Glioblastoma Organoids: Pre-Clinical Applications and Challenges in the Context of Immunotherapy

Malignant brain tumors remain uniformly fatal, even with the best-to-date treatment. For Glioblastoma (GBM), the most severe form of brain cancer in adults, the median overall survival is roughly over a year. New therapeutic options are urgently needed, yet recent clinical trials in the field have been largely disappointing. This is partially due to inappropriate preclinical model systems, which do not reflect the complexity of patient tumors. Furthermore, clinically relevant patient-derived models recapitulating the immune compartment are lacking, which represents a bottleneck for adequate immunotherapy testing. Emerging 3D organoid cultures offer innovative possibilities for cancer modeling. Here, we review available GBM organoid models amenable to a large variety of pre-clinical applications including functional bioassays such as proliferation and invasion, drug screening, and the generation of patient-derived orthotopic xenografts (PDOX) for validation of biological responses in vivo. We emphasize advantages and technical challenges in establishing immunocompetent ex vivo models based on co-cultures of GBM organoids and human immune cells. The latter can be isolated either from the tumor or from patient or donor blood as peripheral blood mononuclear cells (PBMCs). We also discuss the challenges to generate GBM PDOXs based on humanized mouse models to validate efficacy of immunotherapies in vivo. A detailed characterization of such models at the cellular and molecular level is needed to understand the potential and limitations for various immune activating strategies. Increasing the availability of immunocompetent GBM models will improve research on emerging immune therapeutic approaches against aggressive brain cancer.

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The Influence of Methylsulfonylmethane on Inflammation-Associated Cytokine Release before and following Strenuous Exercise

Journal of Sports Medicine ◽

10.1155/2016/7498359 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Mariè van der Merwe ◽

Richard J. Bloomer

Keyword(s):

Whole Blood ◽

Mononuclear Cells ◽

Ex Vivo ◽

Knee Extension ◽

Strenuous Exercise ◽

Peripheral Blood Mononuclear ◽

Physically Active ◽

Inflammatory Molecules

Background. Inflammation is associated with strenuous exercise and methylsulfonylmethane (MSM) has been shown to have anti-inflammatory properties.Methods. Physically active men were supplemented with either placebo or MSM (3 grams per day) for 28 days before performing 100 repetitions of eccentric knee extension exercise.Ex vivoandin vitrotesting consisted of evaluating cytokine production in blood (whole blood and isolated peripheral blood mononuclear cells (PBMCs)) exposed to lipopolysaccharide (LPS), before and through 72 hours after exercise, whilein vivotesting included the evaluation of cytokines before and through 72 hours after exercise.Results. LPS stimulation of whole blood after MSM supplementation resulted in decreased induction of IL-1β, with no effect on IL-6, TNF-α, or IL-8. After exercise, there was a reduced response to LPS in the placebo, but MSM resulted in robust release of IL-6 and TNF-α. A small decrease in resting levels of proinflammatory cytokines was noted with MSM, while an acute postexercise increase in IL-10 was observed with MSM.Conclusion. Strenuous exercise causes a robust inflammatory reaction that precludes the cells from efficiently responding to additional stimuli. MSM appears to dampen the release of inflammatory molecules in response to exercise, resulting in a less incendiary environment, allowing cells to still have the capacity to mount an appropriate response to an additional stimulus after exercise.

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Potential TH9402-Based ECP Treatment for cGvHD Patients.

Blood ◽

10.1182/blood.v104.11.5119.5119 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5119-5119

Author(s):

Annie Levesque ◽

Ann-Louise Savard ◽

Denis-Claude Roy ◽

Francine Foss ◽

Christian Scotto

Keyword(s):

