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Article ; Online: Tie2 Activation via VE-PTP Inhibition With Razuprotafib as an Adjunct to Latanoprost in Patients With Open Angle Glaucoma or Ocular Hypertension.

Brigell, Mitchell / Withers, Barbara / Buch, Akshay / Peters, Kevin G

Translational vision science & technology

2022 Volume 11, Issue 1, Page(s) 7

Abstract: Purpose: To evaluate the ocular hypotensive efficacy and safety of razuprotafib, a novel Tie2 activator, when used as an adjunct to latanoprost in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT).: Methods: Subjects with OAG or ... ...

Abstract	Purpose: To evaluate the ocular hypotensive efficacy and safety of razuprotafib, a novel Tie2 activator, when used as an adjunct to latanoprost in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods: Subjects with OAG or OHT and an unmedicated IOP from ≥22 mm Hg to <36 mm Hg were randomized to one of three treatment arms: razuprotafib every day (QD) + latanoprost; razuprotafib twice daily (BID) + latanoprost; or latanoprost monotherapy. The primary endpoint was change in mean diurnal IOP from baseline at day 28. Results: A total of 194 subjects were randomized, and 193 (99.5%) completed the study. Razuprotafib BID + latanoprost resulted in a significantly larger reduction in diurnal IOP than latanoprost alone (7.95 ± 0.26 mmHg vs. 7.04 ± 0.26 mm Hg, P < 0.05). A smaller improvement was observed after 14 days of treatment (7.62 ± 0.26 mm Hg vs. 7.03 ± 0.26 mm Hg, P = 0.11). Razuprotafib QD dosing did not demonstrate additional IOP lowering compared to latanoprost alone. Conjunctival hyperemia on Day 28 increased by 1.1 units on the four-point Efron scale two hours post dose from a baseline value of 0.6 units, and decreased thereafter. Conclusions: Topical ocular razuprotafib as an adjunct to latanoprost therapy was well tolerated and significantly reduced IOP in patients with OAG/OHT. Translational relevance: These data support the IOP lowering efficacy of targeting Tie2 activation in Schlemm's canal in the relevant patient population.
MeSH term(s)	Antihypertensive Agents/therapeutic use ; Glaucoma, Open-Angle/drug therapy ; Humans ; Intraocular Pressure ; Latanoprost ; Ocular Hypertension/drug therapy ; Prostaglandins F, Synthetic/therapeutic use
Chemical Substances	Antihypertensive Agents ; Prostaglandins F, Synthetic ; Latanoprost (6Z5B6HVF6O)
Language	English
Publishing date	2022-01-27
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2674602-5
ISSN	2164-2591 ; 2164-2591
ISSN (online)	2164-2591
ISSN	2164-2591
DOI	10.1167/tvst.11.1.7
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Article ; Online: Cryo-electron tomography on focused ion beam lamellae transforms structural cell biology.

Berger, Casper / Premaraj, Navya / Ravelli, Raimond B G / Knoops, Kèvin / López-Iglesias, Carmen / Peters, Peter J

Nature methods

2023 Volume 20, Issue 4, Page(s) 499–511

Abstract: Cryogenic electron microscopy and data processing enable the determination of structures of isolated macromolecules to near-atomic resolution. However, these data do not provide structural information in the cellular environment where macromolecules ... ...

Abstract	Cryogenic electron microscopy and data processing enable the determination of structures of isolated macromolecules to near-atomic resolution. However, these data do not provide structural information in the cellular environment where macromolecules perform their native functions, and vital molecular interactions can be lost during the isolation process. Cryogenic focused ion beam (FIB) fabrication generates thin lamellae of cellular samples and tissues, enabling structural studies on the near-native cellular interior and its surroundings by cryogenic electron tomography (cryo-ET). Cellular cryo-ET benefits from the technological developments in electron microscopes, detectors and data processing, and more in situ structures are being obtained and at increasingly higher resolution. In this Review, we discuss recent studies employing cryo-ET on FIB-generated lamellae and the technological developments in ultrarapid sample freezing, FIB fabrication of lamellae, tomography, data processing and correlative light and electron microscopy that have enabled these studies. Finally, we explore the future of cryo-ET in terms of both methods development and biological application.
MeSH term(s)	Electron Microscope Tomography/methods ; Macromolecular Substances
Chemical Substances	Macromolecular Substances
Language	English
Publishing date	2023-03-13
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2169522-2
ISSN	1548-7105 ; 1548-7091
ISSN (online)	1548-7105
ISSN	1548-7091
DOI	10.1038/s41592-023-01783-5
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Article ; Online: Shear stress control of vascular leaks and atheromas through Tie2 activation by VE-PTP sequestration.

