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1. Identification of novel genetic loci for risk of multiple myeloma by functional annotation

Author

Macauda, Angelica, Briem, Klara, Clay-Gilmour, Alyssa, Cozen, Wendy, Försti, Asta, Giaccherini, Matteo, Corradi, Chiara, Sainz, Juan, Niazi, Yasmeen, ter Horst, Rob, Li, Yang, Netea, Mihai G., Vogel, Ulla, Hemminki, Kari, Slager, Susan L., Varkonyi, Judit, Andersen, Vibeke, Iskierka-Jazdzewska, Elzbieta, Mártinez-Lopez, Joaquin, Zaucha, Jan, Camp, Nicola J., Rajkumar, S. Vincent, Druzd-Sitek, Agnieszka, Bhatti, Parveen, Chanock, Stephen J., Kumar, Shaji K., Subocz, Edyta, Mazur, Grzegorz, Landi, Stefano, Machiela, Mitchell J., Jerez, Andrés, Norman, Aaron D., Hildebrandt, Michelle A. T., Kadar, Katalin, Berndt, Sonja I., Ziv, Elad, Buda, Gabriele, Nagler, Arnon, Dumontet, Charles, Raźny, Malgorzata, Watek, Marzena, Butrym, Aleksandra, Grzasko, Norbert, Dudzinski, Marek, Rybicka-Ramos, Malwina, Matera, Eva-Laure, García-Sanz, Ramón, Goldschmidt, Hartmut, Jamroziak, Krzysztof, Jurczyszyn, Artur, Clavero, Esther, Giles, Graham G., Pelosini, Matteo, Zawirska, Daria, Kruszewski, Marcin, Marques, Herlander, Haastrup, Eva, Sánchez-Maldonado, José Manuel, Bertsch, Uta, Rymko, Marcin, Raab, Marc-Steffen, Brown, Elizabeth E., Hofmann, Jonathan N., Vachon, Celine, Campa, Daniele, and Canzian, Federico

Published
2023
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3. Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization

Author

Clavero, Esther, primary, Sanchez-Maldonado, José Manuel, additional, Macauda, Angelica, additional, Ter Horst, Rob, additional, Sampaio-Marques, Belém, additional, Jurczyszyn, Artur, additional, Clay-Gilmour, Alyssa, additional, Stein, Angelika, additional, Hildebrandt, Michelle A. T., additional, Weinhold, Niels, additional, Buda, Gabriele, additional, García-Sanz, Ramón, additional, Tomczak, Waldemar, additional, Vogel, Ulla, additional, Jerez, Andrés, additional, Zawirska, Daria, additional, Wątek, Marzena, additional, Hofmann, Jonathan N., additional, Landi, Stefano, additional, Spinelli, John J., additional, Butrym, Aleksandra, additional, Kumar, Abhishek, additional, Martínez-López, Joaquín, additional, Galimberti, Sara, additional, Sarasquete, María Eugenia, additional, Subocz, Edyta, additional, Iskierka-Jażdżewska, Elzbieta, additional, Giles, Graham G., additional, Rybicka-Ramos, Malwina, additional, Kruszewski, Marcin, additional, Abildgaard, Niels, additional, Verdejo, Francisco García, additional, Sánchez Rovira, Pedro, additional, da Silva Filho, Miguel Inacio, additional, Kadar, Katalin, additional, Razny, Małgorzata, additional, Cozen, Wendy, additional, Pelosini, Matteo, additional, Jurado, Manuel, additional, Bhatti, Parveen, additional, Dudzinski, Marek, additional, Druzd-Sitek, Agnieszka, additional, Orciuolo, Enrico, additional, Li, Yang, additional, Norman, Aaron D., additional, Zaucha, Jan Maciej, additional, Reis, Rui Manuel, additional, Markiewicz, Miroslaw, additional, Rodríguez Sevilla, Juan José, additional, Andersen, Vibeke, additional, Jamroziak, Krzysztof, additional, Hemminki, Kari, additional, Berndt, Sonja I., additional, Rajkumar, Vicent, additional, Mazur, Grzegorz, additional, Kumar, Shaji K., additional, Ludovico, Paula, additional, Nagler, Arnon, additional, Chanock, Stephen J., additional, Dumontet, Charles, additional, Machiela, Mitchell J., additional, Varkonyi, Judit, additional, Camp, Nicola J., additional, Ziv, Elad, additional, Vangsted, Annette Juul, additional, Brown, Elizabeth E., additional, Campa, Daniele, additional, Vachon, Celine M., additional, Netea, Mihai G., additional, Canzian, Federico, additional, Försti, Asta, additional, and Sainz, Juan, additional

Published
2023
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4. Randomized phase II study of weekly carfilzomib 70 mg/m2 and dexamethasone with or without cyclophosphamide in relapsed and/or refractory multiple myeloma patients

