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Article ; Online: Prospects of mitochondrial transplantation in clinical medicine: Aspirations and challenges.

Hosseinian, Sina / Ali Pour, Paria / Kheradvar, Arash

2022 Volume 65, Page(s) 33–44

Abstract: Mitochondria, known as the powerhouse of the cell, are at the center of healthy physiology and provide cells with energy in the form of ATP. These unique organelles are also implicated in many pathological conditions affecting a variety of organs in ... ...

Abstract	Mitochondria, known as the powerhouse of the cell, are at the center of healthy physiology and provide cells with energy in the form of ATP. These unique organelles are also implicated in many pathological conditions affecting a variety of organs in various systems. Recently, mitochondrial transplantation, inspired by mitochondria's endosymbiotic origin, has been attempted as a potential biotherapy in mitigating a variety of pathological conditions. Mitochondrial transplantation consists of the process of isolation, transfer, and uptake of exogenous, intact mitochondria into damaged cells. Here, we discuss mitochondrial transplantation in the context of clinical medicine practiced in neurology, cardiology, pulmonary medicine, and oncology, among others. We outline the role of mitochondria in various pathologies and discuss the state-of-the-art research that potentially form the basis of new therapeutics for the treatment of a variety of diseases due to mitochondrial dysfunction. Lastly, we explore some of the challenges associated with mitochondrial transplantation that must be addressed before mitochondrial transplantation becomes a viable therapeutic option in clinical settings.
MeSH term(s)	Clinical Medicine ; Mitochondria/physiology
Language	English
Publishing date	2022-04-30
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2056923-3
ISSN	1872-8278 ; 1567-7249
ISSN (online)	1872-8278
ISSN	1567-7249
DOI	10.1016/j.mito.2022.04.006
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Article ; Online: Mitochondrial transplantation in cardiomyocytes: foundation, methods, and outcomes.

Ali Pour, Paria / Hosseinian, Sina / Kheradvar, Arash

American journal of physiology. Cell physiology

2021 Volume 321, Issue 3, Page(s) C489–C503

Abstract: Mitochondrial transplantation is emerging as a novel cellular biotherapy to alleviate mitochondrial damage and dysfunction. Mitochondria play a crucial role in establishing cellular homeostasis and providing cell with the energy necessary to accomplish ... ...

Abstract	Mitochondrial transplantation is emerging as a novel cellular biotherapy to alleviate mitochondrial damage and dysfunction. Mitochondria play a crucial role in establishing cellular homeostasis and providing cell with the energy necessary to accomplish its function. Owing to its endosymbiotic origin, mitochondria share many features with their bacterial ancestors. Unlike the nuclear DNA, which is packaged into nucleosomes and protected from adverse environmental effects, mitochondrial DNA are more prone to harsh environmental effects, in particular that of the reactive oxygen species. Mitochondrial damage and dysfunction are implicated in many diseases ranging from metabolic diseases to cardiovascular and neurodegenerative diseases, among others. While it was once thought that transplantation of mitochondria would not be possible due to their semiautonomous nature and reliance on the nucleus, recent advances have shown that it is possible to transplant viable functional intact mitochondria from autologous, allogenic, and xenogeneic sources into different cell types. Moreover, current research suggests that the transplantation could positively modulate bioenergetics and improve disease outcome. Mitochondrial transplantation techniques and consequences of transplantation in cardiomyocytes are the theme of this review. We outline the different mitochondrial isolation and transfer techniques. Finally, we detail the consequences of mitochondrial transplantation in the cardiovascular system, more specifically in the context of cardiomyopathies and ischemia.
MeSH term(s)	Animals ; Cardiomyopathies/metabolism ; Cardiomyopathies/pathology ; Cardiomyopathies/therapy ; Cell Fractionation/methods ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/pathology ; Diabetes Mellitus, Experimental/therapy ; Disease Models, Animal ; Humans ; Injections, Intralesional ; Mitochondria, Heart/physiology ; Mitochondria, Heart/transplantation ; Mitochondria, Heart/ultrastructure ; Mitochondrial Dynamics/physiology ; Myocardial Infarction/metabolism ; Myocardial Infarction/pathology ; Myocardial Infarction/therapy ; Myocardial Reperfusion Injury/metabolism ; Myocardial Reperfusion Injury/pathology ; Myocardial Reperfusion Injury/therapy ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Oxidative Phosphorylation ; Rabbits ; Rats ; Reactive Oxygen Species/metabolism ; Swine
Chemical Substances	Reactive Oxygen Species
Language	English
Publishing date	2021-06-30
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	392098-7
ISSN	1522-1563 ; 0363-6143
ISSN (online)	1522-1563
ISSN	0363-6143
DOI	10.1152/ajpcell.00152.2021
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Article: The Correlation Between Lymphocyte Nadir and Radiation Therapy for Soft Tissue Sarcoma: Defining Key Dosimetric Parameters and Outlining Clinical Significance.

