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1. Genetic and functional analyses of CTBP2 in anorexia nervosa and body weight regulation

Author

Giuranna, Johanna, Zheng, Yiran, Brandt, Matthäus, Jall, Sigrid, Mukherjee, Amrita, Shankhwar, Soni, Renner, Simone, Kurapati, Nirup Kumar, May, Caroline, Peters, Triinu, Herpertz-Dahlmann, Beate, Seitz, Jochen, de Zwaan, Martina, Herzog, Wolfgang, Ehrlich, Stefan, Zipfel, Stephan, Giel, Katrin, Egberts, Karin, Burghardt, Roland, Föcker, Manuel, Marcus, Katrin, Keyvani, Kathy, Müller, Timo D., Schmitz, Frank, Rajcsanyi, Luisa Sophie, and Hinney, Anke

Published
2024
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5. A novel mutation of the calcium sensing receptor gene is associated with chronic pancreatitis in a family with heterozygous SPINK1 mutations

Author

Schmitz Frank, Ansorge Nikolaus, Bulut Kerem, Einwächter Henrik, Hoffmann Peter, Felderbauer Peter, and Schmidt Wolfgang E

Subjects
chronic pancreatitis, idiopathic chronic pancreatitis, SPINK1 mutation, calcium sensing receptor, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Abstract Background The role of mutations in the serine protease inhibitor Kazal type 1 (SPINK1) gene in chronic pancreatitis is still a matter of debate. Active SPINK1 is thought to antagonize activated trypsin. Cases of SPINK1 mutations, especially N34S, have been reported in a subset of patients with idiopathic chronic pancreatitis. However, the inheritance pattern is still unknown. Some cases with N34S heterozygosity have been reported with and without evidence for CP indicating neither an autosomal recessive nor dominant trait. Therefore SPINK1 mutations have been postulated to act as a disease modifier requiring additional mutations in a more complex genetic model. Familial hypocalciuric hypercalcemia (FHH) caused by heterozygous inactivating mutations in the calcium sensing receptor (CASR) gene is considered a benign disorder with elevated plasma calcium levels. Although hypercalcemia represents a risk factor for pancreatitis, increased rates of pancreatitis in patients with FHH have not been reported thus far. Methods We studied a family with a FHH-related hypercalcemia and chronic pancreatitis. DNA samples were analysed for mutations within the cationic trypsinogen (N29I, R122H) and SPINK1 (N34S) gene using melting curve analysis. Mutations within CASR gene were identified by DNA sequencing. Results A N34S SPINK1 mutation was found in all screened family members. However, only two family members developed chronic pancreatitis. These patients also had FHH caused by a novel, sporadic mutation in the CASR gene (518T>C) leading to an amino acid exchange (leucine->proline) in the extracellular domain of the CASR protein. Conclusion Mutations in the calcium sensing receptor gene might represent a novel as yet unidentified predisposing factor which may lead to an increased susceptibility for chronic pancreatitis. Moreover, this family analysis supports the hypothesis that SPINK1 mutations act as disease modifier and suggests an even more complex genetic model in SPINK1 related chronic pancreatitis.

Published
2003
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6. Early Synapse-Specific Alterations of Photoreceptor Mitochondria in the EAE Mouse Model of Multiple Sclerosis.

Author

Ibrahim, Dalia R., Schwarz, Karin, Suiwal, Shweta, Maragkou, Sofia, and Schmitz, Frank

Subjects
SYNAPTIC vesicles, CENTRAL nervous system diseases, STEREOLOGY, MITOCHONDRIAL proteins, ELECTRON microscopy, HOMEOSTASIS
Abstract