Author

Puertas, Borja, primary, González-Calle, Verónica, additional, Sureda, Anna, additional, Moreno, María José, additional, Oriol, Albert, additional, González, Esther, additional, Rosiñol, Laura, additional, López, Jordi, additional, Escalante, Fernando, additional, Martínez-Lopez, Joaquín, additional, Carrillo, Estrella, additional, Clavero, Esther, additional, Ríos-Tamayo, Rafael, additional, Rey-Bua, Beatriz, additional, González-Rodríguez, Ana Pilar, additional, Dourdil, Victoria, additional, De Arriba, Felipe, additional, González, Sonia, additional, Pérez-de-Oteyza, Jaime, additional, Hernández, Miguel T., additional, García-Mateo, Aránzazu, additional, Bargay, Joan, additional, Bladé, Joan, additional, Lahuerta, Juan José, additional, San Miguel, Jesús F., additional, Ocio, Enrique M., additional, and Mateos, María-Victoria, additional

Published
2023
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5. Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization

Author

Clavero, Esther, Martínez López, Joaquín, Sainz, Juan, Clavero, Esther, Martínez López, Joaquín, and Sainz, Juan

Abstract

2023 Descuento MDPI, Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10−9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27− cells (p = 9.3 × 10−4). These results suggest that genetic variants within these six loci influ, European Commission, Instituto de Salud Carlos III, Comunidad Autónoma de Madrid, CRIS foundation against cancer, Cancer Network of Excellence, Dietmar Hopp Foundation, German Ministry of Education and Science, National Cancer Institute of the National Institutes of Health, Foundation for Science and Technology (Portugal), European Regional Development Fund, Depto. de Medicina, Fac. de Medicina, FALSE, pub, Descuento UCM

Published
2023

6. Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma:A Meta-Analysis of Three Large Cohorts and Functional Characterization

Author

Clavero, Esther, Sanchez-Maldonado, José Manuel, Macauda, Angelica, Ter Horst, Rob, Sampaio-Marques, Belém, Jurczyszyn, Artur, Clay-Gilmour, Alyssa, Stein, Angelika, Hildebrandt, Michelle A.T., Weinhold, Niels, Buda, Gabriele, García-Sanz, Ramón, Tomczak, Waldemar, Vogel, Ulla, Jerez, Andrés, Zawirska, Daria, Wątek, Marzena, Hofmann, Jonathan N., Landi, Stefano, Spinelli, John J., Butrym, Aleksandra, Kumar, Abhishek, Martínez-López, Joaquín, Galimberti, Sara, Sarasquete, María Eugenia, Subocz, Edyta, Iskierka-Jażdżewska, Elzbieta, Giles, Graham G., Rybicka-Ramos, Malwina, Kruszewski, Marcin, Abildgaard, Niels, Verdejo, Francisco García, Sánchez Rovira, Pedro, da Silva Filho, Miguel Inacio, Kadar, Katalin, Razny, Małgorzata, Cozen, Wendy, Pelosini, Matteo, Jurado, Manuel, Bhatti, Parveen, Dudzinski, Marek, Druzd-Sitek, Agnieszka, Orciuolo, Enrico, Li, Yang, Norman, Aaron D., Zaucha, Jan Maciej, Reis, Rui Manuel, Markiewicz, Miroslaw, Rodríguez Sevilla, Juan José, Andersen, Vibeke, Jamroziak, Krzysztof, Hemminki, Kari, Berndt, Sonja I., Rajkumar, Vicent, Mazur, Grzegorz, Kumar, Shaji K., Ludovico, Paula, Nagler, Arnon, Chanock, Stephen J., Dumontet, Charles, Machiela, Mitchell J., Varkonyi, Judit, Camp, Nicola J., Ziv, Elad, Vangsted, Annette Juul, Brown, Elizabeth E., Campa, Daniele, Vachon, Celine M., Netea, Mihai G., Canzian, Federico, Försti, Asta, Sainz, Juan, Clavero, Esther, Sanchez-Maldonado, José Manuel, Macauda, Angelica, Ter Horst, Rob, Sampaio-Marques, Belém, Jurczyszyn, Artur, Clay-Gilmour, Alyssa, Stein, Angelika, Hildebrandt, Michelle A.T., Weinhold, Niels, Buda, Gabriele, García-Sanz, Ramón, Tomczak, Waldemar, Vogel, Ulla, Jerez, Andrés, Zawirska, Daria, Wątek, Marzena, Hofmann, Jonathan N., Landi, Stefano, Spinelli, John J., Butrym, Aleksandra, Kumar, Abhishek, Martínez-López, Joaquín, Galimberti, Sara, Sarasquete, María Eugenia, Subocz, Edyta, Iskierka-Jażdżewska, Elzbieta, Giles, Graham G., Rybicka-Ramos, Malwina, Kruszewski, Marcin, Abildgaard, Niels, Verdejo, Francisco García, Sánchez Rovira, Pedro, da Silva Filho, Miguel Inacio, Kadar, Katalin, Razny, Małgorzata, Cozen, Wendy, Pelosini, Matteo, Jurado, Manuel, Bhatti, Parveen, Dudzinski, Marek, Druzd-Sitek, Agnieszka, Orciuolo, Enrico, Li, Yang, Norman, Aaron D., Zaucha, Jan Maciej, Reis, Rui Manuel, Markiewicz, Miroslaw, Rodríguez Sevilla, Juan José, Andersen, Vibeke, Jamroziak, Krzysztof, Hemminki, Kari, Berndt, Sonja I., Rajkumar, Vicent, Mazur, Grzegorz, Kumar, Shaji K., Ludovico, Paula, Nagler, Arnon, Chanock, Stephen J., Dumontet, Charles, Machiela, Mitchell J., Varkonyi, Judit, Camp, Nicola J., Ziv, Elad, Vangsted, Annette Juul, Brown, Elizabeth E., Campa, Daniele, Vachon, Celine M., Netea, Mihai G., Canzian, Federico, Försti, Asta, and Sainz, Juan

