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144 results on '"Iseli, C"'

1. Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance via STING

Author

Bruand, M., Barras, D., Mina, M., Ghisoni, E., Morotti, M., Lanitis, E., Fahr, N., Desbuisson, M., Grimm, A., Zhang, H., Chong, C., Dagher, J., Chee, S., Tsianou, T., Dorier, J., Stevenson, B.J., Iseli, C., Ronet, C., Bobisse, S., Genolet, R., Walton, J., Bassani-Sternberg, M., Kandalaft, L.E., Ren, B., McNeish, I., Swisher, E., Harari, A., Delorenzi, M., Ciriello, G., Irving, M., Rusakiewicz, S., Foukas, P.G., and Martinon, F.

Subjects
BRCA1, CTLA-4, DNA sensing, ICB, PARPi, PD-L1, STING, T cells, VEGF-A, angiogenesis, dual immune checkpoint blockade, ovarian cancer, type I IFN
Abstract

In this study, we investigate mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD). BRCA1 loss is found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I interferon (IFN) and stimulator of IFN genes (STING). BRCA1-mutated (BRCA1 mut ) tumors are thus T cell inflamed at baseline. Genetic deletion or methylation of DNA-sensing/IFN genes or CCL5 chemokine is identified as a potential mechanism to attenuate T cell inflammation. Alternatively, in BRCA1 mut cancers retaining inflammation, STING upregulates VEGF-A, mediating immune resistance and tumor progression. Tumor-intrinsic STING elimination reduces neoangiogenesis, increases CD8 + T cell infiltration, and reverts therapeutic resistance to dual immune checkpoint blockade (ICB). VEGF-A blockade phenocopies genetic STING loss and synergizes with ICB and/or poly(ADP-ribose) polymerase (PARP) inhibitors to control the outgrowth of Trp53 -/- Brca1 -/- but not Brca1 +/+ ovarian tumors in vivo, offering rational combinatorial therapies for HRD cancers.

Published
2021

3. Intraoperative Observational Real-time Electrocochleography as a Predictor of Hearing Loss After Cochlear Implantation: 3 and 12 Month Outcomes

Author

O'Leary, S, Briggs, R, Gerard, J-M, Iseli, C, Wei, BPC, Tari, S, Rousset, A, Bester, C, O'Leary, S, Briggs, R, Gerard, J-M, Iseli, C, Wei, BPC, Tari, S, Rousset, A, and Bester, C

Abstract

OBJECTIVE: A decrease in intracochlear electrocochleographic (ECochG) amplitude during cochlear implantation has been associated with poorer postoperative hearing preservation in several short-term studies. Here, we relate the stability of ECochG during surgery to hearing preservation at 3- and 12-months. METHODS: Patients with hearing ≤80-dB HL at 500 Hz were implanted with a slim-straight electrode array. ECochG responses to short, high-intensity, 500-Hz pure tones of alternating polarity were recorded continuously from the apical-most electrode during implantation. No feedback was provided to the surgeon. ECochG amplitude was derived from the difference response, and implantations classified by the presence ("ECochG drop") or absence ("no drop") of a ≥30% reduction in ECochG amplitude during insertion. Residual hearing (relative and absolute) was reported against the ECochG class. RESULTS: ECochG was recorded from 109 patients. Of these, interpretable ECochG signals were recorded from 95. Sixty-six of 95 patients had an ECochG drop during implantation. Patients with an ECochG drop had poorer preoperative hearing above 1000 Hz. Hearing preservation (in decibels, relative to preoperative levels and functionally) was significantly poorer at 250-, 500-, and 1000-Hz at 3 months in patients exhibiting an ECochG drop. Twelve-month outcomes were available from 85 patients, with significantly poorer functional hearing, and greater relative and absolute hearing loss from 250 to 1000 Hz, when an ECochG drop had been encountered. CONCLUSION: Patients exhibiting ECochG drops during implantation had significantly poorer hearing preservation 12 months later. These observational outcomes support the future development of surgical interventions responsive to real-time intracochlear ECochG. Early intervention to an ECochG drop could potentially lead to prolonged improvements in hearing preservation.

Published
2020

7. Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer

Author

Tanyi, J.L. Bobisse, S. Ophir, E. Tuyaerts, S. Roberti, A. Genolet, R. Baumgartner, P. Stevenson, B.J. Iseli, C. Dangaj, D. Czerniecki, B. Semilietof, A. Racle, J. Michel, A. Xenarios, I. Chiang, C. Monos, D.S. Torigian, D.A. Nisenbaum, H.L. Michielin, O. June, C.H. Levine, B.L. Powel, D.J., Jr. Gfeller, D. Mick, R. Dafni, U. Zoete, V. Harari, A. Coukos, G. Kandalaft, L.E.

Abstract

We conducted a pilot clinical trial testing a personalized vaccine generated by autologous dendritic cells (DCs) pulsed with oxidized autologous whole-tumor cell lysate (OCDC), which was injected intranodally in platinum-treated, immunotherapy-naïve, recurrent ovarian cancer patients. OCDC was administered alone (cohort 1, n = 5), in combination with bevacizumab (cohort 2, n = 10), or bevacizumab plus low-dose intravenous cyclophosphamide (cohort 3, n = 10) until disease progression or vaccine exhaustion. A total of 392 vaccine doses were administered without serious adverse events. Vaccination induced T cell responses to autologous tumor antigen, which were associated with significantly prolonged survival. Vaccination also amplified T cell responses against mutated neoepitopes derived from nonsynonymous somatic tumor mutations, and this included priming of T cells against previously unrecognized neoepitopes, as well as novel T cell clones of markedly higher avidity against previously recognized neoepitopes. We conclude that the use of oxidized whole-tumor lysate DC vaccine is safe and effective in eliciting a broad antitumor immunity, including private neoantigens, and warrants further clinical testing. Copyright © 2018, American Association for the Advancement of Science.