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) linked to many neurological disabilities. The visual system is frequently impaired in MS. In previous studies, we observed early malfunctions of rod photoreceptor ribbon synapses in the EAE mouse model of MS that included alterations in synaptic vesicle cycling and disturbances of presynaptic Ca2+ homeostasis. Since these presynaptic events are highly energy-demanding, we analyzed whether synaptic mitochondria, which play a major role in synaptic energy metabolism, might be involved at that early stage. Rod photoreceptor presynaptic terminals contain a single large mitochondrion next to the synaptic ribbon. In the present study, we analyzed the expression of functionally relevant mitochondrial proteins (MIC60, ATP5B, COX1, PINK1, DRP1) by high-resolution qualitative and quantitative immunofluorescence microscopy, immunogold electron microscopy and quantitative Western blot experiments. We observed a decreased expression of many functionally relevant proteins in the synaptic mitochondria of EAE photoreceptors at an early stage, suggesting that early mitochondrial dysfunctions play an important role in the early synapse pathology. Interestingly, mitochondria in presynaptic photoreceptor terminals were strongly compromised in early EAE, whereas extra-synaptic mitochondria in photoreceptor inner segments remained unchanged, demonstrating a functional heterogeneity of photoreceptor mitochondria. [ABSTRACT FROM AUTHOR]

Published
2025
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7. Decreased Expression of the EAAT5 Glutamate Transporter at Photoreceptor Synapses in Early, Pre-Clinical Experimental Autoimmune Encephalomyelitis, a Mouse Model of Multiple Sclerosis.

Author

El Samad, Ali, Jaffal, Julia, Ibrahim, Dalia R., Schwarz, Karin, and Schmitz, Frank

Subjects
GLUTAMATE transporters, CENTRAL nervous system diseases, WESTERN immunoblotting, STEREOLOGY, GRAY matter (Nerve tissue)
Abstract

Background: Multiple sclerosis is a frequent neuroinflammatory and neurodegenerative disease of the central nervous system that includes alterations in the white and gray matter of the brain. The visual system is frequently affected in multiple sclerosis. Glutamate excitotoxicity might play a role in disease pathogenesis. Methodology: In the present study, we analyzed with qualitative and quantitative immunofluorescence microscopy and Western blot analyses whether alterations in the EAAT5 (SLC1A7) glutamate transporter could be involved in the previously observed alterations in structure and function of glutamatergic photoreceptor ribbon synapses in the EAE mouse model of MS. EAAT5 is a presynaptic glutamate transporter located near the presynaptic release sites. Results: We found that EAAT5 was strongly reduced at the photoreceptor synapses of EAE retinas in comparison to the photoreceptor synapses of the respective control retinas as early as day 9 post-immunization. The Western blot analyses demonstrated a decreased EAAT5 expression in EAE retinas. Conclusions: Our data illustrate early alterations of the EAAT5 glutamate transporter in the early pre-clinical phase of EAE/MS and suggest an involvement of EAAT5 in the previously observed early synaptic changes at photoreceptor synapses. The precise mechanisms need to be elucidated by future investigations. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Avadomide monotherapy in relapsed/refractory DLBCL: safety, efficacy, and a predictive gene classifier

Author

Carpio, Cecilia, Bouabdallah, Reda, Ysebaert, Loïc, Sancho, Juan-Manuel, Salles, Gilles, Cordoba, Raul, Pinto, Antonio, Gharibo, Mecide, Rasco, Drew, Panizo, Carlos, Lopez-Martin, Jose A., Santoro, Armando, Salar, Antonio, Damian, Silvia, Martin, Alejandro, Verhoef, Gregor, Van den Neste, Eric, Wang, Maria, Couto, Suzana, Carrancio, Soraya, Weng, Andrew, Wang, Xuehai, Schmitz, Frank, Wei, Xin, Hege, Kristen, Trotter, Matthew W.B., Risueño, Alberto, Buchholz, Tonia J., Hagner, Patrick R., Gandhi, Anita K., Pourdehnad, Michael, and Ribrag, Vincent

Published
2020
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11. Analytical Post-Embedding Immunogold–Electron Microscopy with Direct Gold-Labelled Monoclonal Primary Antibodies against RIBEYE A- and B-Domain Suggests a Refined Model of Synaptic Ribbon Assembly.