Ku, Eric / Harada, Garrett / Chiao, Elaine / Rao, Pranathi / Hosseinian, Sina / Seyedin, Steven / Healy, Erin / Maxim, Peter / Chow, Warren / Stitzlein, Russell / Limoli, Charles / Harris, Jeremy

Advances in radiation oncology

2023 Volume 9, Issue 1, Page(s) 101309

Abstract: Purpose: The objectives of this study were to identify key dosimetric parameters associated with postradiation therapy lymphopenia and uncover any effect on clinical outcomes.: Methods and materials: This was a retrospective review of 69 patients ( ... ...

Abstract	Purpose: The objectives of this study were to identify key dosimetric parameters associated with postradiation therapy lymphopenia and uncover any effect on clinical outcomes. Methods and materials: This was a retrospective review of 69 patients (between April 2010 and January 2023) who underwent radiation therapy (RT) as a part of curative intent for soft tissue sarcoma (STS) at a single academic institution. All patients with treatment plans available to review and measurable absolute lymphocyte count (ALC) nadir within a year after completion of RT were included. Results: Median follow-up was 22 months after the start of RT. A decrease in lymphocyte count was noted as early as during treatment and persisted at least 3 months after the completion of RT. On multivariable linear regression, the strongest correlations with ALC nadir were mean body dose, body V10 Gy, mean bone dose, bone V10 Gy, and bone V20 Gy. Five-year overall survival was 60% and 5-year disease-free survival was 44%. Advanced T-stage, chemotherapy use, use of intensity-modulated RT, lower ALC nadir, and the development of grade ≥2 lymphopenia at nadir were associated with worse overall survival and disease-free survival. Conclusions: Post-RT lymphopenia was associated with worse outcomes in STS. There were associations between higher body V10 Gy and bone V10 Gy and lower post-RT ALC nadir, despite the varying sites of STS presentation, which aligns with the well-known radiosensitivity of lymphocyte cell lines. These findings support efforts to reduce treatment-related hematopoietic toxicity as a way to improve oncologic outcomes. Additionally, this study supports the idea that the effect of radiation on lymphocyte progenitors in the bone marrow is more significant than that on circulating lymphocytes in treatments with limited involvement of the heart and lung.
Language	English
Publishing date	2023-07-09
Publishing country	United States
Document type	Journal Article
ISSN	2452-1094
ISSN	2452-1094
DOI	10.1016/j.adro.2023.101309
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Article ; Online: Analysis and comparison of SARS-CoV-2 variant antibodies and neutralizing activity for 6 months after a booster mRNA vaccine in a healthcare worker population.

Hosseinian, Sina / de Assis, Rafael / Khalil, Ghali / Luu, Madeleine K / Jain, Aarti / Horvath, Peter / Nakajima, Rie / Palma, Anton M / Hoang, Anthony / Razzak, Eisa / Garcia, Nicholas / Alger, Joshua / Kalantari, Mina / Silzel, Emily K / Jasinskas, Algis / Zaldivar, Frank / Schubl, Sebastian D / Felgner, Philip L / Khan, Saahir

Frontiers in immunology

2023 Volume 14, Page(s) 1166261

Abstract: Introduction: In the context of recurrent surges of SARS-CoV-2 infections, a detailed characterization of antibody persistence over a 6-month period following vaccine booster dose is necessary to crafting effective public health policies on repeat ... ...

