and Surgery.

O'Neill DG, Church DB, McGreevy PD, Thomson PC, Brodbelt DC(2014) PLoS One,9(3).

O'Neill DG, Church DB, McGreevy PD, Thomson PC, Brodbelt DC(2013) The Veterinary Journal,198,638-643.

Mattin MJ, Boswood A, Church DB, Brodbelt DC (2018) Journal of Veterinary Internal Medicine

Mattin MJ, Boswood A, Church DB, McGreevy PD, O'Neill DG, Thomson PC, Brodbelt DC. (2015; Epub ahead of print) Preventive Veterinary Medicine

Mattin MJ, Boswood A, Church DB, Lpez-Alvarez J, McGreevy PD, O'Neill DG, Thomson PC, Brodbelt DC. (2015) Journal of Veterinary Internal Medicine

O'Neill DG, Gostelow R, Orme C, Church D., Niessen SJM, Verheyen K & Brodbelt DC (2016) Journal of Veterinary Internal Medicine

O'Neill DG, Scudder C, Faire JM, Church DB, McGreevy PD, Thomson PC andBrodbelt DC(2016)Journal of Small Animal Practice2016

Mattin MJ, O'Neill DG, Church DB, McGreevy PD, Thomson PC, Brodbelt DC (2014) The Veterinary Record,174(14), 349.

Stephens MJ, O'Neill DG, Church DB, McGreevy PD, Thomson PC, Brodbelt DC (2014) The Veterinary Record.

O'Neill DG, Case J, Boag AK, Church DB, McGreevy PD, Thomson PC & Brodbelt DC (2017) Journal of Small Animal Practice, DOI: 10.1111/jsap.12723, n/a-n/a

Erlen A, Potschka H, Volk HA, Sauter-Louis C, O'Neill DG, (2018) Journal of Veterinary Internal Medicine.

Kearsley-Fleet L, O'Neill DG, Volk HA, Chursh DB, Brodbelt DC (2013) The Veterinary Record;30;172

O'Neill, DG., Corah, CH., Church, DB., Brodbelt, DC., and Rutherford, L. (2018).Canine Genetics and Epidemiology

Shoop SJ,Marlow S,Church DB,English K,McGreevy PD,Stell AJ,Thomson PC,O'Neill DGandBrodbelt DC (2014) Canine Genetics and Epidemiology.

O'Neill, D.G., Lee, M.M, Brodbelt, D.C., Church, D.B. & Sanchez, R.F. (2017) Canine Genetics and Epidemiology 4:5

Anderson KL, O'Neill DG, Brodbelt DC, Church DB, Meeson RL, Sargan D, Summers JF, Zulch H & Collins LM(2018)Scientific Reports

O'Neill DG, Meeson RL, Sheridan A, Church DB andBrodbelt DC (2016) Canine Genetics and Epidemiology

Taylor-Brown FE, Meeson RL, Brodbelt DC, Church DB, McGreevy PD, Thomson PC & O'Neill DG. (2015) Veterinary Surgery

O'Neill D, Jackson C, Guy J, Church D, McGreevy P, Thomson P. & Brodbelt D.(2015) Canine Genetics and Epidemiology

Stevens K.B., O'Neill D.G., Jepson R., Holm L.P., Walker D.J., andCardwell J.M.(2018) Veterinary Record

Hall, J.L., Owen, L., Riddell, A., Church, D.B., Brodbelt, D.C., and O'Neill D.G., (2018)Journal of Small Animal Practice.

O'Neill D.G., O'Sullivan AM, Manson EA, Church DB, Boag AK, McGreevy PD and Brodbelt D.C. and (2017)VeterinaryRecordDOI:10.1136/vr.104108 DOI:10.1111/jsap.12731

O'Neill D.G., Riddell A., Church D.B., Owen L., Brodbelt D.C. and Hall J.L. (2017) Journal of Small Animal Practice DOI:10.1111/jsap.12731

O'Neill DG, Elliott J, Church DB, McGreevy PD, Thomson PC, Brodbelt DC(2013) Journal of Veterinary Internal Medicine;27(4):814-21

Buckland, E., O'Neill, D., Summers, J., Mateus, A., Church, D., Redmond, L. and Brodbelt, D. Veterinary Record (2016) doi:10.1136/vr.103830

Summers JF, Hendricks A, Brodbelt DC (2014) BMC Veterinary Research.

O'Neill DG, Hendricks A, Summers JF,Brodbelt DC(2012) J Small Anim Pract;53(4): 217-22

Muellner, P., Muellner, U., Gates, M. C., Pearce, T., Ahlstrom, C., O'Neill, D., Brodblet, D. & Cave, N. J. (2016) Frontiers in Veterinary Science, 3.

O'Neill DG, Church DB, McGreevy PD, Thomson PC, Brodbelt DC (2014) Canine Genetics and Epidemiology,1:2.

Hoffman, J.M., Creevy, K.E., Franks, A., O'Neill, D.G. and Promislow, D.E.L. (2018) Aging Cell.

Hoffman, J.M., O'Neill, D.G., Creevy, K.E., & Austad, S.N.(2018)The Journals of Gerontology: Series A, 73, 150-156.

Jin, K., Hoffman, J.M., Creevy, K.E., O'Neill, D.G. and Promislow, D.E.L. (2016) Pathobiology of Aging and Age-related Diseases6:33276

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Learn Zone - VetCompass - Royal Veterinary College, RVC

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BRAIN PLASTICITY AND BEHAVIOR – Annual Review of …

Posted: July 17, 2016 at 6:40 am

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Salivary Gland Cancer Treatment – National Cancer Institute

Posted: July 17, 2016 at 6:40 am

General Information About Salivary Gland Cancer Incidence and Mortality

Salivary gland tumors are a morphologically and clinically diverse group of neoplasms, which may present significant diagnostic and management challenges. These tumors are rare, with an overall incidence in the Western world of approximately 2.5 cases to 3.0 cases per 100,000 per year.[1] Malignant salivary gland neoplasms account for more than 0.5% of all malignancies and approximately 3% to 5% of all head and neck cancers.[1,2] Most patients with malignant salivary gland tumors are in the sixth or seventh decade of life.[3,4]

