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  1. AU="Ojeda, Samuel"
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  3. AU="Pinheiro, Paula F"
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  1. Article ; Online: Use of Recombinant Human Bone Morphogenetic Protein-2 After Anterior Cervical Corpectomy and Fusion for the Treatment of Vertebral Osteomyelitis.

    Medina, Adriana Vazquez / Murray Ortiz, Gisela / Estronza Ojeda, Samuel / de Jesus Espinosa, Aixa / Pastrana, Emil A

    World neurosurgery

    2024  

    Abstract: Objective: To report the operative outcomes after treating vertebral osteomyelitis patients with an anterior cervical corpectomy and fusion procedure using recombinant human bone morphogenetic protein-2 (rhBMP-2) as graft material.: Methods: A ... ...

    Abstract Objective: To report the operative outcomes after treating vertebral osteomyelitis patients with an anterior cervical corpectomy and fusion procedure using recombinant human bone morphogenetic protein-2 (rhBMP-2) as graft material.
    Methods: A retrospective review of electronic medical records of 26 adult patients who underwent an anterior cervical corpectomy and fusion procedure for cervical osteomyelitis using rhBMP-2 at the University of Puerto Rico University District Hospital was performed. Indication, preoperative laboratory results, levels of corpectomy, preoperative American Spinal Injury Association Impairment Scale (ASIA) score, complications, fusion evaluation at 12 months, and ASIA score at 12 months were reviewed.
    Results: For the cohort of patients, mean age was 47 ± 13 years and 65% were male. Spinal instability was present in 54%. The levels of corpectomy were: 1 level in 2 cases, 2 levels in 15 cases, 3 levels in 8 cases, and 5 levels in 1 case. Four patients had complications and, of these, 2 experienced dysphagia. The fusion rate was 100% and no reoperations were performed. An improvement in ASIA score was seen for 54% patients at 12-month follow-up.
    Conclusions: This study demonstrates a fusion rate of 100% with no reoperations reported. Recombinant human bone morphogenetic protein-2 could be considered and further researched as grafting material for anterior cervical corpectomy and fusion procedures in cervical osteomyelitis patients.
    Language English
    Publishing date 2024-03-18
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2534351-8
    ISSN 1878-8769 ; 1878-8750
    ISSN (online) 1878-8769
    ISSN 1878-8750
    DOI 10.1016/j.wneu.2024.03.047
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Exploration of bromodomain ligand-linker conjugation sites for efficient CBP/p300 heterobifunctional degrader activity.

    Kumar Tiwari, Praveen / Reddy Doda, Sai / Vannam, Raghu / Hudlikar, Manish / Harrison, Drew A / Ojeda, Samuel / Rai, Sumit / Koglin, Ann-Sophie / Nguyen Gilbert, Angelique / Ott, Christopher J

    Bioorganic & medicinal chemistry letters

    2024  Volume 102, Page(s) 129676

    Abstract: Synthesis of proteolysis targeting chimeras (PROTACs) involves conjugation of an E3 ligase binding ligand to a ligand targeting a protein of interest via a rigid or flexible chemical linker. The choice of linker conjugation site on these ligands can be ... ...

    Abstract Synthesis of proteolysis targeting chimeras (PROTACs) involves conjugation of an E3 ligase binding ligand to a ligand targeting a protein of interest via a rigid or flexible chemical linker. The choice of linker conjugation site on these ligands can be informed by structural analysis of ligand-target binding modes, the feasibility of synthetic procedures to access specific sites, and computational modeling of predicted ternary complex formations. Small molecules that target bromodomains - epigenetic readers of lysine acetylation - typically offer several potential options for linker conjugation sites. Here we describe how varying the linker attachment site (exit vector) on a CBP/p300 bromodomain ligand along with linker length affects PROTAC degradation activity and ternary complex formation. Using kinetic live cell assays of endogenous CBP and p300 protein abundance and bead-based proximity assays for ternary complexes, we describe the structure-activity relationships of a diverse library of CBP/p300 degraders (dCBPs).
    MeSH term(s) Ligands ; Proteins ; Protein Domains ; Protein Binding ; Structure-Activity Relationship ; Proteolysis ; Ubiquitin-Protein Ligases
    Chemical Substances Ligands ; Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2024-02-24
    Publishing country England
    Document type Journal Article
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2024.129676
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Laser Ablation in Pediatric Epilepsy.