Published
2018

12. The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

Author

Bultet, LA, Aguilar-Rodriguez, J, Ahrens, CH, Ahrne, EL, Ai, N, Aimo, L, Akalin, A, Aleksiev, T, Alocci, D, Altenhoff, A, Alves, I, Ambrosini, G, Pedone, PA, Angelina, P, Anisimova, M, Appel, R, Argoud-Puy, G, Arnold, K, Arpat, B, Artimo, P, Ascencao, K, Auchincloss, A, Axelsen, K, Gerritsen, VB, Bairoch, A, Barisal, P, Baratin, D, Barbato, A, Barbie, V, Barras, D, Barreiro, M, Barret, S, Bastian, F, Batista Neto, TM, Baudis, M, Beaudoing, E, Beckmann, JS, Bekkar, AK, Cammoun, LBH, Benmohammed, S, Bernard, M, Bertelli, C, Bertoni, M, Bienert, S, Bignucolo, O, Bilbao, A, Bilican, A, Blank, D, Blatter, M-C, Blum, L, Bocquet, J, Boeckmann, B, Bolleman, JT, Bordoli, L, Bosshard, L, Boucher, G, Bougueleret, L, Boutet, E, Bovigny, C, Bratulic, S, Breuza, L, Bridge, AJ, Britan, A, Brito, F, Frazao, JB, Bruggmann, R, Bucher, P, Burdet, F, Burger, L, Cabello, EM, Gomez, RMC, Calderon, S, Cannarozzi, G, Carl, S, Casas, CC, Catherinet, S, Perier, RC, Charpilloz, C, Chaskar, PD, Chen, W, Pepe, AC, Chopard, B, Chu, HY, Civic, N, Claassen, M, Clottu, S, Colombo, M, Cosandier, I, Coudert, E, Crespo, I, Creus, M, Cuche, B, Cuendet, MA, Cusin, I, Daga, N, Daina, A, Dauvillier, J, David, F, Davydov, I, Ferreira, MDSRM, de Beer, T, de Castro, E, de Santana, C, Delafontaine, J, Delorenzi, M, Delucinge-Vivier, C, Demirel, O, Derham, R, Dermitzakis, EM, Dib, L, Diene, S, Dilek, N, Dilmi, J, Domagalski, MJ, Dorier, J, Dornevil, D, Dousse, A, Dreos, R, Duchen, P, Roggli, PD, Duperret, ID, Durinx, C, Duvaud, S, Engler, R, Frkek, S, Lopez, PE, Fstreicher, A, Excoffier, L, Fabbretti, R, Falcone, J-L, Falquet, L, Famiglietti, ML, Ferreira, A-M, Feuermann, M, Filliettaz, M, Hegel, V, Foucal, A, Franceschini, A, Fucile, G, Gaidatzis, D, Garcia, V, Gasteiger, E, Gateau, A, Gatti, L, Gaudet, P, Gaudinat, A, Gehant, S, Gfeller, D, Gharib, WH, Ghraichy, M, Gidoin, C, Gil, M, Gleizes, A, Gobeill, J, Gonnet, G, Gos, A, Gotz, L, Gouy, A, Grbic, D, Groux, R, Gruaz-Gumowski, N, Grun, D, Gschwind, A, Guex, N, Gupta, S, Getaz, M, Haake, D, Haas, J, Hatzimanikatis, V, Heckel, G, Gardiol, DFH, Hinard, V, Hinz, U, Homicsko, K, Horlacher, O, Hosseini, S-R, Hotz, H-R, Hulo, C, Hundsrucker, C, Ibberson, M, Ilmjarv, S, Ioannidis, V, Ioannidis, P, Iseli, C, Ivanek, R, Iwaszkiewicz, J, Jacquet, P, Jacquot, M, Jagannathan, V, Jan, M, Jensen, J, Johansson, MU, Johner, N, Jungo, F, Junier, T, Kahraman, A, Katsantoni, M, Keller, G, Kerhornou, A, Khalid, F, Klingbiel, D, Kimljenovic, A, Kriventseva, E, Kryuchkova, N, Kumar, S, Kutalik, Z, Kuznetsov, D, Kuzyakiv, R, Lane, L, Lara, V, Ledesma, L, Leleu, M, Lemercier, P, Lew, D, Lieberherr, D, Liechti, R, Lisacek, F, Fischer, H, Litsios, G, Liu, J, Lombardot, T, Mace, A, Maffioletti, S, Mahi, M-A, Maiolo, M, Majjigapu, SR, Malmstrom, L, Mangold, V, Marek, D, Mariethoz, J, Marin, R, Martin, O, Martin, X, Martin-Campos, T, Mary, C, Masclaux, F, Masson, P, Meier, C, Messina, A, Lenoir, MM, Meyer, X, Michel, P-A, Michielin, O, Milanese, A, Missiaglia, E, Perez, JM, Caria, VM, Moret, P, Moretti, S, Morgat, A, Mottaz, A, Mottin, L, Mouscaz, Y, Mueller, M, Murri, R, Mylonas, R, Neuenschwander, S, Nikitin, F, Niknejad, A, Nouspikel, N, Nso, LN, Okoniewski, M, Omasits, U, Paccaud, B, Pachkov, M, Paesano, SG, Pagni, M, Palagi, PM, Pasche, E, Payne, JL, Pedruzzi, I, Peischl, S, Peitsch, M, Perlini, S, Pilbout, S, Podvinec, M, Pohlmann, R, Polizzi, D, Potter, D, Poux, S, Pozzato, M, Pradervand, S, Praz, V, Pruess, M, Pujadas, E, Racle, J, Raschi, M, Ratib, O, Rausell, A, de Laval, VR, Redaschi, N, Rempfer, C, Ren, G, Vandati, RAR, Rib, L, Grognuz, OR, Altimiras, ER, Rivoire, C, Robin, T, Robinson-Rechavi, M, Rodrigues, J, Roechert, B, Roelli, P, Romano, V, Rossier, G, Roth, A, Rougemont, J, Roux, J, Royo, H, Ruch, P, Ruinelli, M, Rustom, M, Sates, A, Roehrig, UF, Rueeger, S, Salamin, N, Sankar, M, Sarkar, N, Saxenhofer, M, Schaeffer, M, Schaerli, Y, Schaper, E, Schmid, A, Schmid, E, Schmid, C, Schmid, M, Schmidt, S, Schmocker, D, Schneider, M, Schuepbach, T, Schwede, T, Schuetz, F, Sengstag, T, Serrano, M, Sethi, A, Shahmirzadi, O, Sigrist, C, Silvestro, D, Simao Neto, FA, Simillion, C, Simonovic, M, Skunca, N, Sluzek, K, Soneson, C, Sprouffske, K, Stadler, M, Staehli, S, Stevenson, B, Stockinger, H, Straszewski, J, Stricker, T, Studer, G, Stutz, A, Suffiotti, M, Sundaram, S, Szklarczyk, D, Szovenyi, P, Tegenfeldt, F, Teixeira, D, Tellenbach, S, Smith, AAT, Tognolli, M, Topolsky, I, Thuong, VDT, Tsantoulis, P, Tzika, AC, Agote, AU, van Nimwegen, E, von