Although exposure to ionizing radiation has been implicated as a cause of salivary gland cancer, the etiology of most salivary gland cancers cannot be determined.[2,3,5,6] Occupations associated with an increased risk for salivary gland cancers include rubber products manufacturing, asbestos mining, plumbing, and some types of woodworking.[3]

Tumors of the salivary glands comprise those in the major glands (e.g., parotid, submandibular, and sublingual) and the minor glands (e.g., oral mucosa, palate, uvula, floor of mouth, posterior tongue, retromolar area and peritonsillar area, pharynx, larynx, and paranasal sinuses).[2,7] Minor salivary gland lesions are most frequently seen in the oral cavity.[2]

Of salivary gland neoplasms, more than 50% are benign, and approximately 70% to 80% of all salivary gland neoplasms originate in the parotid gland.[1,2,8] The palate is the most common site of minor salivary gland tumors. The frequency of malignant lesions varies by site. Approximately 20% to 25% of parotid tumors, 35% to 40% of submandibular tumors, 50% of palate tumors, and more than 90% of sublingual gland tumors are malignant.[1,9]

Histologically, salivary gland tumors represent the most heterogenous group of tumors of any tissue in the body.[10] Although almost 40 histologic types of epithelial tumors of the salivary glands exist, some are exceedingly rare and may be the subject of only a few case reports.[1,11] The most common benign major and minor salivary gland tumor is the pleomorphic adenoma, which comprises about 50% of all salivary gland tumors and 65% of parotid gland tumors.[1] The most common malignant major and minor salivary gland tumor is the mucoepidermoid carcinoma, which comprises about 10% of all salivary gland neoplasms and approximately 35% of malignant salivary gland neoplasms.[1,12] This neoplasm occurs most often in the parotid gland.[2,12,13] This type and other histologic types of salivary gland neoplasms are reviewed in detail in the Cellular Classification of Salivary Gland Treatment section of this summary.

Most patients with benign tumors of the major or minor salivary glands present with painless swelling of the parotid, submandibular, or the sublingual glands. Neurological signs, such as numbness or weakness caused by nerve involvement, typically indicate a malignancy.[2] Facial nerve weakness that is associated with a parotid or submandibular tumor is an ominous sign. Persistent facial pain is highly suggestive of malignancy; approximately 10% to 15% of malignant parotid neoplasms present with pain.[8,14] (Refer to the PDQ summary on Pain for more information.) The majority of parotid tumors, both benign and malignant, however, present as an asymptomatic mass in the gland.[2,8]

Early-stage low-grade malignant salivary gland tumors are usually curable by adequate surgical resection alone. The prognosis is more favorable when the tumor is in a major salivary gland; the parotid gland is most favorable, then the submandibular gland; the least favorable primary sites are the sublingual and minor salivary glands. Large bulky tumors or high-grade tumors carry a poorer prognosis and may best be treated by surgical resection combined with postoperative radiation therapy.[15] The prognosis also depends on the following:[16,17]

Overall, clinical stage, particularly tumor size, may be the crucial factor to determine the outcome of salivary gland cancer and may be more important than histologic grade.[18]

Perineural invasion can also occur, particularly in high-grade adenoid cystic carcinoma, and should be specifically identified and treated.[19] Radiation therapy may increase the chance of local control and increase the survival of patients when adequate margins cannot be achieved.[20][Level of evidence: 3iiiDii] Unresectable or recurrent tumors may respond to chemotherapy.[21-23] Fast neutron-beam radiation therapy or accelerated hyperfractionated photon-beam schedules have been shown to be effective in the treatment of inoperable, unresectable, and recurrent tumors.[24-26]

Complications of surgical treatment for parotid neoplasms include facial nerve dysfunction and Frey syndrome also known as gustatory flushing and sweating and the auriculotemporal syndrome.[8] Frey syndrome has been successfully treated with injections of botulinum toxin A.[27-29]

Note: Other PDQ summaries containing information related to salivary gland cancer include the following:

Salivary gland neoplasms are remarkable for their histologic diversity. These neoplasms include benign and malignant tumors of epithelial, mesenchymal, and lymphoid origin. Salivary gland tumors pose a particular challenge to the surgical pathologist. Differentiating benign from malignant tumors may be difficult, primarily because of the complexity of the classification and the rarity of several entities, which may exhibit a broad spectrum of morphologic diversity in individual lesions.[1] In some cases, hybrid lesions may be seen.[2] The key guiding principle to establish the malignant nature of a salivary gland tumor is the demonstration of an infiltrative margin.[1]

The following cellular classification scheme draws heavily from a scheme published by the Armed Forces Institute of Pathology (AFIP).[3] Malignant nonepithelial neoplasms are included in the scheme because these neoplasms comprise a significant proportion of salivary gland neoplasms seen in the clinical setting. For completeness, malignant secondary tumors are also included in the scheme.

Where AFIP statistics regarding the incidence, or relative frequency, of particular histopathologies are cited, some bias may exist because of the AFIP methods of case accrual as a pathology reference service. When possible, other sources are cited for incidence data. Notwithstanding the AFIP data, the incidence of a particular histopathology has been found to vary considerably depending upon the study cited. This variability in reporting may be partially caused by the rare incidence of many salivary gland neoplasms.