Author

Papadopoulos, Stella, Tinschert, René, Papadopoulos, Iason, Gerloff, Xenia, and Schmitz, Frank

Subjects
IMMUNOGLOBULINS, MONOCLONAL antibodies, MICROSCOPY, KNOCKOUT mice
Abstract

Synaptic ribbons are the eponymous specializations of continuously active ribbon synapses. They are primarily composed of the RIBEYE protein that consists of a unique amino-terminal A-domain and carboxy-terminal B-domain that is largely identical to the ubiquitously expressed transcriptional regulator protein CtBP2. Both RIBEYE A-domain and RIBEYE B-domain are essential for the assembly of the synaptic ribbon, as shown by previous analyses of RIBEYE knockout and knockin mice and related investigations. How exactly the synaptic ribbon is assembled from RIBEYE subunits is not yet clear. To achieve further insights into the architecture of the synaptic ribbon, we performed analytical post-embedding immunogold–electron microscopy with direct gold-labelled primary antibodies against RIBEYE A-domain and RIBEYE B-domain for improved ultrastructural resolution. With direct gold-labelled monoclonal antibodies against RIBEYE A-domain and RIBEYE B-domain, we found that both domains show a very similar localization within the synaptic ribbon of mouse photoreceptor synapses, with no obvious differential gradient between the centre and surface of the synaptic ribbon. These data favour a model of the architecture of the synaptic ribbon in which the RIBEYE A-domain and RIBEYE B-domain are located similar distances from the midline of the synaptic ribbon. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting

Author

Correale, Jorge, Caride, Alejandro, Deri, Norma H., Ballario, Carlos, Broadley, Simon, Kneebone, Chris, Barnett, Michael, Pollard, John, Hodgkinson, Suzanne, Kermode, Allan, Macdonell, Richard, King, John, Butzkueven, Helmut, Lechner-Scott, Jeannette, Saines, Noel, Slee, Mark, Plummer, Chris, Willekens, Barbara, Vanopdenbosch, Ludo, Belachew, Shibeshih, Phan-Ba, Rémy, Delvaux, Valérie, Bissay, Veronique, Debruyne, Jan, Decoo, Danny, Crols, Roeland, Symons, Anoek, Nagels, Guy, Van Pesch, Vincent, Sindic, Christian, Dubois, Benedicte, Medaer, Robert, D'Hooghe, Marie, Guillaume, Daniel, De Smet, Eric, Seeldrayers, Pierrette, Lysandropoulos, Andreas, Vokaer, Mathieu, Geens, Karine, Willems, Christina, Denayer, Pierre, Bureau, Michel, Retif, Cecile, Dupuis, Michel, Bouquiaux, Olivier, Vanderdonckt, Patrick, van Landegem, William, Caekebeke, Jo, Van Ingelghem, Erwin, Peeters, Katelijne, Gerard, Pascale, de Noordhout, Alain Maertens, Desfontaines, Philippe, Urbain, Etienne, Declercq, Inge, Van Wijmeersch, Bart, Vanroose, Erwin, Wibail, Alain, Barthomolé, Emmanuel, Ursell, Melanie, Sweet, Margaret Elizabeth, Howse, David, Jichici, Draga, Shawush, Melad, Namaka, Mike, Traboulsee, Anthony, Hashimoto, Stan, Lo, Raymond, Marchetti, Paul, Lapierre, Yves, Jacques, Francois, MacLean, Gregg, Bhan, Virender, Duquette, Pierre, Stewart, Bradley, Paulseth, John, Kremenchutzky, Marcelo, Vorobeychik, Galina, O'Connor, Paul, Grand'Maison, François, Havrdova, Eva, Meluzinová, Eva, Valis, Martin, Talab, Radomír, Stourac, Pavel, Zapletalová, Olga, Dufek, Michal, Sládková, Vladimíra, Novotna, Alena, Vancurová, Romana, Lhotaková, Libuse, Fiedler, Jiri, Vachova, Marta, Dolezil, David, Stetkarova, Ivana, Rehankova, Adela, Psenica, Petr, Ulehlova, Veronika, Feketova, Sona, Skoda, Ondrej, Färkkilä, Markus, Taneli, Sarasoja, Koivisto, Keijo, Seppä, Juha Matti, Airas, Laura, Elovaara, Irina, Hartikainen, Päivi, Pirttila, Tuula, Louchart, Pierre, Ille, Olivier, Thenint, Jean philippe, Godet, Etienne, Vioud, Marcel Maillet, Colamarino, Renato, Gugenheim, Michel, Grimaud, Jerome, Kopf, Audrey, Billy, Christophe, Huttin, Bernard, Borsotti, Jean paul, Devos, Philippe, Kendjuo, Jean bertin N, Verier, Albert, Chapuis, Stephane, Daluzeau, Nathalie, Angibaud, Gilles, Uriot, Marie-Sylvie Artaud, Ziegler, François, Sellal, François, Moulignier, Antoine, Lavenu, Isabelle, Ismail, Samir, Devy, Richard, Suceveanu, Manuel, Wagner, Marc, Marcel, Sebastien, Derouiche, Faycal, Mostoufizadehghalamfarsa, Sohrab, Delalande, Sophie, Ruggieri, Irene, Van Nieuwenhuyse, Catherine Bossu, Nifle, Chantal, Ondze, Basile, Vasilescu, Carmen Gurau, Vongsouthi, Cyrille, Coustans, Marc, Anne, Olivier, Amevigbe, Josephine, Servan, Jerome, Merienne, Marc, Eck, Philippe, Berroir, Stephane, Busson, Philippe, Barroso, Bruno, Larrieu, Jean-Marc, Giendaj, Catherine Louvet, Malkoun, Imad, Hautecoeur, Patrick, Kwiatkowski, Arnaud, Pouliquen, Andre, Garrigues, Guillaume, Delerue, Olivier, Giraud, Pierric, Gere, Julien, Vaunaize, Jean, Dereeper, Olivier, Seiller, Nicolas, Alsassa, Roger, Vlaicu, Mihaela, Neuville, Veronique, Faucheux, Jean Marc, Bernady, Patricia, Fanjaud, Guy, Viallet, François, Schroeter, Michael, Schlemilch-Paschen, Sylke, Lange, Thomas, Bohr, Kin-Arno, Jendroska, Klaus, Rehkopf, Elisabeth, Bergmann, Arnfin, Kleinschnitz, Christoph, Postert, Thomas, Scholz, Peter, Mauz, Uwe, Stratmann, Hubert, Siefjediers, Veneta, Prantl, Martin, Gehring, Klaus, Zellner, Ruth, Junge, Kathrin, Zellner, Anton, Bacay, Valerina, Schlegel, Eugen, Polzer, Udo, Strauss, Erik, Link, Andreas, Stenzel, Christoph, Freidel, Matthias, Drews, Joachim, Neudert, Christian, Schmitz, Frank, Jaeger, Joachim, Masri, Said, Heuberger, Wolfgang, Trausch, Beate, Ruhnke, Oliver, Scarel, Serena, Bach, Kathlen, Ernst, Michael, Landefeld, Harald, Richter, Nils, Schmidt, Stephan, Krause, Michaela, Dressel, Alezander, Ruth, Roland, Anvari, Kerstin, Gossling, Jens, Schenk, Christoph, Tiedge, Oliver, Bode, Lutz, Eder, Hans-Thomas, Pfeffer, Oliver, Krug, Reinhard, Lassek, Christoph, Fleischer, Eberhard, Meuth, Sven, Klotz, Luisa