Mering, C, Varadarajan, A, Veranneman, M, Verbregue, L, Veuthey, A-L, Vishnyakova, D, Vyas, R, Wagner, A, Walther, D, Wan, HW, Wang, M, Waterhouse, R, Waterhouse, A, Wicki, A, Wigger, L, Wirapati, P, Witschi, U, Wyder, S, Wyler, K, Wuethrich, D, Xenarios, I, Yamada, K, Yan, Z, Yasrebi, H, Zahn, M, Zangger, N, Zdobnov, E, Zerzion, D, Zoete, V, Zoller, S, Bultet, LA, Aguilar-Rodriguez, J, Ahrens, CH, Ahrne, EL, Ai, N, Aimo, L, Akalin, A, Aleksiev, T, Alocci, D, Altenhoff, A, Alves, I, Ambrosini, G, Pedone, PA, Angelina, P, Anisimova, M, Appel, R, Argoud-Puy, G, Arnold, K, Arpat, B, Artimo, P, Ascencao, K, Auchincloss, A, Axelsen, K, Gerritsen, VB, Bairoch, A, Barisal, P, Baratin, D, Barbato, A, Barbie, V, Barras, D, Barreiro, M, Barret, S, Bastian, F, Batista Neto, TM, Baudis, M, Beaudoing, E, Beckmann, JS, Bekkar, AK, Cammoun, LBH, Benmohammed, S, Bernard, M, Bertelli, C, Bertoni, M, Bienert, S, Bignucolo, O, Bilbao, A, Bilican, A, Blank, D, Blatter, M-C, Blum, L, Bocquet, J, Boeckmann, B, Bolleman, JT, Bordoli, L, Bosshard, L, Boucher, G, Bougueleret, L, Boutet, E, Bovigny, C, Bratulic, S, Breuza, L, Bridge, AJ, Britan, A, Brito, F, Frazao, JB, Bruggmann, R, Bucher, P, Burdet, F, Burger, L, Cabello, EM, Gomez, RMC, Calderon, S, Cannarozzi, G, Carl, S, Casas, CC, Catherinet, S, Perier, RC, Charpilloz, C, Chaskar, PD, Chen, W, Pepe, AC, Chopard, B, Chu, HY, Civic, N, Claassen, M, Clottu, S, Colombo, M, Cosandier, I, Coudert, E, Crespo, I, Creus, M, Cuche, B, Cuendet, MA, Cusin, I, Daga, N, Daina, A, Dauvillier, J, David, F, Davydov, I, Ferreira, MDSRM, de Beer, T, de Castro, E, de Santana, C, Delafontaine, J, Delorenzi, M, Delucinge-Vivier, C, Demirel, O, Derham, R, Dermitzakis, EM, Dib, L, Diene, S, Dilek, N, Dilmi, J, Domagalski, MJ, Dorier, J, Dornevil, D, Dousse, A, Dreos, R, Duchen, P, Roggli, PD, Duperret, ID, Durinx, C, Duvaud, S, Engler, R, Frkek, S, Lopez, PE, Fstreicher, A, Excoffier, L, Fabbretti, R, Falcone, J-L, Falquet, L, Famiglietti, ML, Ferreira, A-M, Feuermann, M, Filliettaz, M, Hegel, V, Foucal, A, Franceschini, A, Fucile, G, Gaidatzis, D, Garcia, V, Gasteiger, E, Gateau, A, Gatti, L, Gaudet, P, Gaudinat, A, Gehant, S, Gfeller, D, Gharib, WH, Ghraichy, M, Gidoin, C, Gil, M, Gleizes, A, Gobeill, J, Gonnet, G, Gos, A, Gotz, L, Gouy, A, Grbic, D, Groux, R, Gruaz-Gumowski, N, Grun, D, Gschwind, A, Guex, N, Gupta, S, Getaz, M, Haake, D, Haas, J, Hatzimanikatis, V, Heckel, G, Gardiol, DFH, Hinard, V, Hinz, U, Homicsko, K, Horlacher, O, Hosseini, S-R, Hotz, H-R, Hulo, C, Hundsrucker, C, Ibberson, M, Ilmjarv, S, Ioannidis, V, Ioannidis, P, Iseli, C, Ivanek, R, Iwaszkiewicz, J, Jacquet, P, Jacquot, M, Jagannathan, V, Jan, M, Jensen, J, Johansson, MU, Johner, N, Jungo, F, Junier, T, Kahraman, A, Katsantoni, M, Keller, G, Kerhornou, A, Khalid, F, Klingbiel, D, Kimljenovic, A, Kriventseva, E, Kryuchkova, N, Kumar, S, Kutalik, Z, Kuznetsov, D, Kuzyakiv, R, Lane, L, Lara, V, Ledesma, L, Leleu, M, Lemercier, P, Lew, D, Lieberherr, D, Liechti, R, Lisacek, F, Fischer, H, Litsios, G, Liu, J, Lombardot, T, Mace, A, Maffioletti, S, Mahi, M-A, Maiolo, M, Majjigapu, SR, Malmstrom, L, Mangold, V, Marek, D, Mariethoz, J, Marin, R, Martin, O, Martin, X, Martin-Campos, T, Mary, C, Masclaux, F, Masson, P, Meier, C, Messina, A, Lenoir, MM, Meyer, X, Michel, P-A, Michielin, O, Milanese, A, Missiaglia, E, Perez, JM, Caria, VM, Moret, P, Moretti, S, Morgat, A, Mottaz, A, Mottin, L, Mouscaz, Y, Mueller, M, Murri, R, Mylonas, R, Neuenschwander, S, Nikitin, F, Niknejad, A, Nouspikel, N, Nso, LN, Okoniewski, M, Omasits, U, Paccaud, B, Pachkov, M, Paesano, SG, Pagni, M, Palagi, PM, Pasche, E, Payne, JL, Pedruzzi, I, Peischl, S, Peitsch, M, Perlini, S, Pilbout, S, Podvinec, M, Pohlmann, R, Polizzi, D, Potter, D, Poux, S, Pozzato, M, Pradervand, S, Praz, V, Pruess, M, Pujadas, E, Racle, J, Raschi, M, Ratib, O, Rausell, A, de Laval, VR, Redaschi, N, Rempfer, C, Ren, G, Vandati, RAR, Rib, L, Grognuz, OR, Altimiras, ER, Rivoire, C, Robin, T, Robinson-Rechavi, M, Rodrigues, J, Roechert, B, Roelli, P, Romano, V, Rossier, G, Roth, A, Rougemont, J, Roux, J, Royo, H, Ruch, P, Ruinelli, M, Rustom, M, Sates, A, Roehrig, UF, Rueeger, S, Salamin, N, Sankar, M, Sarkar, N, Saxenhofer, M, Schaeffer, M, Schaerli, Y, Schaper, E, Schmid, A, Schmid, E, Schmid, C, Schmid, M, Schmidt, S, Schmocker, D, Schneider, M, Schuepbach, T, Schwede, T, Schuetz, F, Sengstag, T, Serrano, M, Sethi, A, Shahmirzadi, O, Sigrist, C, Silvestro, D, Simao Neto, FA, Simillion, C, Simonovic, M, Skunca, N, Sluzek, K, Soneson, C, Sprouffske, K, Stadler, M, Staehli, S, Stevenson, B, Stockinger, H, Straszewski, J, Stricker, T, Studer, G, Stutz, A, Suffiotti, M, Sundaram, S, Szklarczyk, D, Szovenyi, P, Tegenfeldt, F, Teixeira, D, Tellenbach, S, Smith, AAT, Tognolli, M, Topolsky, I, Thuong, VDT, Tsantoulis, P, Tzika, AC, Agote, AU, van Nimwegen, E, von Mering, C, Varadarajan, A, Veranneman, M, Verbregue, L, Veuthey, A-L, Vishnyakova, D, Vyas, R, Wagner, A, Walther, D, Wan, HW, Wang, M, Waterhouse, R, Waterhouse, A, Wicki, A, Wigger, L, Wirapati, P, Witschi, U, Wyder, S, Wyler, K, Wuethrich, D, Xenarios, I, Yamada, K, Yan, Z, Yasrebi, H, Zahn, M, Zangger, N, Zdobnov, E, Zerzion, D, Zoete, V, and Zoller, S