The clinician should be aware that several benign epithelial salivary gland neoplasms have malignant counterparts, which are shown below:[3]

Histologic grading of salivary gland carcinomas is important to determine the proper treatment approach, though it is not an independent indicator of the clinical course and must be considered in the context of the clinical stage. Clinical stage, particularly tumor size, may be the critical factor to determine the outcome of salivary gland cancer and may be more important than histologic grade.[1] For example, stage I intermediate-grade or high-grade mucoepidermoid carcinomas can be successfully treated, whereas low-grade mucoepidermoid carcinomas that present as stage III disease may have a very aggressive clinical course.[4]

Grading is used primarily for mucoepidermoid carcinomas, adenocarcinomas, not otherwise specified (NOS), adenoid cystic carcinomas, and squamous cell carcinomas.[1,3] Various other salivary gland carcinomas can also be categorized according to histologic grade as follows:[3,5-8]

Low grade

Low grade, intermediate grade, and high grade

Intermediate grade and high grade

High grade

*[Note: Some investigators consider mucoepidermoid carcinoma to be of only two grades: low grade and high grade.[5]]

Mucoepidermoid carcinoma is a malignant epithelial tumor that is composed of various proportions of mucous, epidermoid (e.g., squamous), intermediate, columnar, and clear cells and often demonstrates prominent cystic growth. It is the most common malignant neoplasm observed in the major and minor salivary glands.[1,9] Mucoepidermoid carcinoma represents 29% to 34% of malignant tumors originating in both major and minor salivary glands.[3,5,10,11] In two large retrospective series, 84% to 93% of cases originated in the parotid gland.[12,13] With regard to malignant tumors of the minor salivary glands, mucoepidermoid carcinoma shows a strong predilection for the lower lip.[3,14] In an AFIP review of civilian cases, the mean age of patients was 47 years, with an age range of 8 years to 92 years.[3] Prior exposure to ionizing radiation appears to substantially increase the risk of developing malignant neoplasms of the major salivary glands, particularly mucoepidermoid carcinoma.[3,13]

Most patients are asymptomatic and present with solitary, painless masses. Symptoms include pain, drainage from the ipsilateral ear, dysphagia, trismus, and facial paralysis.[3] (Refer to the PDQ summary on Pain for more information.)

Microscopic grading of mucoepidermoid carcinoma is important to determine the prognosis.[1,12,15] Mucoepidermoid carcinomas are graded as low grade, intermediate grade, and high grade. Grading parameters with point values include the following:

Total point scores are 0 to 4 for low grade, 5 to 6 for intermediate grade, and 7 to 14 for high grade.

In a retrospective review of 243 cases of mucoepidermoid carcinoma of the major salivary glands, a statistically significant correlation was shown between this point-based grading system and outcome for parotid tumors but not for submandibular tumors.[12] Another retrospective study that used this histologic grading system indicated that tumor grade correlated well with prognosis for mucoepidermoid carcinoma of the major salivary glands, excluding submandibular tumors, and minor salivary glands.[13] A modification of this grading system placed more emphasis on features of tumor invasion.[16] Nonetheless, though tumor grade may be useful, stage appears to be a better indicator of prognosis.[3,16]

Cytogenetically, mucoepidermoid carcinoma is characterized by a t(11;19)(q1421;p1213) translocation, which is occasionally the sole cytogenetic alteration.[17-19] This translocation creates a novel fusion product, MECT1-MAML2, which disrupts a Notch signaling pathway.[20] Notch signaling plays a key role in the normal development of many tissues and cell types, through diverse effects on cellular differentiation, survival, and/or proliferation, and may be involved in a wide variety of human neoplasms.[21]

Rarely, mucoepidermoid carcinoma may originate within the jaws. This tumor type is known as central mucoepidermoid carcinoma.[3] The mandibular to maxillary predilection is approximately 3:1.[22]

Adenoid cystic carcinoma, formerly known as cylindroma, is a slow growing but aggressive neoplasm with a remarkable capacity for recurrence.[23] Morphologically, three growth patterns have been described: cribriform, or classic pattern; tubular; and solid, or basaloid pattern. The tumors are categorized according to the predominant pattern.[3,23-25] The cribriform pattern shows epithelial cell nests that form cylindrical patterns. The lumina of these spaces contain periodic acid-Schiff (PAS)-positive mucopolysaccharide secretions. The tubular pattern reveals tubular structures that are lined by stratified cuboidal epithelium. The solid pattern shows solid groups of cuboidal cells. The cribriform pattern is the most common, and the solid pattern is the least common.[26] Solid adenoid cystic carcinoma is a high-grade lesion with reported recurrence rates of as much as 100% compared with 50% to 80% for the tubular and cribriform variants.[25]

In a review of its case files, the AFIP found adenoid cystic carcinoma to be the fifth most common malignant epithelial tumor of the salivary glands after mucoepidermoid carcinomas; adenocarcinomas, NOS; acinic cell carcinomas; and PLGA.[3] Other series, however, report adenoid cystic carcinoma to be the second most common malignant tumor with an incidence or relative frequency of approximately 20%.[1] In the AFIP data, this neoplasm constitutes approximately 7.5% of all epithelial malignancies and 4% of all benign and malignant epithelial salivary gland tumors. The peak incidence for this tumor is reported to be in the fourth through sixth decades of life.[3]

This neoplasm typically develops as a slow growing swelling in the preauricular or submandibular region. Pain and facial paralysis develop frequently during the course of the disease and are likely related to the associated high incidence of nerve invasion.[3] (Refer to the PDQ summary on Pain for more information.) Regardless of histologic grade, adenoid cystic carcinomas, with their unusually slow biologic growth, tend to have a protracted course and ultimately a poor outcome, with a 10-year survival reported to be less than 50% for all grades.[1,27] These carcinomas typically show frequent recurrences and late distant metastases.[1,28] Clinical stage may be a better prognostic indicator than histologic grade.[28,29] In a retrospective review of 92 cases, a tumor size larger than 4 cm was associated with an unfavorable clinical course in all cases.[30]

Acinic cell carcinoma, also known as acinic cell adenocarcinoma, is a malignant epithelial neoplasm in which the neoplastic cells express acinar differentiation. By conventional use, the term acinic cell carcinoma is defined by cytologic differentiation towards serous acinar cells, as opposed to mucous acinar cells, whose characteristic feature is cytoplasmic periodic acid-Schiff (PAS)-positive zymogen-type secretory granules.[3] In AFIP data of salivary gland neoplasms, acinic cell carcinoma is the third most common salivary gland epithelial neoplasm after mucoepidermoid carcinoma and adenocarcinoma, NOS.[3] In these data, acinic cell carcinoma comprised 17% of primary malignant salivary gland tumors or about 6% of all salivary gland neoplasms; more than 80% occur in the parotid gland; women were affected more than men; and the mean age was 44 years. Other studies have reported a relative frequency of acinic cell carcinoma from 0% to 19% of malignant salivary gland neoplasms.[3]

