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Article ; Online: Sickle red blood cells directly activate neutrophils.

Lee, Grace M / Batchvarova, Milena / Delahunty, Martha / Boateng, Lydia / Boyle, Kimberly / Suggs, Mark A / Telen, Marilyn J

British journal of haematology

2024 Volume 204, Issue 3, Page(s) e28–e30

MeSH term(s)	Humans ; Neutrophils/physiology ; Erythrocytes ; Anemia, Sickle Cell
Language	English
Publishing date	2024-01-17
Publishing country	England
Document type	Letter
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.19300
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Article ; Online: Deciphering and disrupting PIEZO1-TMEM16F interplay in hereditary xerocytosis.

Liang, Pengfei / Zhang, Yang / Wan, Yui Chun S / Ma, Shang / Dong, Ping / Lowry, Augustus J / Francis, Samuel J / Khandelwal, Sanjay / Delahunty, Martha / Telen, Marilyn J / Strouse, John J / Arepally, Gowthami M / Yang, Huanghe

Blood

2023 Volume 143, Issue 4, Page(s) 357–369

Abstract: Abstract: Cell-surface exposure of phosphatidylserine (PS) is essential for phagocytic clearance and blood clotting. Although a calcium-activated phospholipid scramblase (CaPLSase) has long been proposed to mediate PS exposure in red blood cells (RBCs), ...

Abstract	Abstract: Cell-surface exposure of phosphatidylserine (PS) is essential for phagocytic clearance and blood clotting. Although a calcium-activated phospholipid scramblase (CaPLSase) has long been proposed to mediate PS exposure in red blood cells (RBCs), its identity, activation mechanism, and role in RBC biology and disease remain elusive. Here, we demonstrate that TMEM16F, the long-sought-after RBC CaPLSase, is activated by calcium influx through the mechanosensitive channel PIEZO1 in RBCs. PIEZO1-TMEM16F functional coupling is enhanced in RBCs from individuals with hereditary xerocytosis (HX), an RBC disorder caused by PIEZO1 gain-of-function channelopathy. Enhanced PIEZO1-TMEM16F coupling leads to an increased propensity to expose PS, which may serve as a key risk factor for HX clinical manifestations including anemia, splenomegaly, and postsplenectomy thrombosis. Spider toxin GsMTx-4 and antigout medication benzbromarone inhibit PIEZO1, preventing force-induced echinocytosis, hemolysis, and PS exposure in HX RBCs. Our study thus reveals an activation mechanism of TMEM16F CaPLSase and its pathophysiological function in HX, providing insights into potential treatment.
MeSH term(s)	Female ; Humans ; Anemia, Hemolytic, Congenital/genetics ; Calcium/metabolism ; Erythrocytes/metabolism ; Hydrops Fetalis/genetics ; Ion Channels/genetics ; Phospholipid Transfer Proteins/genetics
Chemical Substances	Calcium (SY7Q814VUP) ; Ion Channels ; Phospholipid Transfer Proteins ; PIEZO1 protein, human ; ANO6 protein, human
Language	English
Publishing date	2023-11-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2023021465
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Article ; Online: Therapeutic strategies for sickle cell disease: towards a multi-agent approach.

Telen, Marilyn J / Malik, Punam / Vercellotti, Gregory M

Nature reviews. Drug discovery

2018 Volume 18, Issue 2, Page(s) 139–158

Abstract: For over 100 years, clinicians and scientists have been unravelling the consequences of the A to T substitution in the β-globin gene that produces haemoglobin S, which leads to the systemic manifestations of sickle cell disease (SCD), including vaso- ... ...

