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Article ; Online: Hormetic endoplasmic reticulum stress in hematopoietic stem cells.

Luchsinger, Larry L

2022 Volume 28, Issue 6, Page(s) 417–423

Abstract: Purpose of review: Hematopoietic stem cells (HSCs) possess the ability to regenerate over a lifetime in the face of extreme cellular proliferation and environmental stress. Yet, mechanisms that control the regenerative properties of HSCs remain elusive. ...

Abstract	Purpose of review: Hematopoietic stem cells (HSCs) possess the ability to regenerate over a lifetime in the face of extreme cellular proliferation and environmental stress. Yet, mechanisms that control the regenerative properties of HSCs remain elusive. ER stress has emerged as an important signaling event that supports HSC self-renewal and multipotency. The purpose of this review is to summarize the pathways implicating ER stress as cytoprotective in HSCs. Recent findings: Recent studies have shown multiple signaling cascades of the unfolded protein response (UPR) are persistently activated in healthy HSCs, suggesting that low-dose ER stress is a feature HSCs. Stress adaptation is a feature ascribed to cytoprotection and longevity of cells as well as organisms, in what is known as hormesis. However, assembling this information into useful knowledge to improve the therapeutic application of HSCs remains challenging and the upstream activators and downstream transcriptional programs induced by ER stress that are required in HSCs remain to be discovered. Summary: The maintenance of HSCs requires a dose-dependent simulation of ER stress responses that involves persistent, low-dose UPR. Unraveling the complexity of this signaling node may elucidate mechanisms related to regeneration of HSCs that can be harnessed to expand HSCs for cellular therapeutics ex vivo and transplantation in vivo.
MeSH term(s)	Endoplasmic Reticulum Stress ; Hematopoietic Stem Cells ; Humans ; Regeneration ; Signal Transduction ; Unfolded Protein Response
Language	English
Publishing date	2022-01-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1153887-9
ISSN	1531-7048 ; 1065-6251
ISSN (online)	1531-7048
ISSN	1065-6251
DOI	10.1097/MOH.0000000000000668
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Article ; Online: Vaccine efficacy probable against COVID-19 variants.

Luchsinger, Larry L / Hillyer, Christopher D

Science (New York, N.Y.)

2021 Volume 371, Issue 6534, Page(s) 1116

MeSH term(s)	COVID-19/prevention & control ; COVID-19 Vaccines/immunology ; Humans ; Immunogenicity, Vaccine ; SARS-CoV-2/immunology
Chemical Substances	COVID-19 Vaccines
Language	English
Publishing date	2021-03-09
Publishing country	United States
Document type	Letter
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abg9461
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Article ; Online: Umbilical cord blood: an undervalued and underutilized resource in allogeneic hematopoietic stem cell transplant and novel cell therapy applications.

Shi, Patricia A / Luchsinger, Larry L / Greally, John M / Delaney, Colleen S

Current opinion in hematology

2022 Volume 29, Issue 6, Page(s) 317–326

Abstract: Purpose of review: The purpose of this review is to primarily discuss the unwarranted decline in the use of umbilical cord blood (UCB) as a source of donor hematopoietic stem cells (HSC) for hematopoietic cell transplantation (HCT) and the resulting ... ...