Abstract	Introduction: In the context of recurrent surges of SARS-CoV-2 infections, a detailed characterization of antibody persistence over a 6-month period following vaccine booster dose is necessary to crafting effective public health policies on repeat vaccination. Methods: To characterize the SARS-CoV-2 antibody profile of a healthcare worker population over a 6-month period following mRNA vaccination and booster dose. 323 healthcare workers at an academic medical center in Orange County, California who had completed primary vaccination and booster dose against SARS-CoV-2 were recruited for the study. A total of 690 blood specimens over a 6-month period were collected Results: The primary outcome of this study was the average SARS-CoV-2 antibody level as measured using a novel coronavirus antigen microarray. Additional outcomes measured include levels of antibodies specific to SARS-CoV-2 variants including Delta, Omicron BA.1, and BA.2. We also measured SARS-CoV-2 neutralization capacity for a subset of the population to confirm correlation with antibody levels. Although antibodies against SARS-CoV-2 wane throughout the 6-month period following a booster dose, antibody levels remain higher than pre-boost levels. However, a booster dose of vaccine based on the original Wuhan strain generates approximately 3-fold lower antibody reactivity against Omicron variants BA.1 and BA.2 as compared to the vaccine strain. Despite waning antibody levels, neutralization activity against the vaccine strain is maintained throughout the 6-month period. Discussion: In the context of recurrent surges of SARS-CoV-2 infections, our data indicate that breakthrough infections are likely driven by novel variants with different antibody specificity and not by time since last dose of vaccination, indicating that development of vaccinations specific to these novel variants is necessary to prevent future surges of SARS-CoV-2 infections.
MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19/prevention & control ; Antibodies, Viral ; Health Personnel ; mRNA Vaccines
Chemical Substances	Antibodies, Viral
Language	English
Publishing date	2023-05-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1166261
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Article: Analysis and comparison of SARS-CoV-2 variant antibodies and neutralizing activity for 6 months after a booster mRNA vaccine in a healthcare worker population.

Khan, Saahir / Hosseinian, Sina / Assis, Rafael / Khalil, Ghali / Luu, Madeleine / Jain, Aarti / Horvath, Peter / Nakajima, Rie / Palma, Anton / Hoang, Anthony / Razzak, Eisa / Garcia, Nicholas / Alger, Joshua / Kalantari, Mina / Silzel, Emily / Jasinskas, Algis / Zaldivar, Frank / Schubl, Sebastian / Felgner, Philip

Research square

2022

Abstract: In the context of recurrent surges of SARS-CoV-2 infections, a detailed characterization of antibody persistence over a 6-month period following vaccine booster dose is necessary to crafting effective public health policies on repeat vaccination. To ... ...

Abstract	In the context of recurrent surges of SARS-CoV-2 infections, a detailed characterization of antibody persistence over a 6-month period following vaccine booster dose is necessary to crafting effective public health policies on repeat vaccination. To characterize the SARS-CoV-2 antibody profile of a healthcare worker population over a 6-month period following mRNA vaccination and booster dose. 323 healthcare workers at an academic medical center in Orange County, California who had completed primary vaccination and booster dose against SARS-CoV-2 were recruited for the study. A total of 690 blood specimens over a 6-month period were collected via finger-stick blood and analyzed for the presence of antibodies against 9 SARS-CoV-2 antigens using a coronavirus antigen microarray. The primary outcome of this study was the average SARS-CoV-2 antibody level as measured using a novel coronavirus antigen microarray. Additional outcomes measured include levels of antibodies specific to SARS-CoV-2 variants including Delta, Omicron BA.1, and BA.2. We also measured SARS-CoV-2 neutralization capacity for a subset of the population to confirm correlation with antibody levels. Although antibodies against SARS-CoV-2 wane throughout the 6-month period following a booster dose, antibody levels remain higher than pre-boost levels. However, a booster dose of vaccine generates approximately 3-fold lower antibody reactivity against Omicron variants BA.1 and BA.2 as compared to the original Wuhan strain. Despite waning antibody levels, neutralization activity against the original Wuhan strain is maintained throughout the 6-month period. In the context of recurrent surges of SARS-CoV-2 infections despite vaccination with booster doses, our data indicate that breakthrough infections are likely driven by novel variants with different antibody specificity and not by time since last dose of vaccination, indicating that development of vaccinations specific to these novel variants is necessary to prevent future surges of SARS-CoV-2 infections.
Language	English
Publishing date	2022-12-14
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-2180753/v1
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Article ; Online: Persistence of SARS-CoV-2 Antibodies in Vaccinated Health Care Workers Analyzed by Coronavirus Antigen Microarray.

Hosseinian, Sina / Powers, Kathleen / Vasudev, Milind / Palma, Anton M / de Assis, Rafael / Jain, Aarti / Horvath, Peter / Birring, Paramveer S / Andary, Rana / Au, Connie / Chin, Brandon / Khalil, Ghali / Ventura, Jenny / Luu, Madeleine K / Figueroa, Cesar / Obiero, Joshua M / Silzel, Emily / Nakajima, Rie / Gombrich, William Thomas /

Jasinskas, Algis / Zaldivar, Frank / Schubl, Sebastian / Felgner, Philip L / Khan, Saahir

Frontiers in immunology

2022 Volume 13, Page(s) 817345

Abstract: Recent studies provide conflicting evidence on the persistence of SARS-CoV-2 immunity induced by mRNA vaccines. Here, we aim to quantify the persistence of humoral immunity following vaccination using a coronavirus antigen microarray that includes 10 ... ...