Abstract

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article.

Published
2016

13. Post sequencing gene discovery; novel genes in human chromosome 21 (HC21)

Author

Deutsch, S., Reymond, A., Lyle, R., Antonarakis, S., Camargo, A., de Souza, S., Simpson, A., Stevenson, B., Iseli, C., Bucher, P., and Jongeneel, V.

Subjects
Human genetics -- Research, Down syndrome -- Genetic aspects, Genetic disorders -- Research, Biological sciences
Published
2001

14. A chromosome 21 cSNP map and database

Author

Deustch, S., Iseli, C., Bucher, P., Antonarakis, S.E., and Scott, H.S.

Subjects
Genetic research -- Analysis, Human genetics -- Research, Human chromosome 21 -- Research, Biological sciences
Published
2000

15. Assessment of transcript reconstruction methods for RNA-seq

Author

Steijger, T., Abril, J.F., Engström, P.G., Kokocinski, F., Akerman, M., Alioto, T., Ambrosini, G., Antonarakis, S.E., Behr, J., Bertone, P., Bohnert, R., Bucher, P., Cloonan, N., Derrien, T., Djebali, S., Du, J., Dudoit, S., Gerstein, M., Gingeras, T.R., Gonzalez, D., Grimmond, S.M., Guigó, R., Habegger, L., Harrow, J., Hubbard, T.J., Iseli, C., Jean, G., Kahles, A., Lagarde, J., Leng, J., Lefebvre, G., Lewis, S., Mortazavi, A., Niermann, P., Rätsch, G., Reymond, A., Ribeca, P., Richard, H., Rougemont, J., Rozowsky, J., Sammeth, M., Sboner, A., Schulz, M.H., Searle, S.M., Solorzano, N.D., Solovyev, V., Stanke, M., Stevenson, B.J., Stockinger, H., Valsesia, A., Weese, D., White, S., Wold, B.J., Wu, J., Wu, T.D., Zeller, G., Zerbino, D., Zhang, M.Q., RGASP Consortium, Head of Medical Sequencing, Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centro de Regulación Genómica (CRG), Universitat Pompeu Fabra [Barcelona] (UPF), Department of Statistics [Berkeley], University of California [Berkeley], University of California-University of California, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sanger Institute, Wellcome Trust, Laboratoire d'Informatique de Nantes Atlantique (LINA), Centre National de la Recherche Scientifique (CNRS)-Mines Nantes (Mines Nantes)-Université de Nantes (UN), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Protéines de défense des réponses immune et inflammatoire : identification, régulation et rôles physiopathologiques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne (UNIL), Centre Georges Chevrier. Ordre et désordre dans l'histoire des sociétés (UMR5605) (CGC), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), School of Life Sciences [Lausanne], Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute of Bioinformatics [Lausanne] (SIB), Centro Nacional de Análisi Genómico (CNAG), Centro Nacional de Análisis Genómico, Department of Computer Science [Royal Holloway], Royal Holloway [University of London] (RHUL), University of California [Santa Cruz] (UCSC), University of California, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ), Centro de Regulación Genómica ( CRG ), Universitat Pompeu Fabra [Barcelona], Department of Statistics, Laboratoire d'Informatique de Nantes Atlantique ( LINA ), Mines Nantes ( Mines Nantes ) -Université de Nantes ( UN ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Lausanne ( UNIL ), Centre Georges Chevrier. Ordre et désordre dans l'histoire des sociétés (UMR5605) ( CGC ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Bourgogne ( UB ), Ecole Polytechnique Fédérale de Lausanne ( EPFL ), Swiss Institute of Bioinformatics ( SIB ), Swiss Institute of Bioinformatics, Centro Nacional de Análisi Genómico ( CNAG ), Royal Holloway [University of London] ( RHUL ), University of California [Santa Cruz] ( UCSC ), Swiss Institute of Bioinformatics - Lausanne ( SIB ), Stony Brook University [The State University of New York] ( SBU ), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC), Mines Nantes (Mines Nantes)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL), University of California [Santa Cruz] (UC Santa Cruz), and University of California (UC)