Hildegard, Peglau, Ines, Kukowski, Borries, Herting, Birgit, Guthke, Kersten, Schierenbeck, Jurgen, Brockmeier, Bernd, Albrecht, Holger, Wuttke, Matthias, Augspach-Hofmann, Regine, Gunther, Stefan, Redbrake, Martin, Franke, Christian, Buchner, Klaus, Gratz, Thomas, Horn, Rolf, Doemges, Frank, Schreiber, Martin, Brosch, Thomas, Horn, Markus, Kittlitz, Matthias, Vulturius, Gabriele, Hinse, Paul, Malessa, Rolf, Wiehler, Stephan, Katsarava, Zaza, Kastrup, Oliver, Kausch, Ulrich, Gullekes, Martin, Fickinger, Markus, Wenzel, Wilhelm, Botefur, Ingolf C., Reifschneider, Gerd, Rauer, Sebastian, Lang, Michael, Harms, Lutz, Eckhardt, Ulrich, Cursiefen, Simone, Linker, Ralf, Angstwurm, Klemens, Haas, Judith, Schuetze, Ivo, Rohm, Eva, Stienker-Fisse, H., Sailer, Michael, Bohringer, Johannes, Maurer, Mathias, Bause, Eberhard, Wersching, Ronald, Dachsel, Reinhardt, Domke, Sylke, Hoffman, Frank, Tackenberg, Bjorn, Roch, Kerstin, Ziebold, Uwe, Kallmann, Boris, Buehler, Bernhard, Faiss, Judith, Faiss, Juergen, Schimrigk, Sebastian, Menges, Christian, Knop, Karl Christian, Koehler, Wolfgang, Siever, Arno, Bufler, Johannes, Gramsl, Georg, Kuhnler, Benedicta, Maschke, Matthias, Stogbauer, Florian, Staude, Lisa, Bethke, Florian, Bitsch, Andreas, Harmjanz, Arndt D., Windsheimer, Jorg, Kieseier, Bernd C., Berkenfeld, Ralf, Tumani, Hayrettin, Kirsch, Michael, Wildemann, Brigitte, Daniels, Regina, Gottwald, Klaus, Elias, Wolfgang-Gerhard, Hoffmann, Olaf, Schwab, Matthias, Pilz, Christopher, Klostermann, Fabian, Hellwig, Kerstin, Berthele, Achim, Bayas, Antonios, Molitor, Daniel, Grothe, Christoph, Wagner, Bert, Karageorgiou, Klimentini, Mitsikostas, Dimosthenis, Kodounis, Antonios, Plaitakis, Andreas, Papadimitriou, Alexandros, Grigoriadis, Nikolaos, Vlaikidis, Nikolaos, Koutlas, Evaggelos, Kyritsis, Athanassios, Papathanassopoulos, Panagiotis, Makris, Nikolaos, Tavernarakis, Antonios, Scarpini, Elio, Montanari, Enrico, Marrosu, Maria Giovanna, Trojano, Maria, Amato, Maria Pia, Rottoli, Mariarosa, Lugaresi, Alessandra, Florio, Ciro, Gasperini, Claudio, Grimaldi, Luigi, Millefiorini, Enrico, Koudriavtseva, Tatiana, Perla, Franco, Mantegazza, Renato, Bertolotto, Antonio, Ghezzi, Angelo, Aguilar, Sandra Quinones, Eisenberg, Eli Skromne, Lopez, Leondardo Llamas, Estudillo, Rocio Marquez, Schrijver, H.M., Wittebol, M.C., Baart, J.C., van Golde, A.E.L., Hengstman, G.J.D., Pop, P.H.M., Bos (Geldrop), M., Medaer, R., Schyns-Soeterboek, Angelique, van der Zwart, A., van Diepen, A.J.H., Verheul, G.A.M., Verhagen, W.I.M., Bos (Helmond), M., Witjes, R.J.G.M., Sinnige, L.G.F., van Munster, E.Th.L., Sanders, E.A.C.M., van Dijl, Ron, Hupperts, R.M.M., Frequin, S.T.F.M., Visser, L.H., Henselmans, J.M.L., Moll, J.W.B., Midgard, Rune, Myhr, Kjell Morten, Edland, Astrid, Telstad, Wenche, Hognestad, Tone, Lund, Christian, Hovdal, Harald, Kamaljit, Kaur, Schepel, Jan, Hogenesch, Roelfien Ida, Schüler, Stephan, Odeh, Francis, Alstadhaug, Karl B., Korsgaard, Olav, Farbu, Elisabeth, Ingvaldsen, Teis Barclay, Soares (SCO), Diana, Rente, José, Guerra, José Manuel Costa, Morganho, Armando, Leitão, António, de Sá, João, Sá, Maria José, Marques, Pinto, Veloso, Mário, Baptista, Miguel Viana, Szilasiová, Jarmila, Copikova-Cudrakova, Daniela, Prochazkova, Lubica, Klimová, Eleonóra, Donath, Vladimir, Brozman, Miroslav, Ramo, Cristina, Ruiz, Domingo Pérez, Hernández, Carmen Calles, Sola, María Eugenia Marzo, Moro, Roberto Suarez, Vidal, Jose Antonio, Rodríguez, Ana Belén Caminero, Ozaeta, Gisela Martin, Nadal, Jordi Batlle, Esquide, Amaya Alvarez de Arcaya, Urtaza, Javier Olascoaga, Martínez-Yélamos, Sergio, Arbizu, Txomin, Torrenta, Lluis Ramio i, Boggild, Mike, Wilson, Martin, Al-Araji, Adnan, Nicholas, Richard, Harrower, Timothy, Redmond, Ian, Wolf, Tilo, Osei-Bonsu, Michael, Mazibrada, Gordon, Rog, David, Cottrell, David, Constantinescu, Cris, Gray, Orla, Belhag, Mohamed, Shehu, Abdullah, Rashid, Waqar, Duddy, Martin, Kappos, Ludwig, Wiendl, Heinz, Spelman, Tim, Pellegrini, Fabio, Chen, Yi, Dong, Qunming, and Koendgen, Harold

