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12 results on '"Jalil, Sami"'

1. Truncating NFKB1 variants cause combined NLRP3 inflammasome activation and type I interferon signaling and predispose to necrotizing fasciitis

Author

Nurmi, Katariina, Silventoinen, Kristiina, Keskitalo, Salla, Rajamäki, Kristiina, Kouri, Vesa-Petteri, Kinnunen, Matias, Jalil, Sami, Maldonado, Rocio, Wartiovaara, Kirmo, Nievas, Elma Inés, Denita-Juárez, Silvina Paola, Duncan, Christopher J.A., Kuismin, Outi, Saarela, Janna, Romo, Inka, Martelius, Timi, Parantainen, Jukka, Beklen, Arzu, Bilicka, Marcelina, Matikainen, Sampsa, Nordström, Dan C., Kaustio, Meri, Wartiovaara-Kautto, Ulla, Kilpivaara, Outi, Klein, Christoph, Hauck, Fabian, Jahkola, Tiina, Hautala, Timo, Varjosalo, Markku, Barreto, Goncalo, Seppänen, Mikko R.J., and Eklund, Kari K.

Published
2024
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4. Hepsin promotes breast tumor growth signaling via the TGFβ‐EGFR axis.

Author

Belitškin, Denis, Munne, Pauliina, Pant, Shishir M., Anttila, Johanna M., Suleymanova, Ilida, Belitškina, Kati, Kirchhofer, Daniel, Janetka, James, Käsper, Taivo, Jalil, Sami, Pouwels, Jeroen, Tervonen, Topi A., and Klefström, Juha

Abstract

Hepsin, a type II transmembrane serine protease, is commonly overexpressed in prostate and breast cancer. The hepsin protein is stabilized by the Ras‐MAPK pathway, and, downstream, this protease regulates the degradation of extracellular matrix components and activates growth factor pathways, such as the hepatocyte growth factor (HGF) and transforming growth factor beta (TGFβ) pathway. However, how exactly active hepsin promotes cell proliferation machinery to sustain tumor growth is not fully understood. Here, we show that genetic deletion of the gene encoding hepsin (Hpn) in a WAP‐Myc model of aggressive MYC‐driven breast cancer inhibits tumor growth in the primary syngrafted sites and the growth of disseminated tumors in the lungs. The suppression of tumor growth upon loss of hepsin was accompanied by downregulation of TGFβ and EGFR signaling together with a reduction in epidermal growth factor receptor (EGFR) protein levels. We further demonstrate in 3D cultures of patient‐derived breast cancer explants that both basal TGFβ signaling and EGFR protein expression are inhibited by neutralizing antibodies or small‐molecule inhibitors of hepsin. The study demonstrates a role for hepsin as a regulator of cell proliferation and tumor growth through TGFβ and EGFR pathways, warranting consideration of hepsin as a potential indirect upstream target for therapeutic inhibition of TGFβ and EGFR pathways in cancer. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Hepsin promotes breast tumor growth signaling via the TGFβ‐EGFR axis

Author

Belitškin, Denis, primary, Munne, Pauliina, additional, Pant, Shishir M., additional, Anttila, Johanna M, additional, Suleymanova, Ilida, additional, Belitškina, Kati, additional, Kirchhofer, Daniel, additional, Janetka, James, additional, Käsper, Taivo, additional, Jalil, Sami, additional, Pouwels, Jeroen, additional, Tervonen, Topi, additional, and Klefström, Juha, additional

Published
2023
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8. Simultaneous high-efficiency base editing and reprogramming of patient fibroblasts

Author

Jalil, Sami, Keskinen, Timo, Maldonado, Rocío, Sokka, Joonas, Trokovic, Ras, Otonkoski, Timo, Wartiovaara, Kirmo, STEMM - Stem Cells and Metabolism Research Program, HUS Children and Adolescents, and HUSLAB

Subjects
Resource, GENOMIC DNA, induced pluripotent stem cells, VECTOR, CADASIL, LINES, SENDAI-VIRUS, NOTCH3, disease modeling, Humans, Transgenes, Receptor, Notch3, Cells, Cultured, Gene Editing, 318 Medical biotechnology, familial hypercholesterolemia, Base Sequence, INDUCTION, Endoderm, 1184 Genetics, developmental biology, physiology, reprogramming, Fibroblasts, Cellular Reprogramming, LDLR, Phenotype, Receptors, LDL, Mutation, RNA, 1182 Biochemistry, cell and molecular biology, CRISPR-Cas9, Finnish-founder mutation, PLURIPOTENT STEM-CELLS
Abstract