Clinically, patients typically present with a slowly enlarging mass in the parotid region. Pain is a symptom in more than 33% of patients. (Refer to the PDQ summary on Pain for more information.) For acinic cell carcinoma, staging is likely a better predictor of outcome than histologic grading.[3] In a retrospective review of 90 cases, poor prognostic features included pain or fixation; gross invasion; and microscopic features of desmoplasia, atypia, or increased mitotic activity. Neither morphologic pattern nor cell composition was a predictive feature.[31]

PLGA is a malignant epithelial tumor that is essentially limited to occurrence in minor salivary gland sites and is characterized by bland, uniform nuclear features; diverse but characteristic architecture; infiltrative growth; and perineural infiltration.[3] In a series of 426 minor salivary gland tumors, PLGA represented 11% of all tumors and 26% of those that were malignant.[32] In minor gland sites, PLGA is twice as frequent as adenoid cystic carcinoma, and among all benign and malignant salivary gland neoplasms, only pleomorphic adenoma and mucoepidermoid carcinoma are more common.[3] In the AFIP case files, more than 60% of tumors occurred in the mucosa of either the soft or hard palates, approximately 16% occurred in the buccal mucosa, and 12% occurred in the upper lip. The average age of patients is reported to be 59 years, with 70% of patients between the ages of 50 and 79 years.[3] The female to male ratio is about 2:1, a proportion greater than for malignant salivary gland tumors in general.[3,33]

PLGA typically presents as a firm, nontender swelling involving the mucosa of the hard and soft palates (i.e., it is often found at their junction), the cheek, or the upper lip. Discomfort, bleeding, telangiectasia, or ulceration of the overlying mucosa may occasionally occur.[3] This salivary gland neoplasm typically runs a moderately indolent course. In a study of 40 cases with long-term follow-up, overall survival was 80% at 25 years.[34] Because of the unpredictable behavior of the tumor, some investigators consider the qualifying term, low grade, to be misleading and instead prefer the term, polymorphous adenocarcinoma.[1]

Adenocarcinoma, NOS, is a salivary gland carcinoma that shows glandular or ductal differentiation but lacks the prominence of any of the morphologic features that characterize the other, more specific carcinoma types. The diagnosis of adenocarcinoma, NOS, is essentially one of exclusion. In an AFIP review of cases, adenocarcinoma, NOS, was second only to mucoepidermoid carcinoma in frequency among malignant salivary gland neoplasms.[3] Other series have reported an incidence of 4% to 10%.[1] In AFIP files, the mean patient age was 58 years.[3] Approximately 40% and 60% of tumors occurred in the major and minor salivary glands, respectively. Among the major salivary gland tumors, 90% occurred in the parotid gland. Adenocarcinoma, NOS is graded in a similar way to extrasalivary lesions according to the degree of differentiation.[1] Tumor grades include low grade, intermediate grade, and high-grade categories.[3]

Patients with tumors in the major salivary glands typically present with solitary, painless masses.[35] Two retrospective studies indicate that survival is better for patients with tumors of the oral cavity than for those with tumors of the parotid and submandibular glands.[35,36] These studies differ regarding the prognostic significance of tumor grade.

Basal cell adenocarcinoma, also known as basaloid salivary carcinoma, carcinoma ex monomorphic adenoma, malignant basal cell adenoma, malignant basal cell tumor, and basal cell carcinoma, is an epithelial neoplasm that is cytologically similar to basal cell adenoma but is infiltrative and has a small potential for metastasis.[3] In AFIP case files spanning almost 11 years, basal cell carcinoma comprised 1.6% of all salivary gland neoplasms and 2.9% of salivary gland malignancies.[3] Nearly 90% of tumors occurred in the parotid gland.[3,37] The average age of patients is reported to be 60 years.[3]

Similar to most salivary gland neoplasms, swelling is typically the only sign or symptom experienced.[37] A sudden increase in size may occur in a few patients.[38] Basal cell carcinomas are low-grade carcinomas that are infiltrative, locally destructive, and tend to recur. The carcinomas occasionally metastasize. In a retrospective series that included 29 patients, there were recurrences in 7 patients and metastases in 3 patients.[37] In another retrospective review that included 72 patients, 37% of the patients experienced local recurrences.[38] The overall prognosis for patients with this tumor is good.[37,38]

Clear cell carcinoma, also known as clear cell adenocarcinoma, is a very rare malignant epithelial neoplasm composed of a monomorphous population of cells that have optically clear cytoplasm with standard hematoxylin and eosin stains and lack features of other specific neoplasms. Because of inconsistencies in the methods of reporting salivary gland neoplasms, meaningful incidence rates for this tumor are difficult to derive from the literature.[3] Most cases involve the minor salivary glands.[1,3,39-41] In the AFIP case files, the mean age of patients is approximately 58 years.[3]

In most patients, swelling is the only symptom. Clear cell adenocarcinoma is a low-grade neoplasm. As of 1996, the AFIP reported that no patient is known to have died as a result of this tumor.[3]

Cystadenocarcinoma, also known as malignant papillary cystadenoma, mucus-producing adenopapillary, or nonepidermoid, carcinoma; low-grade papillary adenocarcinoma of the palate; and papillary adenocarcinoma, is a rare malignant epithelial tumor characterized histologically by prominent cystic and, frequently, papillary growth but lacking features that characterize cystic variants of several more common salivary gland neoplasms. Cystadenocarcinoma is the malignant counterpart of cystadenoma.[3]

In a review that included 57 patients, the AFIP found that men and women are affected equally; the average patient age was approximately 59 years; and approximately 65% of the tumors occurred in the major salivary glands, and primarily in the parotid.[3] Most patients present with a slowly growing asymptomatic mass. Clinically, this neoplasm is rarely associated with pain or facial paralysis. Cystadenocarcinoma is considered to be a low-grade neoplasm.[3]

