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Article ; Online: Inotersen: new promise for the treatment of hereditary transthyretin amyloidosis.

Mathew, Veena / Wang, Annabel K

2019 Volume 13, Page(s) 1515–1525

Abstract: Hereditary transthyretin amyloidosis is a fatal autosomal dominant disorder characterized by deposition of transthyretin amyloid into the peripheral nervous system, heart, kidney, and gastrointestinal tract. Previous treatments using liver ... ...

Abstract	Hereditary transthyretin amyloidosis is a fatal autosomal dominant disorder characterized by deposition of transthyretin amyloid into the peripheral nervous system, heart, kidney, and gastrointestinal tract. Previous treatments using liver transplantation and small molecule stabilizers were not effective in stopping disease progression. Inotersen, a 2'-O-methyoxyethyl-modified antisense oligonucleotide, which acts by reducing the production of transthyretin, was recently demonstrated to improve disease course and quality of life in early hereditary transthyretin amyloidosis polyneuropathy in a 15-month Phase III study.
MeSH term(s)	Amyloid Neuropathies, Familial/drug therapy ; Animals ; Humans ; Oligodeoxyribonucleotides, Antisense/therapeutic use ; Oligonucleotides/therapeutic use
Chemical Substances	Oligodeoxyribonucleotides, Antisense ; Oligonucleotides ; Inotersen (0IEO0F56LV)
Language	English
Publishing date	2019-05-06
Publishing country	New Zealand
Document type	Journal Article ; Review
ZDB-ID	2451346-5
ISSN	1177-8881 ; 1177-8881
ISSN (online)	1177-8881
ISSN	1177-8881
DOI	10.2147/DDDT.S162913
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Article ; Online: Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis.

Maynard, Adam G / Pohl, Nancy K / Mueller, Annabel P / Petrova, Boryana / Wong, Alan Y L / Wang, Peng / Culhane, Andrew J / Brook, Jeannette R / Hirsch, Leah M / Hoang, Ngoc / Kirkland, Orville / Braun, Tatum / Ducamp, Sarah / Fleming, Mark D / Li, Hojun / Kanarek, Naama

Science advances

2024 Volume 10, Issue 5, Page(s) eadj9479

Abstract: Folate, an essential vitamin, is a one-carbon acceptor and donor in key metabolic reactions. Erythroid cells harbor a unique sensitivity to folate deprivation, as revealed by the primary pathological manifestation of nutritional folate deprivation: ... ...

Abstract	Folate, an essential vitamin, is a one-carbon acceptor and donor in key metabolic reactions. Erythroid cells harbor a unique sensitivity to folate deprivation, as revealed by the primary pathological manifestation of nutritional folate deprivation: megaloblastic anemia. To study this metabolic sensitivity, we applied mild folate depletion to human and mouse erythroid cell lines and primary murine erythroid progenitors. We show that folate depletion induces early blockade of purine synthesis and accumulation of the purine synthesis intermediate and signaling molecule, 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR), followed by enhanced heme metabolism, hemoglobin synthesis, and erythroid differentiation. This is phenocopied by inhibition of folate metabolism using the inhibitor SHIN1, and by AICAR supplementation. Mechanistically, the metabolically driven differentiation is independent of mechanistic target of rapamycin complex 1 (mTORC1) and adenosine 5'-monophosphate-activated protein kinase (AMPK) and is instead mediated by protein kinase C. Our findings suggest that folate deprivation-induced premature differentiation of erythroid progenitor cells is a molecular etiology to folate deficiency-induced anemia.
MeSH term(s)	Mice ; Humans ; Animals ; Folic Acid/metabolism ; Cell Differentiation ; Cell Line ; Mechanistic Target of Rapamycin Complex 1 ; Purines
Chemical Substances	Folic Acid (935E97BOY8) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Purines
Language	English
Publishing date	2024-01-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adj9479
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Article: Efficient gene knockout and genetic interactions: the IN4MER CRISPR/Cas12a multiplex knockout platform.