Abstract	Purpose of review: The purpose of this review is to primarily discuss the unwarranted decline in the use of umbilical cord blood (UCB) as a source of donor hematopoietic stem cells (HSC) for hematopoietic cell transplantation (HCT) and the resulting important implications in addressing healthcare inequities, and secondly to highlight the incredible potential of UCB and related birthing tissues for the development of a broad range of therapies to treat human disease including but not limited to oncology, neurologic, cardiac, orthopedic and immunologic conditions. Recent findings: When current best practices are followed, unrelated donor umbilical cord blood transplant (CBT) can provide superior quality of life-related survival compared to other allogeneic HSC donor sources (sibling, matched or mismatched unrelated, and haploidentical) through decreased risks of relapse and chronic graft vs. host disease. Current best practices include improved UCB donor selection criteria with consideration of higher resolution human leukocyte antigen (HLA) typing and CD34+ cell dose, availability of newer myeloablative but reduced toxicity conditioning regimens, and rigorous supportive care in the early posttransplant period with monitoring for known complications, especially related to viral and other infections that may require intervention. Emerging best practice may include the use of ex vivo expanded single-unit CBT rather than double-unit CBT (dCBT) or 'haplo-cord' transplant, and the incorporation of posttransplant cyclophosphamide as with haploidentical transplant and/or incorporation of novel posttransplant therapies to reduce the risk of relapse, such as NK cell adoptive transfer. Novel, non-HCT uses of UCB and birthing tissue include the production of UCB-derived immune effector cell therapies such as unmodified NK cells, chimeric antigen receptor-natural killer cells and immune T-cell populations, the isolation of mesenchymal stem cells for immune modulatory treatments and derivation of induced pluripotent stem cells haplobanks for regenerative medicine development and population studies to facilitate exploration of drug development through functional genomics. Summary: The potential of allogeneic UCB for HCT and novel cell-based therapies is undervalued and underutilized. The inventory of high-quality UCB units available from public cord blood banks (CBB) should be expanding rather than contracting in order to address ongoing healthcare inequities and to maintain a valuable source of cellular starting material for cell and gene therapies and regenerative medicine approaches. The expertise in Good Manufacturing Practice-grade manufacturing provided by CBB should be supported to effectively partner with groups developing UCB for novel cell-based therapies.
MeSH term(s)	Cell- and Tissue-Based Therapy ; Cord Blood Stem Cell Transplantation ; Cyclophosphamide ; Fetal Blood ; Graft vs Host Disease ; HLA Antigens/genetics ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Quality of Life ; Receptors, Chimeric Antigen ; Recurrence ; Unrelated Donors
Chemical Substances	HLA Antigens ; Receptors, Chimeric Antigen ; Cyclophosphamide (8N3DW7272P)
Language	English
Publishing date	2022-08-29
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	1153887-9
ISSN	1531-7048 ; 1065-6251
ISSN (online)	1531-7048
ISSN	1065-6251
DOI	10.1097/MOH.0000000000000732
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Article ; Online: Insights into highly engraftable hematopoietic cells from 27-year cryopreserved umbilical cord blood.

Broxmeyer, Hal E / Luchsinger, Larry L / Weinberg, Rona Singer / Jimenez, Alexandra / Frenet, Emeline Masson / Van't Hof, Wouter / Capitano, Maegan L / Hillyer, Christopher D / Kaplan, Mark H / Cooper, Scott / Ropa, James

Cell reports. Medicine

2023 Volume 4, Issue 11, Page(s) 101259

Abstract: Umbilical cord blood transplantation is a life-saving treatment for malignant and non-malignant hematologic disorders. It remains unclear how long cryopreserved units remain functional, and the length of cryopreservation is often used as a criterion to ... ...

Abstract	Umbilical cord blood transplantation is a life-saving treatment for malignant and non-malignant hematologic disorders. It remains unclear how long cryopreserved units remain functional, and the length of cryopreservation is often used as a criterion to exclude older units. We demonstrate that long-term cryopreserved cord blood retains similar numbers of hematopoietic stem and progenitor cells compared with fresh and recently cryopreserved cord blood units. Long-term cryopreserved units contain highly functional cells, yielding robust engraftment in mouse transplantation models. We also leverage differences between units to examine gene programs associated with better engraftment. Transcriptomic analyses reveal that gene programs associated with lineage determination and oxidative stress are enriched in high engrafting cord blood, revealing potential molecular markers to be used as potency markers for cord blood unit selection regardless of length of cryopreservation. In summary, cord blood units cryopreserved for extended periods retain engrafting potential and can potentially be used for patient treatment.
MeSH term(s)	Animals ; Mice ; Humans ; Hematopoietic Stem Cells ; Fetal Blood ; Cryopreservation ; Hematopoietic Stem Cell Transplantation
Language	English
Publishing date	2023-10-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2023.101259
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Article ; Online: COVID19 antibody detection using lateral flow assay tests in a cohort of convalescent plasma donors.