Subjects
Technology, Messenger, RNA, Messenger/metabolism, RNA-Seq, RGASP Consortium, Sequence Analysis, RNA/methods, Biochemistry, Genome, Medical and Health Sciences, Exon, 0302 clinical medicine, Transcription (biology), 2.1 Biological and endogenous factors, ddc:576.5, Aetiology, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Genetics, 0303 health sciences, Genome project, Exons, Biological Sciences, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Drosophila melanogaster, RNA splicing, Sequence Analysis, Algorithms, Biotechnology, RNA Splicing, Computational biology, Biology, Biologia computacional, 03 medical and health sciences, [ INFO.INFO-BI ] Computer Science [cs]/Bioinformatics [q-bio.QM], Empalmament (Genètica), Animals, Humans, Caenorhabditis elegans, Molecular Biology, 030304 developmental biology, GENCODE, Gene Expression Profiling, Intron, Computational Biology, Cell Biology, Computational Biology/methods, Introns, RNA Splice Sites, Software, RNA, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], 030217 neurology & neurosurgery, Developmental Biology
Abstract

We evaluated 25 protocol variants of 14 independent computational methods for exon identification, transcript reconstruction and expression-level quantification from RNA-seq data. Our results show that most algorithms are able to identify discrete transcript components with high success rates but that assembly of complete isoform structures poses a major challenge even when all constituent elements are identified. Expression-level estimates also varied widely across methods, even when based on similar transcript models. Consequently, the complexity of higher eukaryotic genomes imposes severe limitations on transcript recall and splice product discrimination that are likely to remain limiting factors for the analysis of current-generation RNA-seq data. This work was supported by grants BIO2011-26205 and CSD2007-00050 from the Ministerio de Educación y Ciencia

Published
2013

27. A cSNP map and database for human chromosome 21.

Author

Deutsch, S, Iseli, C, Bucher, P, Antonarakis, S E, and Scott, H S

Abstract

Single nucleotide polymorphisms (SNPs) are likely to contribute to the study of complex genetic diseases. The genomic sequence of human chromosome 21q was recently completed with 225 annotated genes, thus permitting efficient identification and precise mapping of potential cSNPs by bioinformatics approaches. Here we present a human chromosome 21 (HC21) cSNP database and the first chromosome-specific cSNP map. Potential cSNPs were generated using three approaches: (1) Alignment of the complete HC21 genomic sequence to cognate ESTs and mRNAs. Candidate cSNPs were automatically extracted using a novel program for context-dependent SNP identification that efficiently discriminates between true variation, poor quality sequencing, and paralogous gene alignments. (2) Multiple alignment of all known HC21 genes to all other human database entries. (3) Gene-targeted cSNP discovery. To date we have identified 377 cSNPs averaging ~1 SNP per 1.5 kb of transcribed sequence, covering 65% of known genes in the chromosome. Validation of our bioinformatics approach was demonstrated by a confirmation rate of 78% for the predicted cSNPs, and in total 32% of the cSNPs in our database have been confirmed. The database is publicly available at http://csnp.unige.ch or http://csnp.isb-sib.ch. These SNPs provide a tool to study the contribution of HC21 loci to complex diseases such as bipolar affective disorder and allele-specific contributions to Down syndrome phenotypes.

Published
2001
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28. trEST, trGEN and Hits: access to databases of predicted protein sequences.

Author

Pagni, M, Iseli, C, Junier, T, Falquet, L, Jongeneel, V, and Bucher, P

Abstract

High throughput genome (HTG) and expressed sequence tag (EST) sequences are currently the most abundant nucleotide sequence classes in the public database. The large volume, high degree of fragmentation and lack of gene structure annotations prevent efficient and effective searches of HTG and EST data for protein sequence homologies by standard search methods. Here, we briefly describe three newly developed resources that should make discovery of interesting genes in these sequence classes easier in the future, especially to biologists not having access to a powerful local bioinformatics environment. trEST and trGEN are regularly regenerated databases of hypothetical protein sequences predicted from EST and HTG sequences, respectively. Hits is a web-based data retrieval and analysis system providing access to precomputed matches between protein sequences (including sequences from trEST and trGEN) and patterns and profiles from Prosite and Pfam. The three resources can be accessed via the Hits home page (http://hits. isb-sib.ch).