Abstract

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10−9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4)

Published
2023

7. Randomized phase II study of weekly carfilzomib 70 mg/m2 and dexamethasone with or without cyclophosphamide in relapsed and/or refractory multiple myeloma patients

Author

Pethema Foundation, International Myeloma Foundation, Puertas Martínez, Borja, González-Calle, Verónica, Sureda, Anna, Moreno, María José, Oriol, Albert, González, Esther, Rosiñol, Laura, López, Jordi, Escalante, Fernando, Martínez-López, Joaquín, Carrillo Cruz, Estrella, Clavero, Esther, Ríos-Tamayo, R., Rey-Bua, Beatriz, Gonzalez-Rodriguez, Ana Pilar, Dourdil, Mª Victoria, Arriba, Felipe de, González, Sonia, Pérez de Oteyza, Jaime, Hernandez, Miguel T., García-Mateo, Aránzazu, Bargay, Joan, Bladé, Joan, Lahuerta, Juan José, San Miguel, Jesús F., Ocio, Enrique M., Mateos, Maria Victoria, Pethema Foundation, International Myeloma Foundation, Puertas Martínez, Borja, González-Calle, Verónica, Sureda, Anna, Moreno, María José, Oriol, Albert, González, Esther, Rosiñol, Laura, López, Jordi, Escalante, Fernando, Martínez-López, Joaquín, Carrillo Cruz, Estrella, Clavero, Esther, Ríos-Tamayo, R., Rey-Bua, Beatriz, Gonzalez-Rodriguez, Ana Pilar, Dourdil, Mª Victoria, Arriba, Felipe de, González, Sonia, Pérez de Oteyza, Jaime, Hernandez, Miguel T., García-Mateo, Aránzazu, Bargay, Joan, Bladé, Joan, Lahuerta, Juan José, San Miguel, Jesús F., Ocio, Enrique M., and Mateos, Maria Victoria

Abstract

In this randomized phase II study (GEM-KyCyDex, clinicaltrials gov. Identifier: NCT03336073), the combination of weekly carfilzomib 70 mg/m2, cyclophosphamide and dexamethasone (KCd) was compared to carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM) after 1-3 prior lines (PL). One hundred and ninety-seven patients were included and randomized 1:1 to receive KCd (97 patients) or Kd (100 patients) in 28-day cycles until progressive disease or unacceptable toxicity occurred. Patient median age was 70 years, and the median number of PL was one (range, 1-3). More than 90% of patients had previously been exposed to proteasome inhibitors, approximetely 70% to immunomodulators, and approximetely 50% were refractory to their last line (mainly lenalidomide) in both groups. After a median follow-up of 37 months, median progression-free survival (PFS) was 19.1 and 16.6 months in KCd and Kd, respectively (P=0.577). Of note, in the post hoc analysis of the lenalidomide-refractory population, the addition of cyclophosphamide to Kd resulted in a significant benefit in terms of PFS: 18.4 versus 11.3 months (hazard ratio =1.7, 95% confidence interval: 1.1-2.7; P=0.043). The overall response rate and the percentage of patients who achieved complete response was around 70% and 20% in both groups. The addition of cyclophosphamide to Kd did not result in any safety signal, except for severe infections (7% vs. 2%). In conclusion, the combination of cyclophosphamide with Kd 70 mg/m2 weekly does not improve outcomes as compared with Kd alone in RRMM after 1-3 PL, but a significant benefit in PFS was observed with the triplet combination in the lenalidomide-refractory population. The administration of weekly carfilzomib 70 mg/m2 was safe and convenient, and, overall, the toxicity was manageable in both arms.