Published
2018
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13. Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity

Author

Zammit, Nathan W., Siggs, Owen M., Gray, Paul E., Horikawa, Keisuke, Langley, David B., Walters, Stacey N., Daley, Stephen R., Loetsch, Claudia, Warren, Joanna, Yap, Jin Yan, Cultrone, Daniele, Russell, Amanda, Malle, Elisabeth K., Villanueva, Jeanette E., Cowley, Mark J., Gayevskiy, Velimir, Dinger, Marcel E., Brink, Robert, Zahra, David, Chaudhri, Geeta, Karupiah, Gunasegaran, Whittle, Belinda, Roots, Carla, Bertram, Edward, Yamada, Michiko, Jeelall, Yogesh, Enders, Anselm, Clifton, Benjamin E., Mabbitt, Peter D., Jackson, Colin J., Watson, Susan R., Jenne, Craig N., Lanier, Lewis L., Wiltshire, Tim, Spitzer, Matthew H., Nolan, Garry P., Schmitz, Frank, Aderem, Alan, Porebski, Benjamin T., Buckle, Ashley M., Abbott, Derek W., Ziegler, John B., Craig, Maria E., Benitez-Aguirre, Paul, Teo, Juliana, Tangye, Stuart G., King, Cecile, Wong, Melanie, Cox, Murray P., Phung, Wilson, Tang, Jia, Sandoval, Wendy, Wertz, Ingrid E., Christ, Daniel, Goodnow, Christopher C., and Grey, Shane T.

Published
2019
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20. A Novel Cre Recombinase Mouse Strain for Cell-Specific Deletion of Floxed Genes in Ribbon Synapse-Forming Retinal Neurons.

Author

Suiwal, Shweta, Wartenberg, Philipp, Boehm, Ulrich, Schmitz, Frank, and Schwarz, Karin

Subjects
DELETION mutation, GREEN fluorescent protein, RECOMBINASES, TAU proteins, PHOTORECEPTORS, RECOMBINANT proteins, RETINAL ganglion cells
Abstract

We generated a novel Cre mouse strain for cell-specific deletion of floxed genes in ribbon synapse-forming retinal neurons. Previous studies have shown that the RIBEYE promotor targets the expression of recombinant proteins such as fluorescently tagged RIBEYE to photoreceptors and retinal bipolar cells and generates fluorescent synaptic ribbons in situ in these neurons. Here, we used the same promotor to generate a novel transgenic mouse strain in which the RIBEYE promotor controls the expression of a Cre-ER(T2) recombinase (RIBEYE-Cre). To visualize Cre expression, the RIBEYE-Cre animals were crossed with ROSA26 tau-GFP (R26-τGFP) reporter mice. In the resulting RIBEYE-Cre/R26 τGFP animals, Cre-mediated removal of a transcriptional STOP cassette results in the expression of green fluorescent tau protein (tau-GFP) that binds to cellular microtubules. We detected robust tau-GFP expression in retinal bipolar cells. Surprisingly, we did not find fluorescent tau-GFP expression in mouse photoreceptors. The lack of tau-GFP reporter protein in these cells could be based on the previously reported absence of tau protein in mouse photoreceptors which could lead to the degradation of the recombinant tau protein. Consistent with this, we detected Cre and tau-GFP mRNA in mouse photoreceptor slices by RT-PCR. The transgenic RIBEYE-Cre mouse strain provides a new tool to study the deletion of floxed genes in ribbon synapse-forming neurons of the retina and will also allow for analyzing gene deletions that are lethal if globally deleted in neurons. [ABSTRACT FROM AUTHOR]