Anvar, Nazanin Esmaeili / Lin, Chenchu / Ma, Xingdi / Wilson, Lori L / Steger, Ryan / Sangree, Annabel K / Colic, Medina / Wang, Sidney H / Doench, John G / Hart, Traver

bioRxiv : the preprint server for biology

2023

Abstract: Genetic interactions mediate the emergence of phenotype from genotype, but initial technologies for combinatorial genetic perturbation in mammalian cells suffer from inefficiency and are challenging to scale. Recent focus on paralog synthetic lethality ... ...

Abstract	Genetic interactions mediate the emergence of phenotype from genotype, but initial technologies for combinatorial genetic perturbation in mammalian cells suffer from inefficiency and are challenging to scale. Recent focus on paralog synthetic lethality in cancer cells offers an opportunity to evaluate different approaches and improve on the state of the art. Here we report a meta-analysis of CRISPR genetic interactions screens, identifying a candidate set of background-independent paralog synthetic lethals, and find that the Cas12a platform provides superior sensitivity and assay replicability. We demonstrate that Cas12a can independently target up to four genes from a single guide array, and we build on this knowledge by constructing a genome-scale library that expresses arrays of four guides per clone, a platform we call 'in4mer'. Our genome-scale human library, with only 49k clones, is substantially smaller than a typical CRISPR/Cas9 monogenic library while also targeting more than four thousand paralog pairs, triples, and quads. Proof of concept screens in four cell lines demonstrate discrimination of core and context-dependent essential genes similar to that of state-of-the-art CRISPR/Cas9 libraries, as well as detection of synthetic lethal and masking/buffering genetic interactions between paralogs of various family sizes, a capability not offered by any extant library. Importantly, the in4mer platform offers a fivefold reduction in the number of clones required to assay genetic interactions, dramatically improving the cost and effort required for these studies.
Language	English
Publishing date	2023-09-05
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.03.522655
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Article ; Online: An aggressive form of transthyretin amyloidosis.

Dasgupta, Noel R / Wang, Annabel K / Hardwick, Joyce / Benson, Merrill D

Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis

2017 Volume 24, Issue sup1, Page(s) 95–96

MeSH term(s)	Adult ; Amyloid Neuropathies, Familial/genetics ; Codon/chemistry ; Codon/genetics ; Female ; Humans ; Male ; Middle Aged ; Mutation/genetics
Chemical Substances	Codon
Language	English
Publishing date	2017-05-01
Publishing country	England
Document type	Case Reports ; Journal Article
ZDB-ID	1205246-2
ISSN	1744-2818 ; 1350-6129
ISSN (online)	1744-2818
ISSN	1350-6129
DOI	10.1080/13506129.2017.1284057
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Article ; Online: Biomechanical analysis of neochordal repair error from diastolic phase inversion of static left ventricular pressurization.

Park, Matthew H / Marin-Cuartas, Mateo / Imbrie-Moore, Annabel M / Wilkerson, Robert J / Pandya, Pearly K / Zhu, Yuanjia / Wang, Hanjay / Borger, Michael A / Woo, Y Joseph

JTCVS techniques

2022 Volume 12, Page(s) 54–64

Abstract: Objective: Neochordal implantation is a common form of surgical mitral valve (MV) repair. However, neochord length is assessed using static left ventricular pressurization, leading surgeons to evaluate leaflet coaptation and valve competency when the ... ...

Abstract	Objective: Neochordal implantation is a common form of surgical mitral valve (MV) repair. However, neochord length is assessed using static left ventricular pressurization, leading surgeons to evaluate leaflet coaptation and valve competency when the left ventricle is dilating instead of contracting physiologically, referred to as diastolic phase inversion (DPI). We hypothesize that the difference in papillary muscle (PM) positioning between DPI and physiologic systole results in miscalculated neochord lengths, which might affect repair performance. Methods: Porcine MVs (n = 6) were mounted in an ex vivo heart simulator and PMs were affixed to robots that accurately simulate PM motion. Baseline hemodynamic and chordal strain data were collected, after which P2 chordae were severed to simulate posterior leaflet prolapse from chordal rupture and subsequent mitral regurgitation. Neochord implantation was performed in the physiologic and DPI static configurations. Results: Although both repairs successfully reduced mitral regurgitation, the DPI repair resulted in longer neochordae (2.19 ± 0.4 mm; Conclusions: By leveraging advanced ex vivo technologies, we were able to quantify the effects of static pressurization on neochordal length determination. Our findings suggest that this post-repair assessment might slightly overestimate the neochordal length and that additional marginal shortening of neochordae might positively affect MV repair performance and durability by reducing load on surrounding native chordae.
Language	English
Publishing date	2022-01-26
Publishing country	United States
Document type	Journal Article
ISSN	2666-2507
ISSN (online)	2666-2507
DOI	10.1016/j.xjtc.2022.01.009
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Article ; Online: A Novel Rheumatic Mitral Valve Disease Model with Ex Vivo Hemodynamic and Biomechanical Validation.