Published
2023

8. Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization

Author

European Commission, Instituto de Salud Carlos III, Fundación CRIS contra el Cáncer, Dietmar Hopp Foundation, Federal Ministry of Education and Research (Germany), Fundação para a Ciência e a Tecnologia (Portugal), Clavero, Esther, Sanchez-Maldonado, José Manuel, Macauda, Angélica, Ter Horst, Rob, Sampaio-Marques, Belém, Jurczyszyn, Artur, Clay-Gilmour, Alyssa, Stein, Angelika, Hildebrandt, Michelle A. T., Weinhold, Niels, Buda, Gabriele, García-Sanz, Ramón, Tomczak, Waldemar, Vogel, Ulla, Jerez, Andrés, Zawirska, Daria, Wątek, Marzena, Hofmann, Jonathan N., Landi, Stefano, Spinelli, John J., Butrym, Aleksandra, Kumar, Abhishek, Martínez-López, Joaquín, Galimberti, Sara, Sarasquete, María Eugenia, Subocz, Edyta, Iskierka-Jażdżewska, Elzbieta, Giles, Graham G., Rybicka-Ramos, Malwina, Kruszewski, Marcin, Abildgaard, Niels, Verdejo, Francisco García, Sánchez Rovira, Pedro, da Silva Filho, Miguel Inacio, Kadar, Katalin, Razny, Małgorzata, Cozen, Wendy, Pelosini, Matteo, Jurado, Manuel, Bhatti, Parveen, Dudzinski, Marek, Druzd-Sitek, Agnieszka, Orciuolo, Enrico, Li, Yang, Norman, Aaron D, Zaucha, Jan Maciej, Reis, Rui Manuel, Markiewicz, Miroslaw, Rodríguez Sevilla, Juan José, Andersen, Vibeke, Jamroziak, Krzysztof, Hemminki, Kari, Berndt, Sonja I., Rajkumar, Vicent, Mazur, Grzegorz, Kumar, Shaji K., Ludovico, Paula, Nagler, Arnon, Chanock, Stephen J., Dumontet, Charles, Machiela, Mitchell J., Varkonyi, Judit, Camp, Nicola J., Ziv, Elad, Vangsted, Annette Juul, Brown, Elizabeth E., Campa, Daniele, Vachon, Celine M., Netea, Mihai G., Canzian, Federico, Försti, Asta, Sainz, Juan, European Commission, Instituto de Salud Carlos III, Fundación CRIS contra el Cáncer, Dietmar Hopp Foundation, Federal Ministry of Education and Research (Germany), Fundação para a Ciência e a Tecnologia (Portugal), Clavero, Esther, Sanchez-Maldonado, José Manuel, Macauda, Angélica, Ter Horst, Rob, Sampaio-Marques, Belém, Jurczyszyn, Artur, Clay-Gilmour, Alyssa, Stein, Angelika, Hildebrandt, Michelle A. T., Weinhold, Niels, Buda, Gabriele, García-Sanz, Ramón, Tomczak, Waldemar, Vogel, Ulla, Jerez, Andrés, Zawirska, Daria, Wątek, Marzena, Hofmann, Jonathan N., Landi, Stefano, Spinelli, John J., Butrym, Aleksandra, Kumar, Abhishek, Martínez-López, Joaquín, Galimberti, Sara, Sarasquete, María Eugenia, Subocz, Edyta, Iskierka-Jażdżewska, Elzbieta, Giles, Graham G., Rybicka-Ramos, Malwina, Kruszewski, Marcin, Abildgaard, Niels, Verdejo, Francisco García, Sánchez Rovira, Pedro, da Silva Filho, Miguel Inacio, Kadar, Katalin, Razny, Małgorzata, Cozen, Wendy, Pelosini, Matteo, Jurado, Manuel, Bhatti, Parveen, Dudzinski, Marek, Druzd-Sitek, Agnieszka, Orciuolo, Enrico, Li, Yang, Norman, Aaron D, Zaucha, Jan Maciej, Reis, Rui Manuel, Markiewicz, Miroslaw, Rodríguez Sevilla, Juan José, Andersen, Vibeke, Jamroziak, Krzysztof, Hemminki, Kari, Berndt, Sonja I., Rajkumar, Vicent, Mazur, Grzegorz, Kumar, Shaji K., Ludovico, Paula, Nagler, Arnon, Chanock, Stephen J., Dumontet, Charles, Machiela, Mitchell J., Varkonyi, Judit, Camp, Nicola J., Ziv, Elad, Vangsted, Annette Juul, Brown, Elizabeth E., Campa, Daniele, Vachon, Celine M., Netea, Mihai G., Canzian, Federico, Försti, Asta, and Sainz, Juan