Abstract	For over 100 years, clinicians and scientists have been unravelling the consequences of the A to T substitution in the β-globin gene that produces haemoglobin S, which leads to the systemic manifestations of sickle cell disease (SCD), including vaso-occlusion, anaemia, haemolysis, organ injury and pain. However, despite growing understanding of the mechanisms of haemoglobin S polymerization and its effects on red blood cells, only two therapies for SCD - hydroxyurea and L-glutamine - are approved by the US Food and Drug Administration. Moreover, these treatment options do not fully address the manifestations of SCD, which arise from a complex network of interdependent pathophysiological processes. In this article, we review efforts to develop new drugs targeting these processes, including agents that reactivate fetal haemoglobin, anti-sickling agents, anti-adhesion agents, modulators of ischaemia-reperfusion and oxidative stress, agents that counteract free haemoglobin and haem, anti-inflammatory agents, anti-thrombotic agents and anti-platelet agents. We also discuss gene therapy, which holds promise of a cure, although its widespread application is currently limited by technical challenges and the expense of treatment. We thus propose that developing systems-oriented multi-agent strategies on the basis of SCD pathophysiology is needed to improve the quality of life and survival of people with SCD.
MeSH term(s)	Anemia, Sickle Cell/drug therapy ; Anemia, Sickle Cell/physiopathology ; Animals ; Antisickling Agents/therapeutic use ; Drug Delivery Systems ; Drug Therapy, Combination ; Genetic Therapy ; Humans
Chemical Substances	Antisickling Agents
Language	English
Publishing date	2018-11-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2062954-0
ISSN	1474-1784 ; 1474-1776
ISSN (online)	1474-1784
ISSN	1474-1776
DOI	10.1038/s41573-018-0003-2
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Zs.A 5564: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Cardiac metastasis from a transitional cell carcinoma: a case report.

Lin, W C / Telen, M J

Medical oncology (Northwood, London, England)

2014 Volume 17, Issue 2, Page(s) 147–150

Abstract: We report the case of a patient with a metastatic tumor in the right ventricle, apparently derived from a transitional cell carcinoma. The patient presented with severe hypoxemia as a result of right-to-left shunt due to the position of the tumor and a ... ...

Abstract	We report the case of a patient with a metastatic tumor in the right ventricle, apparently derived from a transitional cell carcinoma. The patient presented with severe hypoxemia as a result of right-to-left shunt due to the position of the tumor and a patent foramen ovale. The clinical course of this case is presented and the pathophysiology of the physiological effects caused by the metastatic tumor is discussed. The literature concerning cardiac metastases is reviewed.
MeSH term(s)	Aged ; Aged, 80 and over ; Carcinoma, Transitional Cell/pathology ; Carcinoma, Transitional Cell/secondary ; Heart Neoplasms/pathology ; Heart Neoplasms/secondary ; Humans ; Male ; Urinary Bladder Neoplasms/pathology
Language	English
Publishing date	2014-01-14
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	1201189-7
ISSN	1559-131X ; 1357-0560 ; 0736-0118
ISSN (online)	1559-131X
ISSN	1357-0560 ; 0736-0118
DOI	10.1007/BF02796211
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Article ; Online: Multicenter, phase 1 study of etavopivat (FT-4202) treatment for up to 12 weeks in patients with sickle cell disease.

Saraf, Santosh L / Hagar, Robert Ward / Idowu, Modupe / Osunkwo, Ifeyinwa / Cruz, Kimberly / Kuypers, Frans A / Brown, R Clark / Geib, James / Ribadeneira, Maria D / Schroeder, Patricia / Wu, Eric / Forsyth, Sanjeev / Kelly, Patrick F / Kalfa, Theodosia A / Telen, Marilyn J

Blood advances

2024

Abstract: Etavopivat is an investigational, once-daily, oral, selective erythrocyte pyruvate kinase (PKR) activator. A multicenter, randomized, placebo-controlled, double-blind, 3-part, phase 1 study (https://clinicaltrials.gov/study/NCT03815695) was conducted to ... ...