Park, Matthew H / Pandya, Pearly K / Zhu, Yuanjia / Mullis, Danielle M / Wang, Hanjay / Imbrie-Moore, Annabel M / Wilkerson, Robert / Marin-Cuartas, Mateo / Woo, Y Joseph

Cardiovascular engineering and technology

2022 Volume 14, Issue 1, Page(s) 129–140

Abstract: Purpose: Rheumatic heart disease is a major cause of mitral valve (MV) dysfunction, particularly in disadvantaged areas and developing countries. There lacks a critical understanding of the disease biomechanics, and as such, the purpose of this study ... ...

Abstract	Purpose: Rheumatic heart disease is a major cause of mitral valve (MV) dysfunction, particularly in disadvantaged areas and developing countries. There lacks a critical understanding of the disease biomechanics, and as such, the purpose of this study was to generate the first ex vivo porcine model of rheumatic MV disease by simulating the human pathophysiology and hemodynamics. Methods: Healthy porcine valves were altered with heat treatment, commissural suturing, and cyanoacrylate tissue coating, all of which approximate the pathology of leaflet stiffening and thickening as well as commissural fusion. Hemodynamic data, echocardiography, and high-speed videography were collected in a paired manner for control and model valves (n = 4) in an ex vivo left heart simulator. Valve leaflets were characterized in an Instron tensile testing machine to understand the mechanical changes of the model (n = 18). Results: The model showed significant differences indicative of rheumatic disease: increased regurgitant fractions (p < 0.001), reduced effective orifice areas (p < 0.001), augmented transmitral mean gradients (p < 0.001), and increased leaflet stiffness (p = 0.025). Conclusion: This work represents the creation of the first ex vivo model of rheumatic MV disease, bearing close similarity to the human pathophysiology and hemodynamics, and it will be used to extensively study both established and new treatment techniques, benefitting the millions of affected victims.
MeSH term(s)	Humans ; Animals ; Swine ; Mitral Valve/diagnostic imaging ; Rheumatic Heart Disease/pathology ; Mitral Valve Insufficiency/diagnostic imaging ; Heart Valve Diseases/pathology ; Hemodynamics
Language	English
Publishing date	2022-08-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2543111-0
ISSN	1869-4098 ; 1869-408X
ISSN (online)	1869-4098
ISSN	1869-408X
DOI	10.1007/s13239-022-00641-3
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Article ; Online: The Critical Biomechanics of Aortomitral Angle and Systolic Anterior Motion: Engineering Native Ex Vivo Simulation.

Park, Matthew H / Imbrie-Moore, Annabel M / Zhu, Yuanjia / Wilkerson, Robert J / Wang, Hanjay / Park, Grant H / Wu, Catherine A / Pandya, Pearly K / Mullis, Danielle M / Marin-Cuartas, Mateo / Woo, Y Joseph

Annals of biomedical engineering

2022 Volume 51, Issue 4, Page(s) 794–805

Abstract: Systolic anterior motion (SAM) of the mitral valve (MV) is a complex pathological phenomenon often occurring as an iatrogenic effect of surgical and transcatheter intervention. While the aortomitral angle has long been linked to SAM, the mechanistic ... ...