Abstract	Recent studies provide conflicting evidence on the persistence of SARS-CoV-2 immunity induced by mRNA vaccines. Here, we aim to quantify the persistence of humoral immunity following vaccination using a coronavirus antigen microarray that includes 10 SARS-CoV-2 antigens. In a prospective longitudinal cohort of 240 healthcare workers, composite SARS-CoV-2 IgG antibody levels did not wane significantly over a 6-month study period. In the subset of the study population previously exposed to SARS-CoV-2 based on seropositivity for nucleocapsid antibodies, higher composite anti-spike IgG levels were measured before the vaccine but no significant difference from unexposed individuals was observed at 6 months. Age, vaccine type, or worker role did not significantly impact composite IgG levels, although non-significant trends towards lower antibody levels in older participants and higher antibody levels with Moderna vaccine were observed at 6 months. A small subset of our cohort were classified as having waning antibody titers at 6 months, and these individuals were less likely to work in patient care roles and more likely to have prior exposure to SARS-CoV-2.
MeSH term(s)	Aged ; Antibodies, Viral ; COVID-19/prevention & control ; Health Personnel ; Humans ; Immunoglobulin G ; Infant ; Prospective Studies ; SARS-CoV-2
Chemical Substances	Antibodies, Viral ; Immunoglobulin G
Language	English
Publishing date	2022-04-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.817345
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Article ; Online: Integrated Proteomics-Based Physical and Functional Mapping of AXL Kinase Signaling Pathways and Inhibitors Define Its Role in Cell Migration.

Majumder, Anurima / Hosseinian, Sina / Stroud, Mia / Adhikari, Emma / Saller, James J / Smith, Matthew A / Zhang, Guolin / Agarwal, Shruti / Creixell, Marc / Meyer, Benjamin S / Kinose, Fumi / Bowers, Kiah / Fang, Bin / Stewart, Paul A / Welsh, Eric A / Boyle, Theresa A / Meyer, Aaron S / Koomen, John M / Haura, Eric B

Molecular cancer research : MCR

2022 Volume 20, Issue 4, Page(s) 542–555

Abstract: To better understand the signaling complexity of AXL, a member of the tumor-associated macrophage (TAM) receptor tyrosine kinase family, we created a physical and functional map of AXL signaling interactions, phosphorylation events, and target-engagement ...

Abstract	To better understand the signaling complexity of AXL, a member of the tumor-associated macrophage (TAM) receptor tyrosine kinase family, we created a physical and functional map of AXL signaling interactions, phosphorylation events, and target-engagement of three AXL tyrosine kinase inhibitors (TKI). We assessed AXL protein complexes using proximity-dependent biotinylation (BioID), effects of AXL TKI on global phosphoproteins using mass spectrometry, and target engagement of AXL TKI using activity-based protein profiling. BioID identifies AXL-interacting proteins that are mostly involved in cell adhesion/migration. Global phosphoproteomics show that AXL inhibition decreases phosphorylation of peptides involved in phosphatidylinositol-mediated signaling and cell adhesion/migration. Comparison of three AXL inhibitors reveals that TKI RXDX-106 inhibits pAXL, pAKT, and migration/invasion of these cells without reducing their viability, while bemcentinib exerts AXL-independent phenotypic effects on viability. Proteomic characterization of these TKIs demonstrates that they inhibit diverse targets in addition to AXL, with bemcentinib having the most off-targets. AXL and EGFR TKI cotreatment did not reverse resistance in cell line models of erlotinib resistance. However, a unique vulnerability was identified in one resistant clone, wherein combination of bemcentinib and erlotinib inhibited cell viability and signaling. We also show that AXL is overexpressed in approximately 30% to 40% of nonsmall but rarely in small cell lung cancer. Cell lines have a wide range of AXL expression, with basal activation detected rarely. Implications: Our study defines mechanisms of action of AXL in lung cancers which can be used to establish assays to measure drug targetable active AXL complexes in patient tissues and inform the strategy for targeting it's signaling as an anticancer therapy.
MeSH term(s)	Cell Line, Tumor ; Cell Movement ; Drug Resistance, Neoplasm ; ErbB Receptors/metabolism ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proteomics/methods ; Signal Transduction
Chemical Substances	Protein Kinase Inhibitors ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2022-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
DOI	10.1158/1541-7786.MCR-21-0275
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Article ; Online: Risk factors for SARS-CoV-2 seropositivity in a health care worker population during the early pandemic.