Published
2001
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30. Brainstem Auditory Evoked Potentials in Meningomyelocele

Author

Lütschg J, Meyer E, Kaiser G, and Jeanneret-Iseli C

Subjects
Adult, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Meningomyelocele, Adolescent, Electrodiagnosis, Audiology, Postoperative Complications, Reaction Time, medicine, Humans, In patient, Child, Arnold-Chiari syndrome, medicine.diagnostic_test, business.industry, Cranial Nerves, Normal population, General Medicine, medicine.disease, Cerebrospinal Fluid Shunts, Hydrocephalus, Interpeak latency, Child, Preschool, Anesthesia, Pediatrics, Perinatology and Child Health, Evoked Potentials, Auditory, Neurology (clinical), Brainstem, Arnold chiari, business, Brain Stem
Abstract

The brainstem auditory evoked potentials (BAEP) of twenty-seven Myelomeningocele (MMC) patients were analyzed and compared with the results of a normal population. The longest wave V or V-I interpeak latencies were seen in patients with shunted hydrocephalus and cranial nerve defects. The shortest wave V and V-I interpeak latencies were found in patients without hydrocephalus. However, these latencies of MMC patients were significantly longer than the latencies of a normal population. Wave I latencies of all MMC subgroups were not significantly different from the results of the normal probands. It is assumed that V-I interpeak latency prolongation in MMC patients, which is related to the severity of the clinical signs of the Arnold Chiari malformation, is mostly due to an elongation of the brainstem.

Published
1985

35. Untersuchung von Renaturierungskonzepten am Seeufer Gals, Bielersee

Author

Schiefer, A., Iseli, C., Amini, Azin, and De Cesare, Giovanni

Subjects
Wellen- und Strömungsmodellierung, MIKE 21, Seeuferrenaturierung, Habitate, Makrophyten, Ökologische Aufwertung
Abstract

Analyse des ökologischen Aufwertungspotentials am Seeufer Gals (Bielersee, Schweiz), welche mithilfe einer hydrodynamisch- numerischen Modellierung mit der Software MIKE 21 und Bestimmung von Makrophyten vorgenommen wurde. Unter der Annahme von zwei unterschiedlich starken Windszenarien wurden die windinduzierten signifikanten Wellenhöhen und die welleninduzierten Strömungen für verschiedene Varianten simuliert. Die Ergebnisse der Modellierungen zeigten, ob die in den Varianten geplanten Massnahmen eine Reduzierung der Wellenhöhen und der Strömungen verursachen. Das Hauptziel war, Bedingungen zu schaffen, welche den Habitatsansprüchen von Makrophyten zusagen und somit eine Neuansiedlung von Makrophytenarten an dem Seeufer Gals möglich machen und gleichzeitig die Wellenbelastung auf das Ufer zu verringern, um eine fortschreitende Erosion zu vermeiden. Mithilfe einiger Massnahmen konnten erfolgsversprechende Ergebnisse erzielt werden, die zu einer Verbesserung der aktuellen Situation führen würden. Es wurde ebenfalls gezeigt, dass Makrophyten für die Beurteilung eine bedeutende Rolle spielen, doch eine Bewertung nur anhand von ihnen sehr schwierig ist, da sie nicht nur auf Wellen- und Strömungsbedingungen, sondern auf weitere Faktoren und zudem extrem schnell auf deren Veränderungen reagieren. Die Studie wurde im Rahmen einer Masterarbeit an der TU Dresden im Landschaftswerk Biel-Seeland durchgeführt.

38. Ultra high throughput sequencing excludes MDH1 as candidate gene for RP28-linked retinitis pigmentosa

Author

Rio Frio T, Panek S, Iseli C, Sa, Di Gioia, Kumar A, Gal A, and Carlo Rivolta

Subjects
Genetic Loci, Malate Dehydrogenase, Genetic Loci/genetics, Genetic Predisposition to Disease, High-Throughput Screening Assays/methods, Humans, Malate Dehydrogenase/genetics, Polymorphism, Single Nucleotide/genetics, Retinitis Pigmentosa/enzymology, Retinitis Pigmentosa/genetics, Sequence Analysis, DNA/methods, Sequence Analysis, DNA, Polymorphism, Single Nucleotide, Retinitis Pigmentosa, High-Throughput Screening Assays, Research Article
Abstract

PURPOSE: Mutations in IDH3B, an enzyme participating in the Krebs cycle, have recently been found to cause autosomal recessive retinitis pigmentosa (arRP). The MDH1 gene maps within the RP28 arRP linkage interval and encodes cytoplasmic malate dehydrogenase, an enzyme functionally related to IDH3B. As a proof of concept for candidate gene screening to be routinely performed by ultra high throughput sequencing (UHTs), we analyzed MDH1 in a patient from each of the two families described so far to show linkage between arRP and RP28. METHODS: With genomic long-range PCR, we amplified all introns and exons of the MDH1 gene (23.4 kb). PCR products were then sequenced by short-read UHTs with no further processing. Computer-based mapping of the reads and mutation detection were performed by three independent software packages. RESULTS: Despite the intrinsic complexity of human genome sequences, reads were easily mapped and analyzed, and all algorithms used provided the same results. The two patients were homozygous for all DNA variants identified in the region, which confirms previous linkage and homozygosity mapping results, but had different haplotypes, indicating genetic or allelic heterogeneity. None of the DNA changes detected could be associated with the disease. CONCLUSIONS: The MDH1 gene is not the cause of RP28-linked arRP. Our experimental strategy shows that long-range genomic PCR followed by UHTs provides an excellent system to perform a thorough screening of candidate genes for hereditary retinal degeneration.

39. Long-range heterogeneity at the 3' ends of human mRNAs

Author

Iseli, C., Stevenson, B. J., de Souza, S. J., Samaia, H. B., Camargo, A. A., Buetow, K. H., Strausberg, R. L., Simpson, A. J., Bucher, P., and Jongeneel, C. V.

Abstract

The publication of a draft of the human genome and of large collections of transcribed sequences has made it possible to study the complex relationship between the transcriptome and the genome. In the work presented here, we have focused on mapping mRNA 3' ends onto the genome by use of the raw data generated by the expressed sequence tag (EST) sequencing projects. We find that at least half of the human genes encode multiple transcripts whose polyadenylation is driven by multiple signals. The corresponding transcript 3' ends are spread over distances in the kilobase range. This finding has profound implications for our understanding of gene expression regulation and of the diversity of human transcripts, for the design of cDNA microarray probes, and for the interpretation of gene expression profiling experiments.