Abstract

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10−9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27− cells (p = 9.3 × 10−4). These results suggest that genetic variants within these six loci influ

Published
2023

9. Identification of novel genetic loci for risk of multiple myeloma by functional annotation

Author

European Commission, National Cancer Institute (US), National Institutes of Health (US), Projekt DEAL, Macauda, Angelica, Briem, Klara, Clay-Gilmour, Alyssa, Cozen, Wendy, Försti, Asta, Giaccherini, Matteo, Corradi, Chiara, Sainz, Juan, Niazi, Yasmeen, Ter Horst, Rob, Li, Yang, Netea, Mihai G., Vogel, Ulla, Hemminki, Kari, Slager, Susan L., Varkonyi, Judit, Andersen, Vibeke, Iskierka-Jazdzewska, Elżbieta, Martínez-López, Joaquín, Zaucha, Jan, Camp, Nicola J., Rajkumar, S. Vincent, Druzd-Sitek, Agnieszka, Bhatti, Parveen, Chanock, Stephen J., Kumar, Shaji K., Subocz, Edyta, Mazur, Grzegorz, Landi, Stefano, Machiela, Mitchell J., Jerez, Andrés, Norman, Aaron D., Hildebrandt, Michelle A. T., Kadar, Katalin, Berndt, Sonja I., Ziv, Elad, Buda, Gabriele, Nagler, Arnon, Dumontet, Charles, Raźny, Malgorzata, Watek, Marzena, Butrym, Aleksandra, Grzasko, Norbert, Dudzinski, Marek, Rybicka-Ramos, Malwina, Matera, Eva-Laure, García-Sanz, Ramón, Goldschmidt, Hartmut, Jamroziak, Krzysztof, Jurczyszyn, Artur, Clavero, Esther, Giles, Graham G., Pelosini, Matteo, Zawirska, Daria, Kruszewski, Marcin, Marques, Herlander, Haastrup, Eva, Sánchez Maldonado, José Manuel, Bertsch, Uta, Rymko, Marcin, Raab, Marc-Steffen, Brown, Elizabeth E., Hofmann, Jonathan N., Vachon, Celine, Campa, Daniele, Canzian, Federico, European Commission, National Cancer Institute (US), National Institutes of Health (US), Projekt DEAL, Macauda, Angelica, Briem, Klara, Clay-Gilmour, Alyssa, Cozen, Wendy, Försti, Asta, Giaccherini, Matteo, Corradi, Chiara, Sainz, Juan, Niazi, Yasmeen, Ter Horst, Rob, Li, Yang, Netea, Mihai G., Vogel, Ulla, Hemminki, Kari, Slager, Susan L., Varkonyi, Judit, Andersen, Vibeke, Iskierka-Jazdzewska, Elżbieta, Martínez-López, Joaquín, Zaucha, Jan, Camp, Nicola J., Rajkumar, S. Vincent, Druzd-Sitek, Agnieszka, Bhatti, Parveen, Chanock, Stephen J., Kumar, Shaji K., Subocz, Edyta, Mazur, Grzegorz, Landi, Stefano, Machiela, Mitchell J., Jerez, Andrés, Norman, Aaron D., Hildebrandt, Michelle A. T., Kadar, Katalin, Berndt, Sonja I., Ziv, Elad, Buda, Gabriele, Nagler, Arnon, Dumontet, Charles, Raźny, Malgorzata, Watek, Marzena, Butrym, Aleksandra, Grzasko, Norbert, Dudzinski, Marek, Rybicka-Ramos, Malwina, Matera, Eva-Laure, García-Sanz, Ramón, Goldschmidt, Hartmut, Jamroziak, Krzysztof, Jurczyszyn, Artur, Clavero, Esther, Giles, Graham G., Pelosini, Matteo, Zawirska, Daria, Kruszewski, Marcin, Marques, Herlander, Haastrup, Eva, Sánchez Maldonado, José Manuel, Bertsch, Uta, Rymko, Marcin, Raab, Marc-Steffen, Brown, Elizabeth E., Hofmann, Jonathan N., Vachon, Celine, Campa, Daniele, and Canzian, Federico

Abstract

Multiple myeloma (MM) is one of the most common hematological malignancies, accounting for 20% of all newly diagnosed hematological cancers [1]. The most recent data from Cancer Today show that in 2020 the number of new MM cases was 176,404 worldwide

Published
2023

10. OAB-050: Randomized phase 2 study of weekly carfilzomib 70 mg/m2 and dexamethasone plus/minus cyclophosphamide in relapsed and/or refractory multiple (MM) patients (GEMKyCyDex)