Shirakura, Keisuke / Baluk, Peter / Nottebaum, Astrid F / Ipe, Ute / Peters, Kevin G / McDonald, Donald M / Vestweber, Dietmar

EMBO molecular medicine

2023 Volume 15, Issue 4, Page(s) e16128

Abstract: Vascular endothelial protein tyrosine phosphatase (VE-PTP) influences endothelial barrier function by regulating the activation of tyrosine kinase receptor Tie2. We determined whether this action is linked to the development of atherosclerosis by ... ...

Abstract	Vascular endothelial protein tyrosine phosphatase (VE-PTP) influences endothelial barrier function by regulating the activation of tyrosine kinase receptor Tie2. We determined whether this action is linked to the development of atherosclerosis by examining the influence of arterial shear stress on VE-PTP, Tie2 activation, plasma leakage, and atherogenesis. We found that exposure to high average shear stress led to downstream polarization and endocytosis of VE-PTP accompanied by Tie2 activation at cell junctions. In aortic regions with disturbed flow, VE-PTP was not redistributed away from Tie2. Endothelial cells exposed to high shear stress had greater Tie2 activation and less macromolecular permeability than regions with disturbed flow. Deleting endothelial VE-PTP in VE-PTP
MeSH term(s)	Mice ; Animals ; Endothelial Cells/metabolism ; Plaque, Atherosclerotic/metabolism ; Receptor-Like Protein Tyrosine Phosphatases, Class 3/genetics ; Receptor-Like Protein Tyrosine Phosphatases, Class 3/metabolism ; Atherosclerosis/metabolism ; Receptor, TIE-2/genetics ; Receptor, TIE-2/metabolism
Chemical Substances	Receptor-Like Protein Tyrosine Phosphatases, Class 3 (EC 3.1.3.48) ; Receptor, TIE-2 (EC 2.7.10.1)
Language	English
Publishing date	2023-02-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.15252/emmm.202216128
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Article ; Online: Effect of Testosterone on Progression From Prediabetes to Diabetes in Men With Hypogonadism: A Substudy of the TRAVERSE Randomized Clinical Trial.

Bhasin, Shalender / Lincoff, A Michael / Nissen, Steven E / Wannemuehler, Kathleen / McDonnell, Marie E / Peters, Anne L / Khan, Nader / Snabes, Michael C / Li, Xue / Li, Geng / Buhr, Kevin / Pencina, Karol M / Travison, Thomas G

JAMA internal medicine

2024 Volume 184, Issue 4, Page(s) 353–362

Abstract: Importance: The effect of testosterone replacement therapy (TRT) in men with hypogonadism on the risk of progression from prediabetes to diabetes or of inducing glycemic remission in those with diabetes is unknown.: Objective: To evaluate the ... ...

Abstract	Importance: The effect of testosterone replacement therapy (TRT) in men with hypogonadism on the risk of progression from prediabetes to diabetes or of inducing glycemic remission in those with diabetes is unknown. Objective: To evaluate the efficacy of TRT in preventing progression from prediabetes to diabetes in men with hypogonadism who had prediabetes and in inducing glycemic remission in those with diabetes. Design, setting, and participants: This nested substudy, an intention-to-treat analysis, within a placebo-controlled randomized clinical trial (Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men [TRAVERSE]) was conducted at 316 trial sites in the US. Participants included men aged 45 to 80 years with hypogonadism and prediabetes or diabetes who were enrolled in TRAVERSE between May 23, 2018, and February 1, 2022. Intervention: Participants were randomized 1:1 to receive 1.62% testosterone gel or placebo gel until study completion. Main outcomes and measures: The primary end point was the risk of progression from prediabetes to diabetes, analyzed using repeated-measures log-binomial regression. The secondary end point was the risk of glycemic remission (hemoglobin A1c level <6.5% [to convert to proportion of total hemoglobin, multiply by 0.01] or 2 fasting glucose measurements <126 mg/dL [to convert to mmol/L, multiply by 0.0555] without diabetes medication) in men who had diabetes. Results: Of 5204 randomized participants, 1175 with prediabetes (mean [SD] age, 63.8 [8.1] years) and 3880 with diabetes (mean [SD] age, 63.2 [7.8] years) were included in this study. Mean (SD) hemoglobin A1c level in men with prediabetes was 5.8% (0.4%). Risk of progression to diabetes did not differ significantly between testosterone and placebo groups: 4 of 598 (0.7%) vs 8 of 562 (1.4%) at 6 months, 45 of 575 (7.8%) vs 57 of 533 (10.7%) at 12 months, 50 of 494 (10.1%) vs 67 of 460 (14.6%) at 24 months, 46 of 359 (12.8%) vs 52 of 330 (15.8%) at 36 months, and 22 of 164 (13.4%) vs 19 of 121 (15.7%) at 48 months (omnibus test P = .49). The proportions of participants with diabetes who experienced glycemic remission and the changes in glucose and hemoglobin A1c levels were similar in testosterone- and placebo-treated men with prediabetes or diabetes. Conclusions and relevance: In men with hypogonadism and prediabetes, the incidence of progression from prediabetes to diabetes did not differ significantly between testosterone- and placebo-treated men. Testosterone replacement therapy did not improve glycemic control in men with hypogonadism and prediabetes or diabetes. These findings suggest that TRT alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism. Trial registration: ClinicalTrials.gov Identifier: NCT03518034.
MeSH term(s)	Male ; Humans ; Middle Aged ; Testosterone/therapeutic use ; Prediabetic State/drug therapy ; Glycated Hemoglobin ; Hypogonadism/complications ; Hypogonadism/drug therapy ; Hormone Replacement Therapy ; Glucose
Chemical Substances	Testosterone (3XMK78S47O) ; Glycated Hemoglobin ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2024-02-05
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2699338-7
ISSN	2168-6114 ; 2168-6106
ISSN (online)	2168-6114
ISSN	2168-6106
DOI	10.1001/jamainternmed.2023.7862
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Article ; Online: Designed modular protein hydrogels for biofabrication.