Abstract	Etavopivat is an investigational, once-daily, oral, selective erythrocyte pyruvate kinase (PKR) activator. A multicenter, randomized, placebo-controlled, double-blind, 3-part, phase 1 study (https://clinicaltrials.gov/study/NCT03815695) was conducted to characterize the safety and clinical activity of etavopivat. Thirty-six patients with sickle cell disease (SCD) were enrolled into 4 cohorts: one single-dose; two multiple ascending doses; one open-label [OL]. In the OL cohort, 15 patients (median age 33.0 [range, 17‒55] years received 400-mg etavopivat once daily for 12 weeks; 14 completed treatment. Consistent with the mechanism of PKR activation, increases in ATP and decreases in 2,3 diphosphoglycerate were observed and sustained over 12 weeks' treatment. This translated clinically to an increase in hemoglobin (mean maximal increase 1.6 [range, 0.8‒2.8] g/dL), with >1 g/dL increase in 11 (73%) patients during treatment. Additionally, oxygen tension at which hemoglobin is 50% saturated was reduced (P=.0007) with concomitant shift in point-of-sickling (P=.0034) to lower oxygen tension in oxygen-gradient ektacytometry. Hemolysis markers (absolute reticulocyte count, indirect bilirubin, lactate dehydrogenase) decreased from baseline, along with matrix metalloproteinase-9 and erythropoietin. In the OL cohort, adverse events (AEs) were mostly grade 1/2, consistent with underlying SCD; 5 patients had serious AEs. Vaso-occlusive pain episode was the most common treatment-emergent AE (n=7) in the OL cohort. In this first study of etavopivat in SCD, 400 mg once daily for 12 weeks was well-tolerated, resulting in rapid and sustained increases in hemoglobin, improved RBC physiology, and decreased hemolysis.
Language	English
Publishing date	2024-04-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023012467
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Book ; Online: Robust Numerical Tracking of One Path of a Polynomial Homotopy on Parallel Shared Memory Computers

Telen, Simon / Van Barel, Marc / Verschelde, Jan

2020

Abstract: We consider the problem of tracking one solution path defined by a polynomial homotopy on a parallel shared memory computer. Our robust path tracker applies Newton's method on power series to locate the closest singular parameter value. On top of that, ... ...

Abstract	We consider the problem of tracking one solution path defined by a polynomial homotopy on a parallel shared memory computer. Our robust path tracker applies Newton's method on power series to locate the closest singular parameter value. On top of that, it computes singular values of the Hessians of the polynomials in the homotopy to estimate the distance to the nearest different path. Together, these estimates are used to compute an appropriate adaptive stepsize. For n-dimensional problems, the cost overhead of our robust path tracker is O(n), compared to the commonly used predictor-corrector methods. This cost overhead can be reduced by a multithreaded program on a parallel shared memory computer. Comment: Accepted for publication in the proceedings of CASC 2020 (Computer Algebra in Scientific Computing)
Keywords	Mathematics - Numerical Analysis ; Computer Science - Distributed ; Parallel ; and Cluster Computing ; Computer Science - Symbolic Computation
Subject code	518
Publishing date	2020-02-21
Publishing country	us
Document type	Book ; Online
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Article ; Online: Identification of optimal thalassemia screening strategies for migrant populations in Thailand using a qualitative approach.

Xu, Julia Z / Foe, Meghan / Tanongsaksakul, Wilaslak / Suksangpleng, Thidarat / Ekwattanakit, Supachai / Riolueang, Suchada / Telen, Marilyn J / Kaiser, Bonnie N / Viprakasit, Vip

BMC public health

2021 Volume 21, Issue 1, Page(s) 1796

Abstract: Background: Thalassemia is a common inherited hemoglobin disorder in Southeast Asia. Severe thalassemia can lead to significant morbidity for patients and economic strain for under-resourced health systems. Thailand's thalassemia prevention and control ... ...