Summary Human induced pluripotent stem cells (hiPSCs) allow in vitro study of genetic diseases and hold potential for personalized stem cell therapy. Gene editing, precisely modifying specifically targeted loci, represents a valuable tool for different hiPSC applications. This is especially useful in monogenic diseases to dissect the function of unknown mutations or to create genetically corrected, patient-derived hiPSCs. Here we describe a highly efficient method for simultaneous base editing and reprogramming of fibroblasts employing a CRISPR-Cas9 adenine base editor. As a proof of concept, we apply this approach to generate gene-edited hiPSCs from skin biopsies of four patients carrying a Finnish-founder pathogenic point mutation in either NOTCH3 or LDLR genes. We also show LDLR activity restoration after the gene correction. Overall, this method yields tens of gene-edited hiPSC monoclonal lines with unprecedented efficiency and robustness while considerably reducing the cell culture time and thus the risk for in vitro alterations., Graphical abstract, Highlights • Simultaneous base editing and reprogramming efficiently generates corrected hiPSCs • RNA-delivered ABE edits the targeted loci without DSBs or detectable off-targets • The base-edited hiPSCs exhibit normal karyotype and pluripotency • Differentiated patient hiPSCs show phenotype restoration upon gene correction, In this study, Jalil and colleagues develop and test a method for simultaneous hiPSC reprogramming and RNA-delivered adenine base editing. Starting from primary patient-derived fibroblasts, this approach yields several on-target edited isogenic hiPSC lines, with remarkable speed and editing efficiency and without compromising their genetic integrity or their pluripotency quality. The gene editing corrects the cellular disease phenotype.

Published
2021

10. Truncating NFKB1variants cause combined NLRP3 inflammasome activation and type I interferon signaling and predispose to necrotizing fasciitis

Author

Nurmi, Katariina, Silventoinen, Kristiina, Keskitalo, Salla, Rajamäki, Kristiina, Kouri, Vesa-Petteri, Kinnunen, Matias, Jalil, Sami, Maldonado, Rocio, Wartiovaara, Kirmo, Nievas, Elma Inés, Denita-Juárez, Silvina Paola, Duncan, Christopher J.A., Kuismin, Outi, Saarela, Janna, Romo, Inka, Martelius, Timi, Parantainen, Jukka, Beklen, Arzu, Bilicka, Marcelina, Matikainen, Sampsa, Nordström, Dan C., Kaustio, Meri, Wartiovaara-Kautto, Ulla, Kilpivaara, Outi, Klein, Christoph, Hauck, Fabian, Jahkola, Tiina, Hautala, Timo, Varjosalo, Markku, Barreto, Goncalo, Seppänen, Mikko R.J., and Eklund, Kari K.

Abstract

In monogenic autoinflammatory diseases, mutations in genes regulating innate immune responses often lead to uncontrolled activation of inflammasome pathways or the type I interferon (IFN-I) response. We describe a mechanism of autoinflammation potentially predisposing patients to life-threatening necrotizing soft tissue inflammation. Six unrelated families are identified in which affected members present with necrotizing fasciitis or severe soft tissue inflammations. Exome sequencing reveals truncating monoallelic loss-of-function variants of nuclear factor κ light-chain enhancer of activated B cells(NFKB1) in affected patients.In patients’ macrophages and in NFKB1-variant-bearing THP-1 cells, activation increases both interleukin (IL)-1β secretion and IFN-I signaling. Truncation of NF-κB1 impairs autophagy, accompanied by the accumulation of reactive oxygen species and reduced degradation of inflammasome receptor nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3), and Toll/IL-1 receptor domain-containing adaptor protein inducing IFN-β (TRIF), thus leading to combined excessive inflammasome and IFN-I activity. Many of the patients respond to anti-inflammatory treatment, and targeting IL-1β and/or IFN-I signaling could represent a therapeutic approach for these patients.

Published
2024
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11. Author Correction: Remodeling of the Actin/Spectrin Membrane-associated Periodic Skeleton, Growth Cone Collapse and F-Actin Decrease during Axonal Degeneration

Author

Unsain, Nicolas, primary, Bordenave, Martin D., additional, Martinez, Gaby F., additional, Jalil, Sami, additional, von Bilderling, Catalina, additional, Barabas, Federico M., additional, Masullo, Luciano A., additional, Johnstone, Aaron D., additional, Barker, Philip A., additional, Bisbal, Mariano, additional, Stefani, Fernando D., additional, and Cáceres, Alfredo O., additional

Published
2018
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12. Remodeling of the Actin/Spectrin Membrane-associated Periodic Skeleton, Growth Cone Collapse and F-Actin Decrease during Axonal Degeneration

Author

Unsain, Nicolas, primary, Bordenave, Martin D., additional, Martinez, Gaby F., additional, Jalil, Sami, additional, von Bilderling, Catalina, additional, Barabas, Federico M., additional, Masullo, Luciano A., additional, Johnstone, Aaron D., additional, Barker, Philip A., additional, Bisbal, Mariano, additional, Stefani, Fernando D., additional, and Cáceres, Alfredo O., additional

Published
2018
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