Dranseike, Dalia / Ota, Yusuke / Edwardson, Thomas G W / Guzzi, Elia A / Hori, Mao / Nakic, Zrinka Raguz / Deshmukh, Dhananjay V / Levasseur, Mikail D / Mattli, Kevin / Tringides, Christina M / Zhou, Jiangtao / Hilvert, Donald / Peters, Christin / Tibbitt, Mark W

Acta biomaterialia

2024 Volume 177, Page(s) 107–117

Abstract: ... of the fibers and the final storage modulus G' of the materials. The mechanical properties of the hydrogels ... could be tuned over a broad range (G' = 0.1 - 10 kPa), making them suitable for the cultivation and ...

Abstract	Designing proteins that fold and assemble over different length scales provides a way to tailor the mechanical properties and biological performance of hydrogels. In this study, we designed modular proteins that self-assemble into fibrillar networks and, as a result, form hydrogel materials with novel properties. We incorporated distinct functionalities by connecting separate self-assembling (A block) and cell-binding (B block) domains into single macromolecules. The number of self-assembling domains affects the rigidity of the fibers and the final storage modulus G' of the materials. The mechanical properties of the hydrogels could be tuned over a broad range (G' = 0.1 - 10 kPa), making them suitable for the cultivation and differentiation of multiple cell types, including cortical neurons and human mesenchymal stem cells. Moreover, we confirmed the bioavailability of cell attachment domains in the hydrogels that can be further tailored for specific cell types or other biological applications. Finally, we demonstrate the versatility of the designed proteins for application in biofabrication as 3D scaffolds that support cell growth and guide their function. STATEMENT OF SIGNIFICANCE: Designed proteins that enable the decoupling of biophysical and biochemical properties within the final material could enable modular biomaterial engineering. In this context, we present a designed modular protein platform that integrates self-assembling domains (A blocks) and cell-binding domains (B blocks) within a single biopolymer. The linking of assembly domains and cell-binding domains this way provided independent tuning of mechanical properties and inclusion of biofunctional domains. We demonstrate the use of this platform for biofabrication, including neural cell culture and 3D printing of scaffolds for mesenchymal stem cell culture and differentiation. Overall, this work highlights how informed design of biopolymer sequences can enable the modular design of protein-based hydrogels with independently tunable biophysical and biochemical properties.
MeSH term(s)	Humans ; Hydrogels/chemistry ; Proteins/chemistry ; Biocompatible Materials/metabolism ; Mesenchymal Stem Cells ; Biopolymers ; Tissue Engineering
Chemical Substances	Hydrogels ; Proteins ; Biocompatible Materials ; Biopolymers
Language	English
Publishing date	2024-02-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2173841-5
ISSN	1878-7568 ; 1742-7061
ISSN (online)	1878-7568
ISSN	1742-7061
DOI	10.1016/j.actbio.2024.02.019
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Article ; Online: Shear stress control of vascular leaks and atheromas through Tie2 activation by VE‐PTP sequestration

Keisuke Shirakura / Peter Baluk / Astrid F Nottebaum / Ute Ipe / Kevin G Peters / Donald M McDonald / Dietmar Vestweber

EMBO Molecular Medicine, Vol 15, Iss 4, Pp n/a-n/a (2023)

2023

Abstract: Abstract Vascular endothelial protein tyrosine phosphatase (VE‐PTP) influences endothelial barrier function by regulating the activation of tyrosine kinase receptor Tie2. We determined whether this action is linked to the development of atherosclerosis ... ...