Author

Puertas, Borja, primary, González, Verónica, additional, Sureda, Anna, additional, Moreno, Mª José, additional, Oriol, Albert, additional, González, Mª Esther, additional, Rosiñol, Laura, additional, López, Jordi, additional, Escalante, Fernando, additional, López, Joaquín Martinez, additional, Carrillo, Estrella, additional, Clavero, Esther, additional, Rodríguez, Ana Pilar González, additional, Dourdil, Victoria, additional, de la Fuente, Felipe de Arriba, additional, González, Marta Sonia, additional, de Oteyza, Jaime Pérez, additional, Hernández, Miguel teodoro, additional, Mateo, Aránzazu García, additional, Blade, Joan, additional, Palacios, Juan José Lahuerta, additional, San-Miguel, Jesus, additional, Ocio, Enrique, additional, and Mateos, María-Victoria, additional

Published
2022
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11. Sistema de gestión del talento en una organización desde el prisma de la Prevención de Riesgos Laborales

Author

Gandía Clavero, Esther and Laguna Pardo, Víctor Manuel

Abstract

La Gestión del Talento y la Prevención de Riesgos Laborales son dos de los pilares fundamentales para el desarrollo y crecimiento interno de las organizaciones, los cuales no se ponen en valor de manera conjunta.Este trabajo pretende poner en valor ambas áreas integradas, no por separado, y plasmar la creación de valor que tiene para la empresa que estén fusionadas en una sola.El principal objetivo que tiene este trabajo es dar a conocer la importancia que tiene en los resultados finales de la organización la gestión eficiente de ambas partes. Los beneficios que presenta y las posibilidades de evolucionar que tienen las organizaciones si invierten en estas áreas.Para ello se exponen los conceptos más importantes de forma separada de cada una de las áreas y posteriormente de forma integrada, presentando los beneficios y las ventajas que supone para la empresa.Se abarcan los temas principales sobre los procesos de Gestión del Talento Humano, siendo el desarrollo de Selección de personal, Evaluación del desempeño y Formación. Considerándose los principales y más importantes dentro de una organización. Estos se plantean integrándolos dentro de la Prevención de Riesgos Laborales.Para reflejar y hacer una idea de lo que supone dentro de una organización, se ha realizado una encuesta que contempla factores psicosociales tales como la Carga mental, Autonomía temporal, Contenido del trabajo, Supervisión y participación, Definición de rol, Interés por el trabajador y Relaciones personales.En función de los resultados del cuestionario se plantean una serie de líneas de actuación para un plan de acción a desarrollar por la empresa para mejorar los resultados de las próximas encuestas y evolucionar como organización.Finalmente se plantea un desarrollo sobre los temas principales sobre los procesos de Gestión del Talento Humano, citados anteriormente; cerrando el documento con una serie de conclusiones finales.En adición final, se han incluido los Objetivos de Desarrollo Sostenible que están alineados con el Trabajo Final de Grado. Además, se han expuesto las metas que persiguen cada uno de estos. El motivo por el que se ha considerado añadirlos ha sido por la importancia que suponen para la empresa los ODS a modo de guía o mapa que les permitirá identificar si su impacto social, económico y medioambiental aporta valor a la sociedad. Como consecuencia, fortalecen su imagen y relaciones con los distintos grupos de interés.

Published
2022

12. Polymorphisms within the TNFSF4 and MAPKAPK2 Loci Influence the Risk of Developing Invasive Aspergillosis: A Two-Stage Case Control Study in the Context of the aspBIOmics Consortium

Author

Sánchez-Maldonado, Jose Manuel, Moñiz-Díez, Ana, Ter Horst, Rob, Campa, Daniele, Cabrera-Serrano, Antonio José, Martínez-Bueno, Manuel, Garrido-Collado, María Del Pilar, Hernández-Mohedo, Francisca, Fernández-Puerta, Laura, López-Nevot, Miguel Ángel, Cunha, Cristina, González-Sierra, Pedro Antonio, Springer, Jan, Lackner, Michaela, Alcazar-Fuoli, Laura, Fianchi, Luana, Aguado, José María, Pagano, Livio, López-Fernández, Elisa, Clavero, Esther, Potenza, Leonardo, Luppi, Mario, Moratalla, Lucia, Solano, Carlo, Sampedro, Antonio, Cuenca-Estrella, Manuel, Lass-Flörl, Cornelia, Pcraga Study Group, Null, Canzian, Federico, Loeffler, Juergen, Li, Yang, Einsele, Hermann, Netea, Mihai G, Vázquez, Lourde, Carvalho, Agostinho, Jurado, Manuel, Sainz, Juan, Pagano, Livio (ORCID:0000-0001-8287-928X), Sánchez-Maldonado, Jose Manuel, Moñiz-Díez, Ana, Ter Horst, Rob, Campa, Daniele, Cabrera-Serrano, Antonio José, Martínez-Bueno, Manuel, Garrido-Collado, María Del Pilar, Hernández-Mohedo, Francisca, Fernández-Puerta, Laura, López-Nevot, Miguel Ángel, Cunha, Cristina, González-Sierra, Pedro Antonio, Springer, Jan, Lackner, Michaela, Alcazar-Fuoli, Laura, Fianchi, Luana, Aguado, José María, Pagano, Livio, López-Fernández, Elisa, Clavero, Esther, Potenza, Leonardo, Luppi, Mario, Moratalla, Lucia, Solano, Carlo, Sampedro, Antonio, Cuenca-Estrella, Manuel, Lass-Flörl, Cornelia, Pcraga Study Group, Null, Canzian, Federico, Loeffler, Juergen, Li, Yang, Einsele, Hermann, Netea, Mihai G, Vázquez, Lourde, Carvalho, Agostinho, Jurado, Manuel, Sainz, Juan, and Pagano, Livio (ORCID:0000-0001-8287-928X)