Abstract	Background: Thalassemia is a common inherited hemoglobin disorder in Southeast Asia. Severe thalassemia can lead to significant morbidity for patients and economic strain for under-resourced health systems. Thailand's thalassemia prevention and control program has successfully utilized prenatal screening and diagnosis to reduce the incidence of severe thalassemia in Thai populations, but migrant populations are excluded despite having high thalassemia prevalence. We sought to identify key barriers to and facilitators of thalassemia screening and to develop tailored recommendations for providing migrants with access to thalassemia prevention and control. Methods: We conducted 28 in-depth interviews and 4 focus group discussions (FGDs) in Chonburi, Thailand with Myanmar and Cambodian migrants, Thai healthcare providers, Thai parents of children affected by thalassemia, and migrant agents. Results: Participant narratives revealed that migrants' lack of knowledge about the prevalence, manifestations, severity, and inherited nature of thalassemia led to misconceptions, fear, or indifference toward thalassemia and screening. Negative perceptions of pregnancy termination were based in religious beliefs but compounded by other sociocultural factors, presenting a key obstacle to migrant uptake of prenatal screening. Additionally, structural barriers included legal status, competing work demands, lack of health insurance, and language barriers. Participants recommended delivering public thalassemia education in migrants' native languages, implementing carrier screening, and offering thalassemia screening in convenient settings. Conclusions: An effective thalassemia prevention and control program should offer migrants targeted thalassemia education and outreach, universal coverage for thalassemia screening and prenatal care, and options for carrier screening, providing a comprehensive strategy for reducing the incidence of severe thalassemia in Thailand and establishing an inclusive model for regional thalassemia prevention and control.
MeSH term(s)	Child ; Health Services Accessibility ; Humans ; Mass Screening ; Thailand ; Transients and Migrants ; Universal Health Insurance
Language	English
Publishing date	2021-10-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1471-2458
ISSN (online)	1471-2458
DOI	10.1186/s12889-021-11831-4
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Article ; Online: Preferences for potential benefits and risks for gene therapy in the treatment of sickle cell disease.

Gonzalez Sepulveda, Juan Marcos / Yang, Jui-Chen / Reed, Shelby D / Lee, Ting-Hsuan / Ng, Xinyi / Stothers, Sarah / Irony, Telba / Ho, Martin / Rothman, Jennifer A / Badawy, Sherif / Rowley, Carolyn / Little, Jane / Shah, Nirmish R / Li, Kaiwen / Telen, Marilyn J

Blood advances

2023 Volume 7, Issue 23, Page(s) 7371–7381

Abstract: Objective of this study is to quantify benefit-risk tradeoffs pertaining to potential gene therapies among adults and parents/caregivers of children with sickle cell disease (SCD). A discrete-choice experiment survey was developed in which respondents ... ...

Abstract	Objective of this study is to quantify benefit-risk tradeoffs pertaining to potential gene therapies among adults and parents/caregivers of children with sickle cell disease (SCD). A discrete-choice experiment survey was developed in which respondents selected their preferred treatment alternatives in a series of experimentally controlled pairs of hypothetical gene therapies and a "no gene therapy" option. Gene therapy alternatives were defined based on the chance of eliminating SCD symptoms, expected increases in life expectancy they could offer, treatment-related risk of death, and potential increases in lifetime cancer risk. Respondents made selections based on their current disease severity and in the context of expectations of worsened disease. Three clinical sites and 1 patient organization recruited 174 adult patients and 109 parents of children with SCD to complete the survey. Adult and parent respondents were generally willing to choose gene therapies, but the adults required higher expected levels of efficacy (ie, higher chance of eliminating symptoms) than parents to choose gene therapies that conferred mortality risks of ≥10%. When adults and parents of children with less severe symptoms were asked to consider scenarios of higher levels of disease severity, the increased risk tolerance, and the lowest acceptable level of efficacy for gene therapies with mortality risks dropped by >50%. Baseline SCD symptoms are a major driver of gene therapy acceptability. Adults and parents of patients with milder symptoms may prefer other treatment options; however, an expectation of symptoms deterioration triggers strong reassessment of the acceptable benefit-risk balance of this novel technology.
MeSH term(s)	Adult ; Child ; Humans ; Anemia, Sickle Cell/genetics ; Anemia, Sickle Cell/therapy ; Risk Assessment ; Parents ; Surveys and Questionnaires ; Genetic Therapy/adverse effects
Language	English
Publishing date	2023-10-31
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023009680
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Article: Gene-metabolite annotation with shortest reactional distance enhances metabolite genome-wide association studies results.