Abstract	Systolic anterior motion (SAM) of the mitral valve (MV) is a complex pathological phenomenon often occurring as an iatrogenic effect of surgical and transcatheter intervention. While the aortomitral angle has long been linked to SAM, the mechanistic relationship is not well understood. We developed the first ex vivo heart simulator capable of recreating native aortomitral biomechanics, and to generate models of SAM, we performed anterior leaflet augmentation and sequential undersized annuloplasty procedures on porcine aortomitral junctions (n = 6). Hemodynamics and echocardiograms were recorded, and echocardiographic analysis revealed significantly reduced coaptation-septal distances confirming SAM (p = 0.003) and effective manipulation of the aortomitral angle (p < 0.001). Upon increasing the angle in our pathological models, we recorded significant increases (p < 0.05) in both coaptation-septal distance and multiple hemodynamic metrics, such as aortic peak flow and effective orifice area. These results indicate that an increased aortomitral angle is correlated with more efficient hemodynamic performance of the valvular system, presenting a potential, clinically translatable treatment opportunity for reducing the risk and adverse effects of SAM. As the standard of care shifts towards surgical and transcatheter interventions, it is increasingly important to better understand SAM biomechanics, and our advances represent a significant step towards that goal.
MeSH term(s)	Animals ; Swine ; Biomechanical Phenomena ; Mitral Valve/surgery ; Mitral Valve Insufficiency/surgery ; Systole ; Echocardiography
Language	English
Publishing date	2022-10-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	185984-5
ISSN	1573-9686 ; 0191-5649 ; 0090-6964
ISSN (online)	1573-9686
ISSN	0191-5649 ; 0090-6964
DOI	10.1007/s10439-022-03091-z
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Zs.A 1018: Show issues

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Article ; Online: Human Infection Challenge with Serotype 3 Pneumococcus.

Robinson, Ryan E / Mitsi, Elena / Nikolaou, Elissavet / Pojar, Sherin / Chen, Tao / Reiné, Jesús / Nyazika, Tinashe K / Court, James / Davies, Kelly / Farrar, Madlen / Gonzalez-Dias, Patricia / Hamilton, Josh / Hill, Helen / Hitchins, Lisa / Howard, Ashleigh / Hyder-Wright, Angela / Lesosky, Maia / Liatsikos, Konstantinos / Matope, Agnes /

McLenaghan, Daniella / Myerscough, Christopher / Murphy, Annabel / Solórzano, Carla / Wang, Duolao / Burhan, Hassan / Gautam, Manish / Begier, Elizabeth / Theilacker, Christian / Beavon, Rohini / Anderson, Annaliesa S / Gessner, Bradford D / Gordon, Stephen B / Collins, Andrea M / Ferreira, Daniela M

American journal of respiratory and critical care medicine

2022 Volume 206, Issue 11, Page(s) 1379–1392

Abstract: Rationale: ...

Abstract	Rationale:
MeSH term(s)	Humans ; Child ; Infant ; Young Adult ; Adult ; Streptococcus pneumoniae ; Serogroup ; Carrier State ; Pneumococcal Vaccines/therapeutic use ; Pneumococcal Infections/prevention & control ; Nasopharynx/microbiology ; Anti-Bacterial Agents/therapeutic use ; Anti-Bacterial Agents/pharmacology
Chemical Substances	Pneumococcal Vaccines ; Anti-Bacterial Agents
Language	English
Publishing date	2022-07-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.202112-2700OC
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Article ; Online: Small volume biopsy diagnostic yield at initial diagnosis versus recurrence/transformation of follicular lymphoma: A retrospective Cyto-Heme Interinstitutional Collaborative study.

Cancer cytopathology

2022 Volume 131, Issue 5, Page(s) 279–288

Abstract: Background: Few studies have evaluated diagnostic yield of small volume biopsies (SVB) for the diagnosis and management of follicular lymphoma (FL).: Methods: The authors performed a multi-institutional retrospective analysis of SVBs including fine- ... ...