Abstract

nvasive aspergillosis (IA) is a life-threatening infection that affects an increasing number of patients undergoing chemotherapy or allo-transplantation, and recent studies have shown that genetic factors contribute to disease susceptibility. In this two-stage, population-based, case-control study, we evaluated whether 7 potentially functional single nucleotide polymorphisms (SNPs) within the ARNT2 and CX3CR1 genes influence the risk of IA in high-risk hematological patients. We genotyped selected SNPs in a cohort of 500 hematological patients (103 of those had been diagnosed with proven or probable IA), and we evaluated their association with the risk of developing IA. The association of the most interesting markers of IA risk was then validated in a replication population, including 474 subjects (94 IA and 380 non-IA patients). Functional experiments were also performed to confirm the biological relevance of the most interesting markers. The meta-analysis of both populations showed that carriers of the ARNT2 rs1374213G, CX3CR1 rs7631529A, and CX3CR1 rs9823718G alleles (where the RefSeq identifier appears as a subscript) had a significantly increased risk of developing IA according to a log-additive model (P value from the meta-analysis [P Meta] = 9.8 · 10-5, P Meta = 1.5 · 10-4, and P Meta =7.9 · 10-5, respectively). Haplotype analysis also confirmed the association of the CX3CR1 haplotype with AG CGG with an increased risk of IA (P = 4.0 · 10-4). Mechanistically, we observed that monocyte-derived macrophages (MDM) from subjects carrying the ARNTR2 rs1374213G allele or the GG genotype showed a significantly impaired fungicidal activity but that MDM from carriers of the ARNT2 rs1374213G and CX3CR1 rs9823718G or CX3CR1 rs7631529A alleles had deregulated immune responses to Aspergillus conidia. These results, together with those from expression quantitative trait locus (eQTL) data browsers showing a strong correlation of the CX3CR1 rs9823718G allele with lower levels

Published
2020

13. Polymorphisms within the TNFSF4 and MAPKAPK2 Loci Influence the Risk of Developing Invasive Aspergillosis: A Two-Stage Case Control Study in the Context of the aspBIOmics Consortium.

Author

Manuel Sánchez-Maldonado, Jose, Moñiz-Díez, Ana, Horst, Rob ter, Campa, Daniele, José Cabrera-Serrano, Antonio, Martínez-Bueno, Manuel, del Pilar Garrido-Collado, María, Hernández-Mohedo, Francisca, Fernández-Puerta, Laura, Ángel López-Nevot, Miguel, Cunha, Cristina, Antonio González-Sierra, Pedro, Springer, Jan, Lackner, Michaela, Alcazar-Fuoli, Laura, Fianchi, Luana, María Aguado, José, Pagano, Livio, López-Fernández, Elisa, and Clavero, Esther

Subjects
ASPERGILLOSIS, SINGLE nucleotide polymorphisms, MACROPHAGES, MITOGEN-activated protein kinases, B cells
Abstract

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk. [ABSTRACT FROM AUTHOR]

Published
2021
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14. Effect of different CO2 concentrations on biomass, pigment content, and lipid production of the marine diatom <italic>Thalassiosira pseudonana</italic>.

Author

Sabia, Alessandra, Clavero, Esther, Pancaldi, Simonetta, and Salvadó Rovira, Joan

Subjects
*THALASSIOSIRA pseudonana, *CARBON dioxide, *BIOMASS production, *PIGMENTS, *LIPIDS, *FATTY acids
Abstract