Baron, Cantin / Cherkaoui, Sarah / Therrien-Laperriere, Sandra / Ilboudo, Yann / Poujol, Raphaël / Mehanna, Pamela / Garrett, Melanie E / Telen, Marilyn J / Ashley-Koch, Allison E / Bartolucci, Pablo / Rioux, John D / Lettre, Guillaume / Des Rosiers, Christine / Ruiz, Matthieu / Hussin, Julie G

bioRxiv : the preprint server for biology

2023

Abstract: Studies combining metabolomics and genetics, known as metabolite genome-wide association studies (mGWAS), have provided valuable insights into our understanding of the genetic control of metabolite levels. However, the biological interpretation of these ... ...

Abstract	Studies combining metabolomics and genetics, known as metabolite genome-wide association studies (mGWAS), have provided valuable insights into our understanding of the genetic control of metabolite levels. However, the biological interpretation of these associations remains challenging due to a lack of existing tools to annotate mGWAS gene-metabolite pairs beyond the use of conservative statistical significance threshold. Here, we computed the shortest reactional distance (SRD) based on the curated knowledge of the KEGG database to explore its utility in enhancing the biological interpretation of results from three independent mGWAS, including a case study on sickle cell disease patients. Results show that, in reported mGWAS pairs, there is an excess of small SRD values and that SRD values and p-values significantly correlate, even beyond the standard conservative thresholds. The added-value of SRD annotation is shown for identification of potential false negative hits, exemplified by the finding of gene-metabolite associations with SRD ≤1 that did not reach standard genome-wide significance cut-off. The wider use of this statistic as an mGWAS annotation would prevent the exclusion of biologically relevant associations and can also identify errors or gaps in current metabolic pathway databases. Our findings highlight the SRD metric as an objective, quantitative and easy-to-compute annotation for gene-metabolite pairs that can be used to integrate statistical evidence to biological networks.
Language	English
Publishing date	2023-03-24
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.22.533869
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Article ; Online: Gene-metabolite annotation with shortest reactional distance enhances metabolite genome-wide association studies results.

Baron, Cantin / Cherkaoui, Sarah / Therrien-Laperriere, Sandra / Ilboudo, Yann / Poujol, Raphaël / Mehanna, Pamela / Garrett, Melanie E / Telen, Marilyn J / Ashley-Koch, Allison E / Bartolucci, Pablo / Rioux, John D / Lettre, Guillaume / Rosiers, Christine Des / Ruiz, Matthieu / Hussin, Julie G

iScience

2023 Volume 26, Issue 12, Page(s) 108473

Abstract: Metabolite genome-wide association studies (mGWAS) have advanced our understanding of the genetic control of metabolite levels. However, interpreting these associations remains challenging due to a lack of tools to annotate gene-metabolite pairs beyond ... ...

Abstract	Metabolite genome-wide association studies (mGWAS) have advanced our understanding of the genetic control of metabolite levels. However, interpreting these associations remains challenging due to a lack of tools to annotate gene-metabolite pairs beyond the use of conservative statistical significance threshold. Here, we introduce the shortest reactional distance (SRD) metric, drawing from the comprehensive KEGG database, to enhance the biological interpretation of mGWAS results. We applied this approach to three independent mGWAS, including a case study on sickle cell disease patients. Our analysis reveals an enrichment of small SRD values in reported mGWAS pairs, with SRD values significantly correlating with mGWAS p values, even beyond the standard conservative thresholds. We demonstrate the utility of SRD annotation in identifying potential false negatives and inaccuracies within current metabolic pathway databases. Our findings highlight the SRD metric as an objective, quantitative and easy-to-compute annotation for gene-metabolite pairs, suitable to integrate statistical evidence to biological networks.
Language	English
Publishing date	2023-11-14
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.108473
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