    Buckley, Robert / Estronza-Ojeda, Samuel / Ojemann, Jeffrey G

    Neurosurgery clinics of North America

    2016  Volume 27, Issue 1, Page(s) 69–78

    Abstract: Laser ablation is an emerging, minimally invasive treatment for selected children with intractable focal epilepsy with improved procedural morbidity. Data for children lag similar studies in adults, but the hope is for near-equivalent seizure-control ... ...

    Abstract Laser ablation is an emerging, minimally invasive treatment for selected children with intractable focal epilepsy with improved procedural morbidity. Data for children lag similar studies in adults, but the hope is for near-equivalent seizure-control rates and improved neuropsychological outcome when compared with standard open surgical resection. The approach seems particularly beneficial when dealing with deep, focal lesions, such as hypothalamic hamartomas or hippocampal sclerosis.
    MeSH term(s) Brain/surgery ; Child ; Epilepsy/surgery ; Hamartoma/surgery ; Humans ; Hypothalamic Diseases/surgery ; Laser Therapy/methods ; Neurosurgical Procedures/methods ; Seizures/surgery ; Treatment Outcome
    Language English
    Publishing date 2016-01
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1196855-2
    ISSN 1558-1349 ; 1042-3680
    ISSN (online) 1558-1349
    ISSN 1042-3680
    DOI 10.1016/j.nec.2015.08.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Targeted degradation of the enhancer lysine acetyltransferases CBP and p300.

    Vannam, Raghu / Sayilgan, Jan / Ojeda, Samuel / Karakyriakou, Barbara / Hu, Eileen / Kreuzer, Johannes / Morris, Robert / Herrera Lopez, Xcanda Ixchel / Rai, Sumit / Haas, Wilhelm / Lawrence, Michael / Ott, Christopher J

    Cell chemical biology

    2021  Volume 28, Issue 4, Page(s) 503–514.e12

    Abstract: The enhancer factors CREB-binding protein (CBP) and p300 (also known as KAT3A and KAT3B) maintain gene expression programs through lysine acetylation of chromatin and transcriptional regulators and by scaffolding functions mediated by several protein- ... ...

    Abstract The enhancer factors CREB-binding protein (CBP) and p300 (also known as KAT3A and KAT3B) maintain gene expression programs through lysine acetylation of chromatin and transcriptional regulators and by scaffolding functions mediated by several protein-protein interaction domains. Small molecule inhibitors that target some of these domains have been developed; however, they cannot completely ablate p300/CBP function in cells. Here we describe a chemical degrader of p300/CBP, dCBP-1. Leveraging structures of ligand-bound p300/CBP domains, we use in silico modeling of ternary complex formation with the E3 ubiquitin ligase cereblon to enable degrader design. dCBP-1 is exceptionally potent at killing multiple myeloma cells and can abolish the enhancer that drives MYC oncogene expression. As an efficient degrader of this unique class of acetyltransferases, dCBP-1 is a useful tool alongside domain inhibitors for dissecting the mechanism by which these factors coordinate enhancer activity in normal and diseased cells.
    MeSH term(s) CREB-Binding Protein/antagonists & inhibitors ; CREB-Binding Protein/metabolism ; Cells, Cultured ; E1A-Associated p300 Protein/antagonists & inhibitors ; E1A-Associated p300 Protein/metabolism ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Female ; Humans ; Male ; Models, Molecular ; Molecular Structure ; Small Molecule Libraries/chemical synthesis ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology
    Chemical Substances Enzyme Inhibitors ; Small Molecule Libraries ; CREB-Binding Protein (EC 2.3.1.48) ; CREBBP protein, human (EC 2.3.1.48) ; E1A-Associated p300 Protein (EC 2.3.1.48) ; EP300 protein, human (EC 2.3.1.48)
    Language English
    Publishing date 2021-01-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2451-9448
    ISSN (online) 2451-9448
    DOI 10.1016/j.chembiol.2020.12.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