Abstract	Background: Few studies have evaluated diagnostic yield of small volume biopsies (SVB) for the diagnosis and management of follicular lymphoma (FL). Methods: The authors performed a multi-institutional retrospective analysis of SVBs including fine-needle aspiration (FNA) and needle core biopsy (NCB) for initial FL diagnosis and suspected recurrence or transformation of FL. A total of 676 workups beginning with SVB were assessed for the mean number of biopsies per workup, the proportion of workups requiring multiple biopsies, and the proportion with a complete diagnosis including grade, on initial biopsy. Results: Compared to workups performed for question transformation/recurrence, those done for initial FL diagnosis were significantly more likely to require multiple biopsies (p < .01), had a higher mean number of biopsies per workup (1.7 vs. 1.1, absolute standardized difference = 1.1), and a lower complete diagnosis rate at initial biopsy (39% vs. 56%). At initial FL diagnosis, NCB +/- FNA was associated with fewer biopsies per workup compared to FNA +/- CB (1.2 vs. 1.9), fewer workups requiring multiple biopsies (23% vs. 83%), and a higher complete diagnosis rate (71% vs. 18%). In contrast, during assessment for transformation/recurrence, NCB and FNA showed a similar mean number of biopsies per workup (1.2 vs. 1.2) and few workups required multiple biopsies (6% vs. 19%). Conclusions: SVB at initial FL diagnosis often required additional biopsies to establish a complete diagnosis. In contrast, when assessing for transformed/recurrent FL, additional biopsies were generally not obtained regardless of SVB type, suggesting that in these clinical settings SVB may be sufficient for clinical decision-making.
MeSH term(s)	Humans ; Lymphoma, Follicular/diagnosis ; Lymphoma, Follicular/pathology ; Retrospective Studies ; Biopsy, Fine-Needle ; Biopsy, Large-Core Needle ; Clinical Decision-Making
Language	English
Publishing date	2022-12-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2594979-2
ISSN	1934-6638 ; 1934-662X
ISSN (online)	1934-6638
ISSN	1934-662X
DOI	10.1002/cncy.22676
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Zs.A 6893: Show issues

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Article ; Online: Diagnostic Discrepancies in Small-volume Biopsy for the Initial Diagnosis, Recurrence, and Transformation of Follicular Lymphoma: A Multi-Institutional Collaborative Study.

The American journal of surgical pathology

2022 Volume 47, Issue 2, Page(s) 212–217

Abstract: Small-volume biopsies (SVBs) including fine-needle aspiration (FNA), cell block, and needle core biopsies (NCB) are increasingly utilized to diagnose and guide the clinical management of lymphoma. We established a multi-institutional interdisciplinary ... ...

Abstract	Small-volume biopsies (SVBs) including fine-needle aspiration (FNA), cell block, and needle core biopsies (NCB) are increasingly utilized to diagnose and guide the clinical management of lymphoma. We established a multi-institutional interdisciplinary collaboration of cytopathologists, hematopathologists, and oncologists focused on the role of SVB in the management of patients with follicular lymphoma (FL). To assess the performance characteristics of SVB in this setting, we evaluated all consecutive SVBs performed for clinical indications of initial diagnosis, recurrence, or transformation of FL over a 5-year period and focused on the 182 that had at least one subsequent biopsy within 3 months as part of the same clinical work-up. The most common outcome of a subsequent biopsy as part of the same clinical work-up was a more specific diagnosis usually assigning the pathologic grade (111/182, 61%), followed by a complete agreement with the SVB (24/182, 13%), and change from nondiagnostic on initial biopsy to diagnostic on subsequent biopsy (21/182, 12%). A minority resulted in a diagnostic change from benign to lymphoma (17/182, 9%), a change in FL grade (5/182, 3%), or change in the lymphoma diagnostic category (4/182, 2%). There were no cases where an initial diagnosis of lymphoma was overturned. The distribution of discrepancies was similar across initial SVB types (FNA, FNA + cell block, NCB with or without FNA). Tissue limitations were noted in a minority of cases (53/182, 29%) and were enriched among initially nondiagnostic biopsies (16/21, 76%). Flow cytometry immunophenotyping was performed in the majority of cases both at the first and last biopsy (147/182, 81%). SVB can be a powerful method to detect FL in various clinical indications, with discrepant cases mostly resulting from a refinement in the initial diagnosis.
MeSH term(s)	Humans ; Lymphoma, Follicular/diagnosis ; Biopsy, Fine-Needle/methods ; Biopsy, Large-Core Needle ; Flow Cytometry ; Retrospective Studies
Language	English
Publishing date	2022-12-20
Publishing country	United States
Document type	Multicenter Study ; Journal Article
ZDB-ID	752964-8
ISSN	1532-0979 ; 0147-5185
ISSN (online)	1532-0979
ISSN	0147-5185
DOI	10.1097/PAS.0000000000001985
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