Abstract	Abstract Vascular endothelial protein tyrosine phosphatase (VE‐PTP) influences endothelial barrier function by regulating the activation of tyrosine kinase receptor Tie2. We determined whether this action is linked to the development of atherosclerosis by examining the influence of arterial shear stress on VE‐PTP, Tie2 activation, plasma leakage, and atherogenesis. We found that exposure to high average shear stress led to downstream polarization and endocytosis of VE‐PTP accompanied by Tie2 activation at cell junctions. In aortic regions with disturbed flow, VE‐PTP was not redistributed away from Tie2. Endothelial cells exposed to high shear stress had greater Tie2 activation and less macromolecular permeability than regions with disturbed flow. Deleting endothelial VE‐PTP in VE‐PTPiECKO mice increased Tie2 activation and reduced plasma leakage in atheroprone regions. ApoE−/− mice bred with VE‐PTPiECKO mice had less plasma leakage and fewer atheromas on a high‐fat diet. Pharmacologic inhibition of VE‐PTP by AKB‐9785 had similar anti‐atherogenic effects. Together, the findings identify VE‐PTP as a novel target for suppression of atherosclerosis.
Keywords	aorta ; atherosclerosis ; endothelial junctions ; laminar flow ; vascular leakage ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
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Article ; Online: Introduction to Radiomics and Artificial Intelligence: A Primer for Radiologists.

Haneberg, Adam G / Pierre, Kevin / Winter-Reinhold, Eric / Hochhegger, Bruno / Peters, Keith R / Grajo, Joseph / Arreola, Manuel / Asadizanjani, Navid / Bian, Jiang / Mancuso, Anthony / Forghani, Reza

Seminars in roentgenology

2023 Volume 58, Issue 2, Page(s) 152–157

Abstract: Health informatics and artificial intelligence (AI) are expected to transform the healthcare enterprise and the future practice of radiology. There is an increasing body of literature on radiomics and deep learning/AI applications in medical imaging. ... ...

Abstract	Health informatics and artificial intelligence (AI) are expected to transform the healthcare enterprise and the future practice of radiology. There is an increasing body of literature on radiomics and deep learning/AI applications in medical imaging. There are also a steadily increasing number of FDA cleared AI applications in radiology. It is therefore essential for radiologists to have a basic understanding of these approaches, whether in academia or private practice. In this article, we will provide an overview of the field and familiarize the readers with the fundamental concepts behind these approaches.
MeSH term(s)	Humans ; Artificial Intelligence ; Radiologists ; Radiology/methods ; Radiography ; Forecasting
Language	English
Publishing date	2023-03-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	80310-8
ISSN	1558-4658 ; 0037-198X
ISSN (online)	1558-4658
ISSN	0037-198X
DOI	10.1053/j.ro.2023.02.002
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Article ; Online: Decreased nasal polyp eosinophils but increased mast cells in a patient with aspirin-exacerbated respiratory disease treated with reslizumab.

Staudacher, Anna G / Peters, Anju T / Carter, Roderick G / Welch, Kevin C / Stevens, Whitney W

Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology

2020 Volume 125, Issue 4, Page(s) 490–493.e2

MeSH term(s)	Anti-Asthmatic Agents/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Asthma, Aspirin-Induced/drug therapy ; Asthma, Aspirin-Induced/immunology ; Eosinophils/drug effects ; Female ; Humans ; Mast Cells/drug effects ; Middle Aged ; Nasal Polyps/drug therapy ; Nasal Polyps/immunology ; Rhinitis/drug therapy ; Rhinitis/immunology ; Sinusitis/drug therapy ; Sinusitis/immunology
Chemical Substances	Anti-Asthmatic Agents ; Antibodies, Monoclonal, Humanized ; reslizumab (35A26E427H)
Language	English
Publishing date	2020-07-04
Publishing country	United States
Document type	Case Reports ; Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1228189-x
ISSN	1534-4436 ; 0003-4738 ; 1081-1206
ISSN (online)	1534-4436
ISSN	0003-4738 ; 1081-1206
DOI	10.1016/j.anai.2020.06.043
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Article ; Online: Applications of Artificial Intelligence in the Radiology Roundtrip: Process Streamlining, Workflow Optimization, and Beyond.