Published
2024
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22. Bone marrow microenvironments that contribute to patient outcomes in newly diagnosed multiple myeloma: A cohort study of patients in the Total Therapy clinical trials

Author

Danziger, Samuel A., McConnell, Mark, Gockley, Jake, Young, Mary H., Rosenthal, Adam, Schmitz, Frank, Reiss, David J., Farmer, Phil, Alapat, Daisy V., Singh, Amrit, Ashby, Cody, Bauer, Michael, Ren, Yan, Smith, Kelsie, Couto, Suzana S., van Rhee, Frits, Davies, Faith, Zangari, Maurizio, Petty, Nathan, Orlowski, Robert Z., Dhodapkar, Madhav V., Copeland, Wilbert B., Fox, Brian, Hoering, Antje, Fitch, Alison, Newhall, Katie, Barlogie, Bart, Trotter, Matthew W. B., Hershberg, Robert M., Walker, Brian A., Dervan, Andrew P., Ratushny, Alexander V., and Morgan, Gareth J.

Subjects
Physiological aspects, Development and progression, Prognosis, Health aspects, Bone marrow -- Physiological aspects -- Health aspects, Monocytes -- Physiological aspects -- Health aspects, Granulocytes -- Physiological aspects -- Health aspects, Multiple myeloma -- Development and progression -- Prognosis
Abstract

Author(s): Samuel A. Danziger 1,*, Mark McConnell 1, Jake Gockley 2, Mary H. Young 2, Adam Rosenthal 3, Frank Schmitz 2, David J. Reiss 1, Phil Farmer 4, Daisy V. [...], Background The tumor microenvironment (TME) is increasingly appreciated as an important determinant of cancer outcome, including in multiple myeloma (MM). However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases. Methods and findings Between 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5-29, 49-69 versus 70-82 months, X.sup.2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI -1 to 31, 92-120 versus 113-129 months, X.sup.2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8.sup.+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6-36, 49-73 versus 74-90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies. Conclusions In this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in particular monocytes and granulocytes, which are often ignored in microenvironment studies.

Published
2020
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28. The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection

Author

Schliehe, Christopher, Flynn, Elizabeth K, Vilagos, Bojan, Richson, Udochuku, Swaminathan, Savitha, Bosnjak, Berislav, Bauer, Lisa, Kandasamy, Richard K, Griesshammer, Isabel M, Kosack, Lindsay, Schmitz, Frank, Litvak, Vladimir, Sissons, James, Lercher, Alexander, Bhattacharya, Anannya, Khamina, Kseniya, Trivett, Anna L, Tessarollo, Lino, Mesteri, Ildiko, Hladik, Anastasiya, Merkler, Doron, Kubicek, Stefan, Knapp, Sylvia, Epstein, Michelle M, Symer, David E, Aderem, Alan, and Bergthaler, Andreas

Published
2015
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32. A FOXO3-IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses

Author

Litvak, Vladimir, Ratushny, Alexander V., Lampano, Aaron E., Schmitz, Frank, Huang, Albert C., Raman, Ayush, Rust, Alistair G., Bergthaler, Andreas, Aitchison, John D., and Aderem, Alan

Subjects
Physiological aspects, Research, Biological response modifiers -- Physiological aspects -- Research, Genes -- Physiological aspects -- Research, Interferon -- Physiological aspects -- Research
Abstract

Antiviral responses must be tightly regulated to defend rapidly against infection while minimizing inflammatory damage. Type 1 interferons (IFN-I) are crucial mediators of antiviral responses (1) and their transcription is [...]