Ragnesola, Brett / Jin, Daniel / Lamb, Christopher C / Shaz, Beth H / Hillyer, Christopher D / Luchsinger, Larry L

BMC research notes

2020 Volume 13, Issue 1, Page(s) 372

Abstract: Objective: COVID19 has caused a global and ongoing pandemic. The need for population seroconversion data is apparent to monitor and respond to the pandemic. Using a lateral flow assay (LFA) testing platform, the seropositivity in 63 New York Blood ... ...

Abstract	Objective: COVID19 has caused a global and ongoing pandemic. The need for population seroconversion data is apparent to monitor and respond to the pandemic. Using a lateral flow assay (LFA) testing platform, the seropositivity in 63 New York Blood Center (NYBC) Convelescent Plasma (CP) donor samples were evaluated for the presence of COVID19 specific IgG and IgM. Results: CP donors showed diverse antibody result. Convalescent donor plasma contains SARS-CoV-2 specific antibodies. Weak antibody bands may identify low titer CP donors. LFA tests can identify antibody positive individuals that have recovered from COVID19. Confirming suspected cases using antibody detection could help inform the patient and the community as to the relative risk to future exposure and a better understanding of disease exposure.
MeSH term(s)	Antibodies, Viral/blood ; Antibody Specificity ; Antigens, Viral/immunology ; Betacoronavirus/immunology ; Blood Donors ; Clinical Laboratory Techniques/methods ; Convalescence ; Coronavirus Infections/diagnosis ; Coronavirus Infections/therapy ; Gold Colloid ; Humans ; Immunization, Passive ; Immunoassay/methods ; Immunoglobulin G/blood ; Immunoglobulin M/blood ; Nucleocapsid Proteins/immunology ; Pandemics ; Plasma ; Pneumonia, Viral/diagnosis ; Point-of-Care Testing ; Protein Domains ; Recombinant Proteins/immunology ; Reproducibility of Results ; Sensitivity and Specificity ; Seroconversion ; Spike Glycoprotein, Coronavirus/immunology
Chemical Substances	Antibodies, Viral ; Antigens, Viral ; Gold Colloid ; Immunoglobulin G ; Immunoglobulin M ; Nucleocapsid Proteins ; Recombinant Proteins ; Spike Glycoprotein, Coronavirus ; nucleocapsid protein, Coronavirus ; spike protein, SARS-CoV-2
Keywords	covid19
Language	English
Publishing date	2020-08-06
Publishing country	England
Document type	Clinical Trial ; Journal Article
ZDB-ID	2413336-X
ISSN	1756-0500 ; 1756-0500
ISSN (online)	1756-0500
ISSN	1756-0500
DOI	10.1186/s13104-020-05212-0
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Article ; Online: COVID19 antibody detection using lateral flow assay tests in a cohort of convalescent plasma donors

Ragnesola, Brett / Jin, Daniel / Lamb, Christopher C. / Shaz, Beth H. / Hillyer, Christopher D. / Luchsinger, Larry L.

BMC Research Notes

2020 Volume 13, Issue 1

Keywords	General Biochemistry, Genetics and Molecular Biology ; General Medicine ; covid19
Language	English
Publisher	Springer Science and Business Media LLC
Publishing country	us
Document type	Article ; Online
ZDB-ID	2413336-X
ISSN	1756-0500
ISSN	1756-0500
DOI	10.1186/s13104-020-05212-0
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Article ; Online: Hemolysis-driven IFNα production impairs erythropoiesis by negatively regulating EPO signaling in sickle cell disease.

Han, Yongshuai / Gao, Chengjie / Liu, Yunfeng / Zhang, Huan / Wang, Shihui / Zhao, Huizhi / Bao, Weili / Guo, Xinhua / Vinchi, Francesca / Lobo, Cheryl / Shi, Patricia / Mendelson, Avital / Luchsinger, Larry / Zhong, Hui / Yazdanbakhsh, Karina / An, Xiuli

Blood

2024 Volume 143, Issue 11, Page(s) 1018–1031

Abstract: Abstract: Disordered erythropoiesis is a feature of many hematologic diseases, including sickle cell disease (SCD). However, very little is known about erythropoiesis in SCD. Here, we show that although bone marrow (BM) erythroid progenitors and ... ...