45. DNA methylation by CcrM contributes to genome maintenance in the Agrobacterium tumefaciens plant pathogen.

Author

Martin S, Fournes F, Ambrosini G, Iseli C, Bojkowska K, Marquis J, Guex N, and Collier J

Subjects
Promoter Regions, Genetic, Biofilms growth & development, Operon genetics, Site-Specific DNA-Methyltransferase (Adenine-Specific), Agrobacterium tumefaciens genetics, DNA Methylation, Genome, Bacterial, DNA Replication genetics, Gene Expression Regulation, Bacterial, Bacterial Proteins genetics, Bacterial Proteins metabolism, Replication Origin genetics
Abstract

The cell cycle-regulated DNA methyltransferase CcrM is conserved in most Alphaproteobacteria, but its role in bacteria with complex or multicentric genomes remains unexplored. Here, we compare the methylome, the transcriptome and the phenotypes of wild-type and CcrM-depleted Agrobacterium tumefaciens cells with a dicentric chromosome with two essential replication origins. We find that DNA methylation has a pleiotropic impact on motility, biofilm formation and viability. Remarkably, CcrM promotes the expression of the repABCCh2 operon, encoding proteins required for replication initiation/partitioning at ori2, and represses gcrA, encoding a conserved global cell cycle regulator. Imaging ori1 and ori2 in live cells, we show that replication from ori2 is often delayed in cells with a hypo-methylated genome, while ori2 over-initiates in cells with a hyper-methylated genome. Further analyses show that GcrA promotes the expression of the RepCCh2 initiator, most likely through the repression of a RepECh2 anti-sense RNA. Altogether, we propose that replication at ori1 leads to a transient hemi-methylation and activation of the gcrA promoter, allowing repCCh2 activation by GcrA and contributing to initiation at ori2. This study then uncovers a novel and original connection between CcrM-dependent DNA methylation, a conserved epigenetic regulator and genome maintenance in an Alphaproteobacterial pathogen., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Published
2024
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46. tRNA-derived fragments in T lymphocyte-beta cell crosstalk and in type 1 diabetes pathogenesis in NOD mice.

Author

Brozzi F, Jacovetti C, Cosentino C, Menoud V, Wu K, Bayazit MB, Abdulkarim B, Iseli C, Guex N, Guay C, and Regazzi R

Subjects
Animals, Mice, Female, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes immunology, Apoptosis, Islets of Langerhans metabolism, Islets of Langerhans immunology, Extracellular Vesicles metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, RNA, Untranslated genetics, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 metabolism, Diabetes Mellitus, Type 1 genetics, Mice, Inbred NOD, Insulin-Secreting Cells metabolism, RNA, Transfer genetics, RNA, Transfer metabolism
Abstract

Aims/hypothesis: tRNAs play a central role in protein synthesis. Besides this canonical function, they were recently found to generate non-coding RNA fragments (tRFs) regulating different cellular activities. The aim of this study was to assess the involvement of tRFs in the crosstalk between immune cells and beta cells and to investigate their contribution to the development of type 1 diabetes., Methods: Global profiling of the tRFs present in pancreatic islets of 4- and 8-week-old NOD mice and in extracellular vesicles released by activated CD4 + T lymphocytes was performed by small RNA-seq. Changes in the level of specific fragments were confirmed by quantitative PCR. The transfer of tRFs from immune cells to beta cells occurring during insulitis was assessed using an RNA-tagging approach. The functional role of tRFs increasing in beta cells during the initial phases of type 1 diabetes was determined by overexpressing them in dissociated islet cells and by determining the impact on gene expression and beta cell apoptosis., Results: We found that the tRF pool was altered in the islets of NOD mice during the initial phases of type 1 diabetes. Part of these changes were triggered by prolonged exposure of beta cells to proinflammatory cytokines (IL-1β, TNF-α and IFN-γ) while others resulted from the delivery of tRFs produced by CD4 + T lymphocytes infiltrating the islets. Indeed, we identified several tRFs that were enriched in extracellular vesicles from CD4 + /CD25 - T cells and were transferred to beta cells upon adoptive transfer of these immune cells in NOD.SCID mice. The tRFs delivered to beta cells during the autoimmune reaction triggered gene expression changes that affected the immune regulatory capacity of insulin-secreting cells and rendered the cells more prone to apoptosis., Conclusions/interpretation: Our data point to tRFs as novel players in the crosstalk between the immune system and insulin-secreting cells and suggest a potential involvement of this novel class of non-coding RNAs in type 1 diabetes pathogenesis., Data Availability: Sequences are available from the Gene Expression Omnibus (GEO) with accession numbers GSE242568 and GSE256343., (© 2024. The Author(s).)

Published
2024
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47. Generation of induced pluripotent stem cells from ADHD patients who do or do not respond to Methylphenidate treatment.

Author

Yde Ohki CM, Walter NM, Rickli M, Iseli C, Werling AM, Döring C, Rubio B, Hoffmann P, Herms S, Walitza S, and Grünblatt E