The marine diatom Thalassiosira pseudonana grown under air (0.04% CO2) and 1 and 5% CO2 concentrations was evaluated to determine its potential for CO2 mitigation coupled with biodiesel production. Results indicated that the diatom cultures grown at 1 and 5% CO2 showed higher growth rates (1.14 and 1.29 div day−1, respectively) and biomass productivities (44 and 48 mgAFDWL−1 day−1) than air grown cultures (with 1.13 div day−1 and 26 mgAFDWL−1 day−1). The increase of CO2 resulted in higher cell volume and pigment content per cell of T. pseudonana. Interestingly, lipid content doubled when air was enriched with 1–5% CO2. Moreover, the analysis of the fatty acid composition of T. pseudonana revealed the predominance of monounsaturated acids (palmitoleic-16:1 and oleic-18:1) and a decrease of the saturated myristic acid-14:0 and polyunsaturated fatty acids under high CO2 levels. These results suggested that T. pseudonana seems to be an ideal candidate for biodiesel production using flue gases. [ABSTRACT FROM AUTHOR]

Published
2018
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15. Randomized phase II study of weekly carfilzomib 70 mg/m 2 and dexamethasone with or without cyclophosphamide in relapsed and/or refractory multiple myeloma patients.

Author

Puertas B, González-Calle V, Sureda A, Moreno MJ, Oriol A, González E, Rosiñol L, López J, Escalante F, Martínez-Lopez J, Carrillo E, Clavero E, Ríos-Tamayo R, Rey-Bua B, González-Rodríguez AP, Dourdil V, De Arriba F, González S, Pérez-de-Oteyza J, Hernández MT, García-Mateo A, Bargay J, Bladé J, Lahuerta JJ, San Miguel JF, Ocio EM, and Mateos MV

Subjects
Humans, Aged, Lenalidomide therapeutic use, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide adverse effects, Dexamethasone adverse effects, Multiple Myeloma drug therapy
Abstract

In this randomized phase II study (GEM-KyCyDex, clinicaltrials gov. Identifier: NCT03336073), the combination of weekly carfilzomib 70 mg/m2, cyclophosphamide and dexamethasone (KCd) was compared to carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM) after 1-3 prior lines (PL). One hundred and ninety-seven patients were included and randomized 1:1 to receive KCd (97 patients) or Kd (100 patients) in 28-day cycles until progressive disease or unacceptable toxicity occurred. Patient median age was 70 years, and the median number of PL was one (range, 1-3). More than 90% of patients had previously been exposed to proteasome inhibitors, approximetely 70% to immunomodulators, and approximetely 50% were refractory to their last line (mainly lenalidomide) in both groups. After a median follow-up of 37 months, median progression-free survival (PFS) was 19.1 and 16.6 months in KCd and Kd, respectively (P=0.577). Of note, in the post hoc analysis of the lenalidomide-refractory population, the addition of cyclophosphamide to Kd resulted in a significant benefit in terms of PFS: 18.4 versus 11.3 months (hazard ratio =1.7, 95% confidence interval: 1.1-2.7; P=0.043). The overall response rate and the percentage of patients who achieved complete response was around 70% and 20% in both groups. The addition of cyclophosphamide to Kd did not result in any safety signal, except for severe infections (7% vs. 2%). In conclusion, the combination of cyclophosphamide with Kd 70 mg/m2 weekly does not improve outcomes as compared with Kd alone in RRMM after 1-3 PL, but a significant benefit in PFS was observed with the triplet combination in the lenalidomide-refractory population. The administration of weekly carfilzomib 70 mg/m2 was safe and convenient, and, overall, the toxicity was manageable in both arms.

Published
2023
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16. Polymorphisms within the TNFSF4 and MAPKAPK2 Loci Influence the Risk of Developing Invasive Aspergillosis: A Two-Stage Case Control Study in the Context of the aspBIOmics Consortium.

Author

Sánchez-Maldonado JM, Moñiz-Díez A, Ter Horst R, Campa D, Cabrera-Serrano AJ, Martínez-Bueno M, Garrido-Collado MDP, Hernández-Mohedo F, Fernández-Puerta L, López-Nevot MÁ, Cunha C, González-Sierra PA, Springer J, Lackner M, Alcazar-Fuoli L, Fianchi L, Aguado JM, Pagano L, López-Fernández E, Clavero E, Potenza L, Luppi M, Moratalla L, Solano C, Sampedro A, Cuenca-Estrella M, Lass-Flörl C, Pcraga Study Group, Canzian F, Loeffler J, Li Y, Einsele H, Netea MG, Vázquez L, Carvalho A, Jurado M, and Sainz J

Abstract

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4 rs7526628T/T genotype had a significantly increased risk of developing IA ( p = 0.00022). We also found that carriers of the TNFSF4 rs7526628T allele showed decreased serum levels of TNFSF14 protein ( p = 0.0027), and that their macrophages had a decreased fungicidal activity ( p = 0.048). In addition, we observed that each copy of the MAPKAPK2 rs12137965G allele increased the risk of IA by 60% ( p = 0.0017), whereas each copy of the MAPKAPK2 rs17013271T allele was estimated to decrease the risk of developing the disease ( p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2 rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood ( p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin ( p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2 rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells ( p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells ( p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.

Published
2020
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