Abstract	Abstract: Disordered erythropoiesis is a feature of many hematologic diseases, including sickle cell disease (SCD). However, very little is known about erythropoiesis in SCD. Here, we show that although bone marrow (BM) erythroid progenitors and erythroblasts in Hbbth3/+ thalassemia mice were increased more than twofold, they were expanded by only ∼40% in Townes sickle mice (SS). We further show that the colony-forming ability of SS erythroid progenitors was decreased and erythropoietin (EPO)/EPO receptor (EPOR) signaling was impaired in SS erythroid cells. Furthermore, SS mice exhibited reduced responses to EPO. Injection of mice with red cell lysates or hemin, mimicking hemolysis in SCD, led to suppression of erythropoiesis and reduced EPO/EPOR signaling, indicating hemolysis, a hallmark of SCD, and could contribute to the impaired erythropoiesis in SCD. In vitro hemin treatment did not affect Stat5 phosphorylation, suggesting that hemin-induced erythropoiesis suppression in vivo is via an indirect mechanism. Treatment with interferon α (IFNα), which is upregulated by hemolysis and elevated in SCD, led to suppression of mouse BM erythropoiesis in vivo and human erythropoiesis in vitro, along with inhibition of Stat5 phosphorylation. Notably, in sickle erythroid cells, IFN-1 signaling was activated and the expression of cytokine inducible SH2-containing protein (CISH), a negative regulator of EPO/EPOR signaling, was increased. CISH deletion in human erythroblasts partially rescued IFNα-mediated impairment of cell growth and EPOR signaling. Knocking out Ifnar1 in SS mice rescued the defective BM erythropoiesis and improved EPO/EPOR signaling. Our findings identify an unexpected role of hemolysis on the impaired erythropoiesis in SCD through inhibition of EPO/EPOR signaling via a heme-IFNα-CISH axis.
MeSH term(s)	Mice ; Animals ; Humans ; Erythropoiesis/physiology ; STAT5 Transcription Factor/metabolism ; Hemolysis ; Hemin/metabolism ; Receptors, Erythropoietin/genetics ; Receptors, Erythropoietin/metabolism ; Anemia, Sickle Cell/complications
Chemical Substances	STAT5 Transcription Factor ; Hemin (743LRP9S7N) ; Receptors, Erythropoietin
Language	English
Publishing date	2024-01-15
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.2023021658
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Article ; Online: COVID19 antibody detection using lateral flow assay tests in a cohort of convalescent plasma donors

Ragnesola, Brett / Jin, Daniel / Lamb, Chris / Shaz, Beth H. / Hillyer, Christopher D. / Luchsinger, Larry L.

BMC Research Notes, 13(1):372

2020

Abstract: OBJECTIVE: COVID19 has caused a global and ongoing pandemic. The need for population seroconversion data is apparent to monitor and respond to the pandemic. Using a lateral flow assay (LFA) testing platform, the seropositivity in 63 New York Blood Center ...

Abstract	OBJECTIVE: COVID19 has caused a global and ongoing pandemic. The need for population seroconversion data is apparent to monitor and respond to the pandemic. Using a lateral flow assay (LFA) testing platform, the seropositivity in 63 New York Blood Center (NYBC) Convelescent Plasma (CP) donor samples were evaluated for the presence of COVID19 specific IgG and IgM. RESULTS: CP donors showed diverse antibody result. Convalescent donor plasma contains SARS-CoV-2 specific antibodies. Weak antibody bands may identify low titer CP donors. LFA tests can identify antibody positive individuals that have recovered from COVID19. Confirming suspected cases using antibody detection could help inform the patient and the community as to the relative risk to future exposure and a better understanding of disease exposure.
Keywords	COVID-19 ; Antibody testing ; Convalescent plasma ; covid19
Language	English
Publishing country	de
Document type	Article ; Online
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Article ; Online: COVID19 antibody detection using lateral flow assay tests in a cohort of convalescent plasma donors

Brett Ragnesola / Daniel Jin / Christopher C. Lamb / Beth H. Shaz / Christopher D. Hillyer / Larry L. Luchsinger

BMC Research Notes, Vol 13, Iss 1, Pp 1-

2020 Volume 7

Abstract: Abstract Objective COVID19 has caused a global and ongoing pandemic. The need for population seroconversion data is apparent to monitor and respond to the pandemic. Using a lateral flow assay (LFA) testing platform, the seropositivity in 63 New York ... ...