Published
2012

43. Role of caveolae in the pathogenesis of cholesterol-induced gallbladder muscle hypomotility

Author

Xiao, Zuoliang, Schmitz, Frank, Pricolo, Victor E., Biancani, Piero, and Behar, Jose

Subjects
Caveolae -- Research, Cholecystokinin -- Research, Cholesterol -- Research, Cholesterol -- Health aspects, G proteins -- Research, Gallbladder -- Research, Gallbladder -- Physiological aspects, Biological sciences
Abstract

Muscle cells from human gallbladders (GB) with cholesterol stones (ChS) exhibit a defective contraction, excess cholesterol (Ch) in the plasma membrane, and lower binding of CCK-1 receptors. These abnormalities improved after muscle cells were incubated with Ch-free liposomes that remove the excess Ch from the plasma membrane. The present studies were designed to investigate the role of caveolin-3 proteins (Cav-3) in the pathogenesis of these abnormalities. Muscle cells from GB with ChS exhibit higher Ch levels in the plasma membrane that were mostly localized in caveolae and associated with parallel increases in the expression of Cav-3 in the caveolae compared with that in GB with pigment stones (PS). The overall number of CCK-1 receptors in the plasma membrane was not different between muscle cells from GB with ChS and PS, but they were increased in the caveolae in muscle cells from GB with ChS. Treatment of muscle cells from GB with ChS with a G[[alpha].sub.i3] protein fragment increased the total binding of CCK-1 receptors (from 8.3 to 11.2%) and muscle contraction induced by CCK-8 (from 11.2 to 17.3% shortening). However, G[[alpha].sub.q/11] protein fragment had no such effect. Moreover, neither fragment had any effect on muscle cells from GB with PS. We conclude that the defective contraction of muscle cells with excessive Ch levels in the plasma membrane is due to an increased expression of Cav-3 that results in the sequestration of CCK-1 receptors in the caveolae, probably by inhibiting the functions of G[[alpha].sub.i3] proteins. caveolin-3 proteins; cholecystokinin-1 receptors; G protein fragments doi:10.1152/ajpgi.00495.2006

Published
2007

50. The glucagon-like peptide-1 metabolite GLP-1-(9-36) amide reduces postprandial glycemia independently of gastric emptying and insulin secretion in humans

Author

Meier, Juris J., Gethmann, Arnica, Nauck, Michael A., Gotze, Oliver, Schmitz, Frank, Deacon, Carolyn F., Gallwitz, Baptist, Schmidt, Wolfgang E., and Hoist, Jens J.

Subjects
Homeostasis -- Research, Hormones -- Properties, Hormones -- Research, Pancreatic beta cells -- Research, Gastrointestinal system -- Motility, Gastrointestinal system -- Analysis, Gastrointestinal system -- Research, Biological sciences
Abstract

Glucagon-like peptide 1 (GLP-1) lowers glycemia by modulating gastric emptying and endocrine pancreatic secretion. Rapidly after its secretion, GLP1-(7-36) amide is degraded to the metabolite GLP-1-(9-36) amide. The effects of GLP-1-(9-36) amide in humans are less well characterized. Fourteen healthy volunteers were studied with intravenous infusion of GLP-1-(7-36) amide, GLP-1-(9-36) amide, or placebo over 390 min. After 30 min, a solid test meal was served, and gastric emptying was assessed. Blood was drawn for GLP-1 (total and intact), glucose, insulin, C-peptide, and glucagon measurements. Administration of GLP-1-(7-36) amide and GLP-1-(9-36) amide significantly raised total GLP-1 plasma levels. Plasma concentrations of intact GLP-I increased to 21 [+ or +] 5 pmol/1 during the infusion of GLP-1-(7-36) amide but remained unchanged during GLP-1-(9-36) amide infusion [5 [+ or -] 3 pmol/l; P < 0.001 vs. GLP-1-(7-36) amide administration]. GLP-1-(7-36) amide reduced fasting and postprandial glucose concentrations (P < 0.001) and delayed gastric emptying (P < 0.001). The GLP-1 metabolite had no influence on insulin or C-peptide concentrations. Glucagon levels were lowered by GLP-1-(7-36) amide but not by GLP-1-(9-36) amide. However, the postprandial rise in glycemia was reduced significantly (by ~6 mg/dl) by GLP-1-(9-36) amide (P < 0.05). In contrast, gastric emptying was completely unaffected by the GLP-1 metabolite. The GLP-1 metabolite lowers postprandial glycemia independently of changes in insulin and glucagon secretion or in the rate of gastric emptying. Most likely, this is because of direct effects on glucose disposal. However, the glucose-lowering potential of GLP-1-(9-36) amide appears to be small compared with that of intact GLP-1-(7-36) amide. insulin secretion; gastric emptying; incretin hormones; glucose homeostasis

Published
2006

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