Sebaceous adenocarcinoma is a rare malignant epithelial tumor composed of islands and sheets of cells that have morphologically atypical nuclei, an infiltrative growth pattern, and focal sebaceous differentiation. This is a very rare tumor, as few cases have been reported in the literature.[3] Almost all cases occur in the parotid gland.[3] The average age of patients is reported to be 69 years.[42]

An equal number of patients present with a painless, slow-growing, asymptomatic swelling or pain. A few experience facial paralysis.[3] Most sebaceous adenocarcinomas are probably intermediate-grade malignancies. Tumor recurs in about 33% of cases.[43,44]

Sebaceous lymphadenocarcinoma is an extremely rare malignant tumor that represents carcinomatous transformation of sebaceous lymphadenoma. The carcinoma element may be sebaceous adenocarcinoma or some other specific or nonspecific form of salivary gland cancer.[3] Only three cases have been reported in the literature.[43,45] The three cases occurred in or around the parotid gland. All patients were in their seventh decade of life. Two of the three patients were asymptomatic. One had tenderness on palpation. Case reports suggest that this is a low-grade malignancy with a good prognosis.[44,45]

Oncocytic carcinoma, also known as oncocytic adenocarcinoma, is a rare, predominantly oncocytic neoplasm whose malignant nature is reflected both by its abnormal morphologic features and infiltrative growth. Oncocytic carcinoma represents less than 1% of almost 3,100 salivary gland tumors accessioned to the AFIP files during a 10-year period.[3] Most cases occur in the parotid gland. The average age of patients in the AFIP series was 63 years.[3]

Approximately 33% of the patients usually develop parotid masses that cause pain or paralysis.[46] Oncocytic carcinoma is a high-grade carcinoma. Tumors smaller than 2 cm have a better prognosis than larger tumors.[6]

Salivary duct carcinoma, also known as salivary duct adenocarcinoma, is a rare, typically high-grade malignant epithelial neoplasm composed of structures that resemble expanded salivary gland ducts. A low-grade variant exists.[47] Incidence rates vary depending upon the study cited.[3] In the AFIP files, salivary duct carcinomas represent only 0.2% of all epithelial salivary gland neoplasms. More than 85% of cases involve the parotid gland and approximately 75% of patients are men. The peak incidence is reported to be in the seventh and eighth decades of life.[3]

Clinically, parotid swelling is the most common sign. Facial nerve dysfunction or paralysis occur in more than 25% of patients and may be the initial manifestation.[3] The high-grade variant of this neoplasm is one of the most aggressive types of salivary gland carcinoma and is typified by local invasion, lymphatic and hematogenous spread, and poor prognosis.[3,7] In a retrospective review of 104 cases, 33% of patients developed local recurrence, and 46% of patients developed distant metastasis.[48]

Mucinous adenocarcinoma is a rare malignant neoplasm characterized by large amounts of extracellular epithelial mucin that contains cords, nests, and solitary epithelial cells. The incidence is unknown. Limited data indicate that most, if not all, occur in the major salivary glands with the submandibular gland as the predominant site.[3,49] These tumors may be associated with dull pain and tenderness.[3,49] This neoplasm may be considered to be low grade.[3]

The classification of malignant mixed tumors, includes three distinct clinicopathologic entities: carcinoma ex pleomorphic adenoma, carcinosarcoma, and metastasizing mixed tumor. Carcinoma ex pleomorphic adenoma constitutes the vast majority of cases, whereas carcinosarcoma, a true malignant mixed tumor, and metastasizing mixed tumor are extremely rare.[3]

Carcinoma ex pleomorphic adenoma, also known as carcinoma ex mixed tumor, is a carcinoma that shows histologic evidence of arising from or in a benign pleomorphic adenoma.[50] Diagnosis requires the identification of benign tumor in the tissue sample.[51] The incidence or relative frequency of this tumor varies considerably depending on the study cited.[1] A review of material at the AFIP showed carcinoma ex pleomorphic adenoma to comprise 8.8% of all mixed tumors and 4.6% of all malignant salivary gland tumors, ranking it as the sixth most common malignant salivary gland tumor after mucoepidermoid carcinoma; adenocarcinoma, NOS; acinic cell carcinoma; polymorphous low-grade adenocarcinoma; and adenoid cystic carcinoma.[3] The neoplasm occurs primarily in the major salivary glands.[52]

The most common clinical presentation is a painless mass.[3] Approximately 33% of patients may experience facial paralysis.[53] Depending on the series cited, survival times vary significantly: 25% to 65% at 5 years, 24% to 50% at 10 years, 10% to 35% at 15 years, and 0% to 38% at 20 years.[3] In addition to tumor stage, histologic grade and degree of invasion are important parameters to determine prognosis.[54]

Carcinosarcoma, also known as true malignant mixed tumor, is a rare malignant salivary gland neoplasm that contains both carcinoma and sarcoma components. Either or both components are expressed in metastatic foci. Some carcinosarcomas develop de novo while others develop in association with benign mixed tumor. This neoplasm is rare; only eight cases exist in the AFIP case files.[3] At one facility, only 11 cases were recorded over a 32-year period.[8] The majority of tumors occur in the major salivary glands.

Swelling, pain, nerve palsy, and ulceration have been frequent clinical findings. Carcinosarcoma is an aggressive, high-grade malignancy. In the largest series reported, which consisted of 12 cases, the average survival period was 3.6 years.[8]

Metastasizing mixed tumor is a very rare histologically benign salivary gland neoplasm that inexplicably metastasizes. Often a long interval occurs between the diagnosis of the primary tumor and the metastases. The histologic features are within the spectrum of features that typify pleomorphic adenoma.[3] The majority occur in the major salivary glands. The primary neoplasm is typically a single, well-defined mass. Recurrences, which may be multiple, have been reported to occur for as many as 26 years after excision of the primary neoplasm.[55]