Abstract	Abstract Objective COVID19 has caused a global and ongoing pandemic. The need for population seroconversion data is apparent to monitor and respond to the pandemic. Using a lateral flow assay (LFA) testing platform, the seropositivity in 63 New York Blood Center (NYBC) Convelescent Plasma (CP) donor samples were evaluated for the presence of COVID19 specific IgG and IgM. Results CP donors showed diverse antibody result. Convalescent donor plasma contains SARS-CoV-2 specific antibodies. Weak antibody bands may identify low titer CP donors. LFA tests can identify antibody positive individuals that have recovered from COVID19. Confirming suspected cases using antibody detection could help inform the patient and the community as to the relative risk to future exposure and a better understanding of disease exposure.
Keywords	Covid-19 ; Antibody testing ; Convalescent plasma ; Medicine ; R ; Biology (General) ; QH301-705.5 ; Science (General) ; Q1-390 ; covid19
Subject code	610
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Low Seroprevalence of SARS-CoV-2 in Rhode Island blood donors during may 2020 as determined using multiple serological assay formats.

Nesbitt, Daniel J / Jin, Daniel P / Hogan, Joseph W / Yang, Jenny / Chen, Haidee / Chan, Philip A / Simon, Melissa J / Vargas, Matthew / King, Ewa / Huard, Richard C / Bandy, Utpala / Hillyer, Christopher D / Luchsinger, Larry L

BMC infectious diseases

2021 Volume 21, Issue 1, Page(s) 871

Abstract: Background: Epidemic projections and public health policies addressing Coronavirus disease (COVID)-19 have been implemented without data reporting on the seroconversion of the population since scalable antibody testing has only recently become available. ...

Abstract	Background: Epidemic projections and public health policies addressing Coronavirus disease (COVID)-19 have been implemented without data reporting on the seroconversion of the population since scalable antibody testing has only recently become available. Methods: We measured the percentage of severe acute respiratory syndrome- Coronavirus-2 (SARS-CoV-2) seropositive individuals from 2008 blood donors drawn in the state of Rhode Island (RI). We utilized multiple antibody testing platforms, including lateral flow immunoassays (LFAs), enzyme-linked immunosorbent assays (ELISAs) and high throughput serological assays (HTSAs). To estimate seroprevalence, we utilized the Bayesian statistical method to adjust for sensitivity and specificity of the commercial tests used. Results: We report than an estimated seropositive rate of RI blood donors of approximately 0.6% existed in April-May of 2020. Daily new case rates peaked in RI in late April 2020. We found HTSAs and LFAs were positively correlated with ELISA assays to detect antibodies specific to SARS-CoV-2 in blood donors. Conclusions: These data imply that seroconversion, and thus infection, is likely not widespread within this population. We conclude that IgG LFAs and HTSAs are suitable to conduct seroprevalence assays in random populations. More studies will be needed using validated serological tests to improve the precision and report the kinetic progression of seroprevalence estimates.
MeSH term(s)	Antibodies, Viral/blood ; Bayes Theorem ; Blood Donors ; COVID-19/epidemiology ; Humans ; Rhode Island/epidemiology ; SARS-CoV-2 ; Seroepidemiologic Studies
Chemical Substances	Antibodies, Viral
Language	English
Publishing date	2021-08-25
Publishing country	England
Document type	Journal Article
ZDB-ID	2041550-3
ISSN	1471-2334 ; 1471-2334
ISSN (online)	1471-2334
ISSN	1471-2334
DOI	10.1186/s12879-021-06438-4
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