Abstract

As a neurodevelopmental multifactorial disorder whose prevalence has been increasing worldwide, attention-deficit hyperactivity disorder (ADHD) is considered a public health concern. Methylphenidate (MPH) is the drug of choice for ADHD; however, not all patients respond fully to this treatment. Therefore, exploring the underlying molecular mechanisms involved in ADHD and potential novel therapeutic targets is crucial. Here, we generated induced pluripotent stem cells (iPSCs) from Peripheral Blood Mononuclear Cells (PBMCs) retrieved from four ADHD patients (two MPH responders and two non-responders) using Sendai virus. These lines might be helpful for the in vitro investigation of ADHD pathophysiology in a patient-specific manner., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Susanne Walitza reports a relationship with Swiss National Science Foundation that includes: funding grants. Susanne Walitza reports a relationship with European Commission Seventh Framework Programme for Research that includes: funding grants. Susanne Walitza reports a relationship with Gesamtstrategie Hochspezialisierte Medizin of the Canton of Zurich that includes: funding grants. Susanne Walitza reports a relationship with Federal Institute for Drugs and Medical Devices that includes: funding grants. Susanne Walitza reports a relationship with Zürcher Impulsprogramm zur nachhaltigen Entwicklung der Psychiatrie that includes: funding grants. Susanne Walitza reports a relationship with Hartmann Müller Foundation for Medical Research that includes: funding grants. Susanne Walitza reports a relationship with Olga Mayenfisch Foundation that includes: funding grants. Susanne Walitza reports a relationship with Gertrud Thalmann Fonds of the UPK Basel that includes: funding grants. Susanne Walitza reports a relationship with Vontobel Foundation that includes: funding grants. Susanne Walitza reports a relationship with Uniscientia Foundation that includes: funding grants. Susanne Walitza reports a relationship with Erika Schwarz Foundation that includes: funding grants. Susanne Walitza reports a relationship with Gesundheitsförderung Schweiz that includes: funding grants. Susanne Walitza reports a relationship with Heuberg Fonds that includes: funding grants. Susanne Walitza reports a relationship with National Government of Health (BAG) that includes: funding grants. Susanne Walitza reports a relationship with Horizon Europe that includes: funding grants. Susanne Walitza reports a relationship with Georg Thieme Verlag KG that includes: consulting or advisory. Susanne Walitza reports a relationship with Hogrefe Publishing Group that includes: consulting or advisory. Susanne Walitza reports a relationship with W Kohlhammer GmbH that includes: consulting or advisory. Susanne Walitza reports a relationship with Springer Nature Deutschland GmbH Heidelberg that includes: consulting or advisory. Susanne Walitza reports a relationship with Beltz Publishing Group that includes: consulting or advisory. Susanne Walitza reports a relationship with Takeda Pharmaceuticals USA Inc that includes: speaking and lecture fees. Outside professional activities and interests from Prof. Susanne Walitza are declared under the link of the University of Zurich www.uzh.ch/prof/ssl-dir/interessenbindungen/client/web/ If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Published
2024
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48. Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.

Author

Bassani S, Chrast J, Ambrosini G, Voisin N, Schütz F, Brusco A, Sirchia F, Turban L, Schubert S, Abou Jamra R, Schlump JU, DeMille D, Bayrak-Toydemir P, Nelson GR, Wong KN, Duncan L, Mosera M, Gilissen C, Vissers LELM, Pfundt R, Kersseboom R, Yttervik H, Hansen GÅM, Smeland MF, Butler KM, Lyons MJ, Carvalho CMB, Zhang C, Lupski JR, Potocki L, Flores-Gallegos L, Morales-Toquero R, Petit F, Yalcin B, Tuttle A, Elloumi HZ, McCormick L, Kukolich M, Klaas O, Horvath J, Scala M, Iacomino M, Operto F, Zara F, Writzl K, Maver A, Haanpää MK, Pohjola P, Arikka H, Kievit AJA, Calandrini C, Iseli C, Guex N, and Reymond A

Subjects
Animals, Female, Humans, Male, Loss of Function Mutation, Mutation, Missense, Phenotype, Intellectual Disability genetics, Transcriptome, Zebrafish genetics
Abstract

Background: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects., Methods: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants., Results: We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation., Conclusions: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious., (© 2024. The Author(s).)

Published
2024
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49. Inhibition of anti-tumor immunity by melanoma cell-derived Activin-A depends on STING.

Author

Pinjusic K, Ambrosini G, Lourenco J, Fournier N, Iseli C, Guex N, Egorova O, Nassiri S, and Constam DB

Subjects
Animals, Mice, Signal Transduction, Tumor Microenvironment, Activins metabolism, Melanoma immunology, Transforming Growth Factor beta metabolism, Tumor Escape
Abstract

The transforming growth factor-β (TGF-β) family member activin A (hereafter Activin-A) is overexpressed in many cancer types, often correlating with cancer-associated cachexia and poor prognosis. Activin-A secretion by melanoma cells indirectly impedes CD8 + T cell-mediated anti-tumor immunity and promotes resistance to immunotherapies, even though Activin-A can be proinflammatory in other contexts. To identify underlying mechanisms, we here analyzed the effect of Activin-A on syngeneic grafts of Braf mutant YUMM3.3 mouse melanoma cells and on their microenvironment using single-cell RNA sequencing. We found that the Activin-A-induced immune evasion was accompanied by a proinflammatory interferon signature across multiple cell types, and that the associated increase in tumor growth depended at least in part on pernicious STING activity within the melanoma cells. Besides corroborating a role for proinflammatory signals in facilitating immune evasion, our results suggest that STING holds considerable potential as a therapeutic target to mitigate tumor-promoting Activin-A signaling at least in melanoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pinjusic, Ambrosini, Lourenco, Fournier, Iseli, Guex, Egorova, Nassiri and Constam.)

Published
2024
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50. A phase 1 trial of adoptive transfer of vaccine-primed autologous circulating T cells in ovarian cancer.

Author

Bobisse S, Bianchi V, Tanyi JL, Sarivalasis A, Missiaglia E, Pétremand R, Benedetti F, Torigian DA, Genolet R, Barras D, Michel A, Mastroyannis SA, Zsiros E, Dangaj Laniti D, Tsourti Z, Stevenson BJ, Iseli C, Levine BL, Speiser DE, Gfeller D, Bassani-Sternberg M, Powell DJ Jr, June CH, Dafni U, Kandalaft LE, Harari A, and Coukos G

Subjects
Humans, Female, Adoptive Transfer, Vaccination, T-Lymphocytes, Ovarian Neoplasms therapy, Vaccines
Abstract

We have previously shown that vaccination with tumor-pulsed dendritic cells amplifies neoantigen recognition in ovarian cancer. Here, in a phase 1 clinical study ( NCT01312376 /UPCC26810) including 19 patients, we show that such responses are further reinvigorated by subsequent adoptive transfer of vaccine-primed, ex vivo-expanded autologous peripheral blood T cells. The treatment is safe, and epitope spreading with novel neopeptide reactivities was observed after cell infusion in patients who experienced clinical benefit, suggesting reinvigoration of tumor-sculpting immunity., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Published
2023
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