Primary squamous cell carcinoma, also known as primary epidermoid carcinoma, is a malignant epithelial neoplasm of the major salivary glands that is composed of squamous (i.e., epidermoid) cells. Diagnosis requires the exclusion of primary disease located in some other head and neck site; indeed, most squamous cell carcinomas of the major salivary glands represent metastatic disease.[3] This diagnosis is not made in minor salivary glands because distinction from the more common mucosal squamous cell carcinoma is not possible.[3] Previous exposure to ionizing radiation appears to increase the risk for developing this neoplasm.[11,56,57] The median time between radiation therapy and diagnosis of the neoplasm is approximately 15.5 years.[11] The reported frequency of this tumor among all major salivary gland tumors has varied from 0.9% to 4.7%.[3,10] In AFIP major salivary gland accessions from 1985 to 1996, primary squamous cell carcinoma comprised 2.7% of all tumors; 5.4% of malignant tumors; and 2.5% and 2.8%, respectively, of all parotid and submandibular tumors.[3] The average age in the AFIP registry was 64 years.[3] This neoplasm occurs in the parotid gland almost nine times more often than in the submandibular gland.[3,57] There is a strong male predilection.[3,11,57-59] This tumor is graded in a similar way to extrasalivary lesions according to the degree of differentiation, namely, low grade, intermediate grade, and high grade.[1]

Most patients present with an asymptomatic mass in the parotid region. Other symptoms may include a painful mass and facial nerve palsy.[57] The prognosis for this neoplasm is poor. In a 30-year retrospective analysis of 50 cases of squamous cell carcinoma of the salivary glands, survival rates at 5 years and 10 years were 24% and 18%, respectively.[57]

Epithelial-myoepithelial carcinoma, also known as adenomyoepithelioma, clear cell adenoma, tubular solid adenoma, monomorphic clear cell tumor, glycogen-rich adenoma, glycogen-rich adenocarcinoma, clear cell carcinoma, and salivary duct carcinoma, is an uncommon, low-grade epithelial neoplasm composed of variable proportions of ductal and large, clear-staining, differentiated myoepithelial cells. The tumor comprises approximately 1% of all epithelial salivary gland neoplasms.[3,60] It is predominantly a tumor of the parotid gland. In the AFIP case files, the mean age of patients is about 60 years and about 60% of the patients are female.[3]

Localized swelling is commonly the only symptom, but occasionally patients experience facial weakness or pain.[61,62] Overall, epithelial-myoepithelial carcinoma is a low-grade carcinoma that recurs frequently, has a tendency to metastasize to periparotid and cervical lymph nodes, and occasionally results in distant metastasis and death.[60,62-64]

Anaplastic small cell carcinoma of the salivary glands was first described in 1972.[65] Subsequent histochemical and electron microscopic studies have supported the neuroendocrine nature of this tumor.[66,67] Microscopically, the tumor cells have oval, hyperchromatic nuclei and scant amount of cytoplasm and are organized in sheets, strands, and nests. The mitotic rate is high. Neuroendocrine carcinomas are more frequently found in the minor salivary glands and have a better survival rate compared with small cell carcinomas of the lung.[68] The undifferentiated counterpart of this neoplasm is the small cell undifferentiated carcinoma.

Undifferentiated carcinomas of salivary glands are a group of uncommon malignant epithelial neoplasms that lack the specific light-microscopic morphologic features of other types of salivary gland carcinomas. These carcinomas are histologically similar to undifferentiated carcinomas that arise in other organs and tissues. Accordingly, metastatic carcinoma is a primary concern in the differential diagnosis of these neoplasms.[3]

Small cell undifferentiated carcinoma, also known as extrapulmonary oat cell carcinoma, is a rare, primary malignant tumor that, with conventional light microscopy, is composed of undifferentiated cells and, with ultrastructural or immunohistochemical studies, does not demonstrate neuroendocrine differentiation. This is the undifferentiated counterpart of anaplastic small cell carcinoma (Refer to the anaplastic small cell carcinoma section in the Cellular Classification of Salivary Gland Cancer section of this summary for more information.)

In an AFIP review of case files, small cell carcinoma represented 1.8% of all major salivary gland malignancies; the mean age of patients was 56 years.[3] In 50% of the cases, patients present with an asymptomatic parotid mass of 3 months' or less duration.[68-70] This is a high-grade neoplasm. In a retrospective review of 12 cases, a tumor size of more than 4 cm was found to be the most important predictor of behavior. In another small retrospective series, estimated survival rates at 2 and 5 years were 70% and 46%, respectively.[68]

Large cell undifferentiated carcinoma is a tumor in which features of acinar, ductal, epidermoid, or myoepithelial differentiation are absent under light microscopy, though occasionally, poorly formed ductlike structures are found. This neoplasm accounts for approximately 1% of all epithelial salivary gland neoplasms.[3,53,71,72] Most of these tumors occur in the parotid gland.[70,72] In AFIP data, the peak incidence is in the seventh to eighth decades of life.[3]

Rapid growth of a parotid swelling is a common clinical presentation.[59] This is a high-grade neoplasm that frequently metastasizes and has a poor prognosis. Neoplasms 4 cm or larger may have a particularly poor outcome.[70,72]

Lymphoepithelial carcinoma, also known as undifferentiated carcinoma with lymphoid stroma and carcinoma ex lymphoepithelial lesion, is an undifferentiated tumor that is associated with a dense lymphoid stroma. An exceptionally high incidence of this tumor is found in the Eskimo and Inuit populations.[3,73] This neoplasm has been associated with Epstein-Barr virus infection.[74,75] Of the occurrences, 80% are in the parotid gland.[3]

In addition to the presence of a parotid or submandibular mass, pain is a frequent symptom, and facial nerve palsy occurs in as many as 20% of patients.[76] (Refer to the PDQ summary on Pain for more information.) Of the patients, more than 40% have metastases to cervical lymph nodes at initial presentation, 20% develop local recurrences or lymph node metastases, and 20% develop distant metastases within 3 years following therapy.[73,76-78]

Myoepithelioma carcinoma is a rare, malignant salivary gland neoplasm in which the tumor cells almost exclusively manifest myoepithelial differentiation. This neoplasm represents the malignant counterpart of benign myoepithelioma.[3] To date, the largest series reported involves 25 cases.[79] Approximately 66% of the tumors occur in the parotid gland.[3,74] The mean age of patients is reported to be 55 years.[79]