Pierre, Kevin / Haneberg, Adam G / Kwak, Sean / Peters, Keith R / Hochhegger, Bruno / Sananmuang, Thiparom / Tunlayadechanont, Padcha / Tighe, Patrick J / Mancuso, Anthony / Forghani, Reza

Seminars in roentgenology

2023 Volume 58, Issue 2, Page(s) 158–169

Abstract: There are many impactful applications of artificial intelligence (AI) in the electronic radiology roundtrip and the patient's journey through the healthcare system that go beyond diagnostic applications. These tools have the potential to improve quality ... ...

Abstract	There are many impactful applications of artificial intelligence (AI) in the electronic radiology roundtrip and the patient's journey through the healthcare system that go beyond diagnostic applications. These tools have the potential to improve quality and safety, optimize workflow, increase efficiency, and increase patient satisfaction. In this article, we review the role of AI for process improvement and workflow enhancement which includes applications beginning from the time of order entry, scan acquisition, applications supporting the image interpretation task, and applications supporting tasks after image interpretation such as result communication. These non-diagnostic workflow and process optimization tasks are an important part of the arsenal of potential AI tools that can streamline day to day clinical practice and patient care.
MeSH term(s)	Humans ; Artificial Intelligence ; Workflow ; Radiology/methods
Language	English
Publishing date	2023-03-23
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	80310-8
ISSN	1558-4658 ; 0037-198X
ISSN (online)	1558-4658
ISSN	0037-198X
DOI	10.1053/j.ro.2023.02.003
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Article ; Online: Targeting Tie2 for Treatment of Diabetic Retinopathy and Diabetic Macular Edema.

Campochiaro, Peter A / Peters, Kevin G

Current diabetes reports

2016 Volume 16, Issue 12, Page(s) 126

Abstract: Tie2 is a tyrosine kinase receptor located predominantly on vascular endothelial cells that plays a central role in vascular stability. Angiopoietin-1 (Angpt1), produced by perivascular cells, binds, clusters, and activates Tie2, leading to Tie2 ... ...

Abstract	Tie2 is a tyrosine kinase receptor located predominantly on vascular endothelial cells that plays a central role in vascular stability. Angiopoietin-1 (Angpt1), produced by perivascular cells, binds, clusters, and activates Tie2, leading to Tie2 autophosphorylation and downstream signaling. Activated Tie2 increases endothelial cell survival, adhesion, and cell junction integrity, thereby stabilizing the vasculature. Angiopoietin-2 (Angpt2) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) are negative regulators increased by hypoxia; they inactivate Tie2, destabilizing the vasculature and increasing responsiveness to vascular endothelial growth factor (VEGF) and other inflammatory cytokines that stimulate vascular leakage and neovascularization. AKB-9778 is a small-molecule antagonist of VE-PTP which increases phosphorylation of Tie2 even in the presence of high Angpt2 levels. In preclinical studies, AKB-9778 reduced VEGF-induced leakage and ocular neovascularization (NV) and showed additive benefit when combined with VEGF suppression. In two clinical trials in diabetic macular edema (DME) patients, subcutaneous injections of AKB-9778 were safe and provided added benefit to VEGF suppression. Preliminary data suggest that AKB-9778 monotherapy improves diabetic retinopathy. These data suggest that Tie2 activation may be a valuable strategy to treat or prevent diabetic retinopathy.
MeSH term(s)	Angiopoietin-1/physiology ; Angiopoietin-2/physiology ; Aniline Compounds/therapeutic use ; Diabetic Retinopathy/drug therapy ; Humans ; Macular Edema/drug therapy ; Receptor, TIE-2/antagonists & inhibitors ; Receptor, TIE-2/physiology ; Receptor-Like Protein Tyrosine Phosphatases, Class 3/physiology ; Signal Transduction ; Sulfonic Acids/therapeutic use ; Vascular Endothelial Growth Factor A/metabolism
Chemical Substances	AKB-9778 ; Angiopoietin-1 ; Angiopoietin-2 ; Aniline Compounds ; Sulfonic Acids ; Vascular Endothelial Growth Factor A ; Receptor, TIE-2 (EC 2.7.10.1) ; Receptor-Like Protein Tyrosine Phosphatases, Class 3 (EC 3.1.3.48)
Language	English
Publishing date	2016-12
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2065167-3
ISSN	1539-0829 ; 1534-4827
ISSN (online)	1539-0829
ISSN	1534-4827
DOI	10.1007/s11892-016-0816-5
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