Schubl, Sebastian D / Figueroa, Cesar / Palma, Anton M / de Assis, Rafael R / Jain, Aarti / Nakajima, Rie / Jasinskas, Algimantas / Brabender, Danielle / Hosseinian, Sina / Naaseh, Ariana / Hernandez Dominguez, Oscar / Runge, Ava / Skochko, Shannon / Chinn, Justine / Kelsey, Adam J / Lai, Kieu T / Zhao, Weian / Horvath, Peter / Tifrea, Delia /

Grigorian, Areg / Gonzales, Abran / Adelsohn, Suzanne / Zaldivar, Frank / Edwards, Robert / Amin, Alpesh N / Stamos, Michael J / Barie, Philip S / Felgner, Philip L / Khan, Saahir

BMC infectious diseases

2023 Volume 23, Issue 1, Page(s) 330

Abstract: Background: While others have reported severe acute respiratory syndrome-related coronavirus 2(SARS-CoV-2) seroprevalence studies in health care workers (HCWs), we leverage the use of a highly sensitive coronavirus antigen microarray to identify a group ...

Abstract	Background: While others have reported severe acute respiratory syndrome-related coronavirus 2(SARS-CoV-2) seroprevalence studies in health care workers (HCWs), we leverage the use of a highly sensitive coronavirus antigen microarray to identify a group of seropositive health care workers who were missed by daily symptom screening that was instituted prior to any epidemiologically significant local outbreak. Given that most health care facilities rely on daily symptom screening as the primary method to identify SARS-CoV-2 among health care workers, here, we aim to determine how demographic, occupational, and clinical variables influence SARS-CoV-2 seropositivity among health care workers. Methods: We designed a cross-sectional survey of HCWs for SARS-CoV-2 seropositivity conducted from May 15th to June 30th 2020 at a 418-bed academic hospital in Orange County, California. From an eligible population of 5,349 HCWs, study participants were recruited in two ways: an open cohort, and a targeted cohort. The open cohort was open to anyone, whereas the targeted cohort that recruited HCWs previously screened for COVID-19 or work in high-risk units. A total of 1,557 HCWs completed the survey and provided specimens, including 1,044 in the open cohort and 513 in the targeted cohort. Demographic, occupational, and clinical variables were surveyed electronically. SARS-CoV-2 seropositivity was assessed using a coronavirus antigen microarray (CoVAM), which measures antibodies against eleven viral antigens to identify prior infection with 98% specificity and 93% sensitivity. Results: Among tested HCWs (n = 1,557), SARS-CoV-2 seropositivity was 10.8%, and risk factors included male gender (OR 1.48, 95% CI 1.05-2.06), exposure to COVID-19 outside of work (2.29, 1.14-4.29), working in food or environmental services (4.85, 1.51-14.85), and working in COVID-19 units (ICU: 2.28, 1.29-3.96; ward: 1.59, 1.01-2.48). Amongst 1,103 HCWs not previously screened, seropositivity was 8.0%, and additional risk factors included younger age (1.57, 1.00-2.45) and working in administration (2.69, 1.10-7.10). Conclusion: SARS-CoV-2 seropositivity is significantly higher than reported case counts even among HCWs who are meticulously screened. Seropositive HCWs missed by screening were more likely to be younger, work outside direct patient care, or have exposure outside of work.
MeSH term(s)	Humans ; Male ; SARS-CoV-2 ; COVID-19/epidemiology ; Cross-Sectional Studies ; Pandemics ; Seroepidemiologic Studies ; Health Personnel ; Antibodies, Viral
Chemical Substances	Antibodies, Viral
Language	English
Publishing date	2023-05-16
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/s12879-023-08284-y
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Article ; Online: Prospects of mitochondrial transplantation in clinical medicine: Aspirations and challenges.

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Article ; Online: Mitochondrial transplantation in cardiomyocytes: foundation, methods, and outcomes.

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Article: The Correlation Between Lymphocyte Nadir and Radiation Therapy for Soft Tissue Sarcoma: Defining Key Dosimetric Parameters and Outlining Clinical Significance.

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Article ; Online: Analysis and comparison of SARS-CoV-2 variant antibodies and neutralizing activity for 6 months after a booster mRNA vaccine in a healthcare worker population.

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Article: Analysis and comparison of SARS-CoV-2 variant antibodies and neutralizing activity for 6 months after a booster mRNA vaccine in a healthcare worker population.

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Article ; Online: Persistence of SARS-CoV-2 Antibodies in Vaccinated Health Care Workers Analyzed by Coronavirus Antigen Microarray.

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Article ; Online: Integrated Proteomics-Based Physical and Functional Mapping of AXL Kinase Signaling Pathways and Inhibitors Define Its Role in Cell Migration.

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Article ; Online: Risk factors for SARS-CoV-2 seropositivity in a health care worker population during the early pandemic.

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