The majority of patients present with the primary complaint of a painless mass.[79] This is an intermediate grade to high-grade carcinoma.[3,79] Histologic grade does not appear to correlate well with clinical behavior; tumors with a low-grade histologic appearance may behave aggressively.[79]

Adenosquamous carcinoma is an extremely rare malignant neoplasm that simultaneously arises from surface mucosal epithelium and salivary gland ductal epithelium. The carcinoma shows histopathologic features of both squamous cell carcinoma and adenocarcinoma. Only a handful of reports have discussed this tumor.[3]

In addition to swelling, adenosquamous carcinoma produces visible changes in the mucosa including erythema, ulceration, and induration. Pain frequently accompanies ulceration. Limited data indicate that this is a highly aggressive neoplasm with a poor prognosis.[3]

Lymphomas and benign lymphoepithelial lesion

Lymphomas of the major salivary glands are characteristically of the non-Hodgkin type. In an AFIP review of case files, non-Hodgkin lymphoma accounted for 16.3% of all malignant tumors that occurred in the major salivary glands; disease in the parotid gland accounted for about 80% of all cases.[3]

Patients with benign lymphoepithelial lesion (e.g., Mikulicz disease), which is a manifestation of the autoimmune disease, Sjgren syndrome, are at an increased risk for development of non-Hodgkin lymphoma.[80-84] Benign lymphoepithelial lesion is clinically characterized by diffuse and bilateral enlargement of the salivary and lacrimal glands.[23] Morphologically, a salivary gland lesion is composed of prominent myoepithelial islands surrounded by a lymphocytic infiltrate. Germinal centers are often present in the lymphocytic infiltrate.[23] Immunophenotypically and genotypically, the lymphocytic infiltrate is composed of B-lymphocytes and T-lymphocytes, which are polyclonal. In some instances, the B-cell lymphocytic infiltrate can undergo clonal expansion and evolve into frank non-Hodgkin lymphoma. The vast majority of the non-Hodgkin lymphomas arising in a background of benign lymphoepithelial lesions are marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT).[81-84] MALT lymphomas of the salivary glands, like their counterparts in other anatomic sites, typically display relatively indolent clinical behavior.[3,85]

Primary non-MALT lymphomas of the salivary glands may also occur and appear to have a prognosis similar to those in patients who have histologically identical nodal lymphomas.[86,87] Unlike non-Hodgkin lymphoma, involvement of the major salivary glands by Hodgkin lymphoma is rare. Most tumors occur in the parotid gland.[3] The most common histologic types encountered are the nodular sclerosing and lymphocyte-predominant variants.[88,89]

Mesenchymal neoplasms

Mesenchymal neoplasms account for 1.9% to 5% of all neoplasms that occur within the major salivary glands.[90,91] These cellular classifications pertain to major salivary gland tumors. Because the minor salivary glands are small and embedded within fibrous connective tissue, fat, and skeletal muscle, the origin of a mesenchymal neoplasm from stroma cannot be determined.[3] The types of benign mesenchymal salivary gland neoplasms include hemangiomas, lipomas, and lymphangiomas.

Malignant mesenchymal salivary gland neoplasms include malignant schwannomas, hemangiopericytomas, malignant fibrous histiocytomas, rhabdomyosarcomas, and fibrosarcomas, among others; in the major salivary glands, these neoplasms represent approximately 0.5% of all benign and malignant salivary gland tumors and approximately 1.5% of all malignant tumors.[90,92,93] Of importance is to establish a primary salivary gland origin for these tumors by excluding the possibilities of metastasis and direct extension from other sites. In addition, the diagnosis of salivary gland carcinosarcoma should be excluded.[3] Primary salivary gland sarcomas behave like their soft tissue counterparts in which prognosis is related to sarcoma type, histologic grade, tumor size, and stage.[93,94] (Refer to the PDQ summary on Adult Soft Tissue Sarcoma Treatment for more information.) A comprehensive review of salivary gland mesenchymal neoplasms can be found elsewhere.[95]

Malignant neoplasms whose origins lie outside the salivary glands may involve the major salivary glands by:[3]

Direct invasion of nonsalivary gland tumors into the major salivary glands is principally from squamous cell and basal cell carcinomas of the overlying skin.

Approximately 80% of metastases to the major salivary glands may be from primary tumors elsewhere in the head and neck; the remaining 20% may be from infraclavicular sites.[96,97] The parotid gland is the site of 80% to 90% of the metastases, and the remainder involve the submandibular gland.[97,98] In a decade-long AFIP experience, metastatic tumors constituted approximately 10% of malignant neoplasms in the major salivary glands, exclusive of malignant lymphomas.[3] The majority of metastatic primary tumors to the major salivary glands are squamous cell carcinomas and melanomas from the head and neck that presumably reach the parotid gland via the lymphatic system; infraclavicular primary tumors, such as the lung, kidney, and breast, reach the salivary glands by a hematogenous route.[97-99] The peak incidence for metastatic tumors in the salivary glands is reported to be in the seventh decade of life.[3]

In general, tumors of the major salivary glands are staged according to size, extraparenchymal extension, lymph node involvement (in parotid tumors, whether or not the facial nerve is involved), and presence of metastases.[1-4] Tumors arising in the minor salivary glands are staged according to the anatomic site of origin (e.g., oral cavity and sinuses).