    Takahashi, Mariko / Chong, Harrison B / Zhang, Siwen / Yang, Tzu-Yi / Lazarov, Matthew J / Harry, Stefan / Maynard, Michelle / Hilbert, Brendan / White, Ryan D / Murrey, Heather E / Tsou, Chih-Chiang / Vordermark, Kira / Assaad, Jonathan / Gohar, Magdy / Dürr, Benedikt R / Richter, Marianne / Patel, Himani / Kryukov, Gregory / Brooijmans, Natasja /
    Alghali, Aliyu Sidi Omar / Rubio, Karla / Villanueva, Antonio / Zhang, Junbing / Ge, Maolin / Makram, Farah / Griesshaber, Hanna / Harrison, Drew / Koglin, Ann-Sophie / Ojeda, Samuel / Karakyriakou, Barbara / Healy, Alexander / Popoola, George / Rachmin, Inbal / Khandelwal, Neha / Neil, Jason R / Tien, Pei-Chieh / Chen, Nicholas / Hosp, Tobias / van den Ouweland, Sanne / Hara, Toshiro / Bussema, Lillian / Dong, Rui / Shi, Lei / Rasmussen, Martin Q / Domingues, Ana Carolina / Lawless, Aleigha / Fang, Jacy / Yoda, Satoshi / Nguyen, Linh Phuong / Reeves, Sarah Marie / Wakefield, Farrah Nicole / Acker, Adam / Clark, Sarah Elizabeth / Dubash, Taronish / Kastanos, John / Oh, Eugene / Fisher, David E / Maheswaran, Shyamala / Haber, Daniel A / Boland, Genevieve M / Sade-Feldman, Moshe / Jenkins, Russell W / Hata, Aaron N / Bardeesy, Nabeel M / Suvà, Mario L / Martin, Brent R / Liau, Brian B / Ott, Christopher J / Rivera, Miguel N / Lawrence, Michael S / Bar-Peled, Liron

    Cell

    2024  Volume 187, Issue 10, Page(s) 2536–2556.e30

    Abstract: Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this ... ...

    Abstract Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity.
    MeSH term(s) Animals ; Humans ; Mice ; Cell Line, Tumor ; Cysteine/metabolism ; Cysteine/chemistry ; Ligands ; Melanoma/metabolism ; Neoplasms/drug therapy ; Neoplasms/metabolism ; NF-kappa B/chemistry ; NF-kappa B/metabolism ; Oxidation-Reduction ; Signal Transduction ; SOXE Transcription Factors/chemistry ; SOXE Transcription Factors/metabolism
    Chemical Substances Cysteine (K848JZ4886) ; Ligands ; NF-kappa B ; SOX10 protein, human ; SOXE Transcription Factors
    Language English
    Publishing date 2024-04-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2024.03.027
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

    Takahashi, Mariko / Chong, Harrison B / Zhang, Siwen / Lazarov, Matthew J / Harry, Stefan / Maynard, Michelle / White, Ryan / Murrey, Heather E / Hilbert, Brendan / Neil, Jason R / Gohar, Magdy / Ge, Maolin / Zhang, Junbing / Durr, Benedikt R / Kryukov, Gregory / Tsou, Chih-Chiang / Brooijmans, Natasja / Alghali, Aliyu Sidi Omar / Rubio, Karla /
    Vilanueva, Antonio / Harrison, Drew / Koglin, Ann-Sophie / Ojeda, Samuel / Karakyriakou, Barbara / Healy, Alexander / Assaad, Jonathan / Makram, Farah / Rachman, Inbal / Khandelwal, Neha / Tien, Pei-Chieh / Popoola, George / Chen, Nicholas / Vordermark, Kira / Richter, Marianne / Patel, Himani / Yang, Tzu-Yi / Griesshaber, Hanna / Hosp, Tobias / van den Ouweland, Sanne / Hara, Toshiro / Bussema, Lily / Dong, Rui / Shi, Lei / Rasmussen, Martin Q / Domingues, Ana Carolina / Lawless, Aleigha / Fang, Jacy / Yoda, Satoshi / Nguyen, Linh Phuong / Reeves, Sarah Marie / Wakefield, Farrah Nicole / Acker, Adam / Clark, Sarah Elizabeth / Dubash, Taronish / Fisher, David E / Maheswaran, Shyamala / Haber, Daniel A / Boland, Genevieve / Sade-Feldman, Moshe / Jenkins, Russel / Hata, Aaron / Bardeesy, Nabeel / Suva, Mario L / Martin, Brent / Liau, Brian / Ott, Christopher / Rivera, Miguel N / Lawrence, Michael S / Bar-Peled, Liron

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this ... ...

    Abstract Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed
    Language English
    Publishing date 2023-10-23
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.20.563287
    Database MEDical Literature Analysis and Retrieval System OnLINE

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