Clinical stage, particularly tumor size, may be the critical factor to determine the outcome of salivary gland cancer and may be more important than histologic grade.[5,6] Diagnostic imaging studies may be used in staging. With excellent spatial resolution and superior soft tissue contrast, magnetic resonance imaging (MRI) offers advantages over computed tomographic scanning in the detection and localization of head and neck tumors. Overall, MRI is the preferred modality for evaluation of suspected neoplasms of the salivary glands.[7]

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define salivary gland cancer.[5]

The minimum therapy for low-grade malignancies of the superficial portion of the parotid gland is a superficial parotidectomy. For all other lesions, a total parotidectomy is often indicated. The facial nerve or its branches should be resected if involved by tumor; repair can be done simultaneously. Growing evidence suggests that postoperative radiation therapy augments surgical resection, particularly for the high-grade neoplasms, when margins are close or involved, when tumors are large, or when histologic evidence of lymph node metastases is present.[1-8] Clinical trials, which have been completed in the United States and England, indicate that fast neutron-beam radiation therapy improves disease-free survival and overall survival in patients with unresectable tumors or for patients with recurrent neoplasms.[9-12] Facilities with fast neutron-beam radiation therapy are of limited availability in the United States. Accelerated hyperfractionated photon-beam radiation therapy has also resulted in high rates of long-term local regional controls.[13,14] The use of chemotherapy for malignant salivary gland tumors remains under evaluation.[15-19]

Low-grade stage I tumors of the salivary gland are curable with surgery alone.[1-3] Radiation therapy may be used for tumors for which resection involves a significant cosmetic or functional deficit or as an adjuvant to surgery when positive margins are present.[4] Neutron-beam therapy is effective in the treatment of poor-prognosis patients with malignant salivary gland tumors.[5-7]

High-grade stage I salivary gland tumors that are confined to the gland in which they arise may be cured by surgery alone, though adjuvant radiation therapy may be used, especially with the presence of positive margins.

Standard treatment options:

Treatment options under clinical evaluation:

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage I salivary gland cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Low-grade stage II tumors of the salivary gland may be cured with surgery alone.[1-3] Radiation therapy as primary treatment may be used for tumors for which resection involves a significant cosmetic or functional deficit or as an adjuvant to surgery when positive margins are present.[4]

High-grade stage II salivary gland tumors that are confined to the gland in which they arise may be cured by surgery alone, though adjuvant radiation therapy may be used, especially if positive margins are present. Primary radiation therapy may be given for tumors that are inoperable, unresectable, or recurrent. Fast neutron-beam radiation therapy has been shown to improve disease-free survival and overall survival in this clinical situation.[5-7]

Standard treatment options:

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Dr Emille Reid | Physician | Kuils River | Cape Town

Posted: July 17, 2016 at 6:40 am

Practice Details Practice Number: 0175986 Qualifications: MBChB (Stell), MMed(Int)(Stell), DipHIVMan(CMSA), BScHons(MedSc)(Epidemiology&Statistics)(Stell) Office Contact Person: Hanli, Amelia or Fatima (Practice manager) Telephone No: 021948 4776 Fax No: 021948 3350 Cell No: 083292 4212 After Hours Telephone No: 083292 4212 Email Address: emille@egreid.com Website Address: Physical Address: Suite 4H, Fourth Floor, Riverside View, Netcare Kuils River, Van Riebeeck Road, Kuils River, 7580 Social Networks Postal Address: PO Box 150, Soneike, 7583 Detailed information and specialities Emille Reid is a specialist with an interest in Infectious Diseases. He runs a busy HIV clinic (as part of his general practice) and provide evidence-based in-hospital care as part of a supportive medical team of specialists at the Netcare Kuils River Hospital. He has a particular interest in caring for the critically ill whilst in icu as well as those suffering from HIV, TB and general- and tropical infections infections. He is a keen teacher who very often give lectures at medical school and provide training to nurses, general practitioners and specialists. Contact Form Please feel free to contact the doctor or if you have any questions for the doctor please fill in the form below: Map GPS Co-Ordinates: View Larger Map

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Dr Emille Reid | Physician | Kuils River | Cape Town

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Edward A. Stadtmauer, MD profile | PennMedicine.org

Posted: July 17, 2016 at 6:40 am

International Myeloma Working Group, Member

American College of Physicians, Fellow

American Federation for Clinical Research, 1993-94 Eastern Section, Hematology/Oncology Session Chairman

American Society for Blood and Marrow Transplantation

American Society of Clinical Oncology, 1995-96 Member, ASCO Program Committee 1995-96 Member, Bone Marrow Transplantation, High Dose Chemotherapy and Cytokines Subcommittee 2004-present Member, Editorial Board Journal of Clinical Oncology

American Society of Hematology, 2001,2004,2008, 2010 Abstract Reviewer/Session Moderator, Clinical Bone Marrow Transplantation

Autologous Bone Marrow Transplant Registry (ABMTR/CIBMTR), 2000-2006 Member, ABMTR Advisory Board 2004-2006 Member, ABMTR Executive Committee 2004-2006 Chairman, ABMTR Nominating Committee 2006-2008 Member, CIBMTR Nominating Committee 2006-2008 Member, CIBMTR Advisory Committee 2008-Present Co-Chair, CIBMTR Solid Tumor Working Committee 2006-present Member, CIBMTR Clinical Trials Advisory Committee

Bone Marrow Transplant Clinical Trials Network, 2001-Principal Investigator, University of Pennsylvania 2001-2005 Chairman, Administration/Operations Committee 2001-2005 Member, Executive Committee 2001-Present Member, Steering Committee 2001-Present Member, Member, Publications Committee, Chair 2007-2011 2005-Present Member, BMT-CTN Myeloma Intergroup Working Committee, Chair 2012-Present 2006-Present, Chair, Publications Committee

Eastern Cooperative Oncology Group, 1990-Member, Bone Marrow Transplant Core Committee 1993-Co-chairman, Bone Marrow Transplant Committee 1991-Member, Leukemia Core Committee 1992-Member, Myeloma Core Committee 1998-Member, Lymphoma Core Committee

Foundation for the Accreditation of Hematopoietic Cell Therapy, 1999-Inspection Team, Member 1999-Team Leader, Clinical Program Inspector 2000-Stem Cell Collection Facility Inspector 2004-Member, Accrediation Committee

Membership in National Scientific Review Panels, 2002, Ad hoc Member, NIH Clinical Oncology Study Section 2005-present, Ad hoc Member, NHLBI Program Project Reviews 2006-present, Member, Leukemia and Lyumphoma Society, Clinical Development Program, Grant Review Subcommittee

NIAID Hematopoietic Stem Cell Transplantation Data Safety Monitoring Board (HSCT DSMB), 2005-present, Member

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