T Cells ◽

Cell Death ◽

Mononuclear Cells ◽

Ex Vivo ◽

Chronic Phase ◽

Dose Effect ◽

Peripheral Blood Mononuclear ◽

Hematopoietic Stem

Abstract Although the risk of graft versus host disease (GvHD) can be reduced by improved donor-recipient matching and by the depletion of T cells before transplantation, GvHD still develops in 30–70% of allogeneic hematopoietic stem cell transplantation (HSCT) patients. The chronic phase of the disease (cGvHD), for which the pathogenesis is similar to autoimmune diseases, involves profound immune dysregulation leading to both immunodeficiency and autoimmunity. Standard therapies for cGvHD such as corticosteroids and immunosuppressants are associated with high toxicity and have demonstrated limited efficacy in patients with extensive disease. Extracorporeal photopheresis (ECP) has been shown by others in the clinic as a non-aggressive and beneficial alternative treatment for cGvHD, inducing Th1/Th2 immunomodulation that restores immunological tolerance. Celmed has developed an alternative approach to eliminate immunoreactive T cells using the Theralux™ photodynamic cell therapy (PDT) system based on the use of the rhodamine-123 derivative TH9402 illuminated ex vivo with a visible light source (λ =514nm). It has been suggested that the apoptotic cells, when returned to the patient, may be able to modulate the immune system as seen with other ECP methods. We aimed to evaluate in vivo and in vitro the possibility of also using the Theralux™ system in the ECP setting. A preliminary mouse model suggested that splenic T cells pre-treated with the Theralux™ system were able to induce an improvement of overall survival (p<0.05) in mice with acute GvHD. Additionally, we developed a simplified PDT process and conducted a series of experiments with peripheral blood mononuclear cells (PBMCs) isolated from healthy volunteers. These studies have shown that the intra- and inter-donor variability in TH9402 incorporation are very low (~5% and 10%, respectively). A dose-effect study has shown a relationship of the PDT conditions with the levels of cell death, allowing significant control of the level of apoptosis induced. Phenotypic analyses have shown that this process results in an increase of AnnexinV positive cells as well as a decrease in the absolute number of CD3+ cells, CD19+/CD20+ cells and CD14+ cells and an increase in CD11c+ cells. This would suggest that apoptosis could be induced in both autoreactive T and B cells which could potentially stimulate an immune response against them. Moreover, the increase in CD11c+ cells combined with the decrease in CD14+ cells could reflect the maturation of macrophages into dendritic cells that are very potent antigen presenting cells. The mechanism by which these specific PDT conditions induce cell death is still under investigation but preliminary studies have shown that the cell death in unselected resting PBMCs may be caspase-independent. Finally, the evaluation of the effect of PDT on samples from cGvHD patients also demonstrated the capacity of this treatment strategy to induce apoptosis in these cells. Based on these data, we intend to begin a pilot clinical study evaluating two controlled PDT conditions inducing different levels of apoptosis in order to assess the safety and biological effect of the Theralux™ ECP system to treat patients with cGvHD.

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Functional Role of pX Open Reading Frame II of Human T-Lymphotropic Virus Type 1 in Maintenance of Viral Loads In Vivo

Journal of Virology ◽

10.1128/jvi.74.3.1094-1100.2000 ◽

2000 ◽

Vol 74 (3) ◽

pp. 1094-1100 ◽

Cited By ~ 78

Author(s):

Joshua T. Bartoe ◽

Björn Albrecht ◽

Nathaniel D. Collins ◽

Michael D. Robek ◽

Lee Ratner ◽

...

Keyword(s):

Virus Type ◽

Mononuclear Cells ◽

Ex Vivo ◽

Peripheral Blood Mononuclear ◽

T Lymphotropic Virus ◽

Viral Loads

ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma and is associated with a variety of immune-mediated disorders. The role of four open reading frames (ORFs), located between env and the 3′ long terminal repeat of HTLV-1, in mediating disease is not entirely clear. By differential splicing, ORF II encodes two proteins, p13II and p30II, both of which have not been functionally defined. p13II localizes to mitochondria and may alter the configuration of the tubular network of this cellular organelle. p30II localizes to the nucleolus and shares homology with the transcription factors Oct-1 and -2, Pit-1, and POU-M1. Both p13II and p30II are dispensable for infection and immortalization of primary human and rabbit lymphocytes in vitro. To test the role of ORF II gene products in vivo, we inoculated rabbits with lethally irradiated cell lines expressing the wild-type molecular clone of HTLV-1 (ACH.1) or a clone containing selected mutations in ORF II (ACH.30/13.1). ACH.1-inoculated animals maintained higher HTLV-1-specific antibody titers than animals inoculated with ACH.30/13.1. Viral p19 antigen was transiently detected in ex vivo cultures of peripheral blood mononuclear cells (PBMC) from only two ACH.30/13.1-inoculated rabbits, while PBMC cultures from all ACH.1-inoculated rabbits routinely produced p19 antigen. In only three of six animals exposed to the ACH.p30II/p13IIclone could provirus be consistently PCR amplified from extracted PBMC DNA and quantitative competitive PCR showed the proviral loads in PBMC from ACH.p30II/p13II-infected rabbits to be dramatically lower than the proviral loads in rabbits exposed to ACH. Our data indicate selected mutations in pX ORF II diminish the ability of HTLV-1 to maintain high viral loads in vivo and suggest an important function for p13II and p30II in viral pathogenesis.

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Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1417320112 ◽

2015 ◽

Vol 112 (19) ◽

pp. 6140-6145 ◽

Cited By ~ 301

Author(s):

Emanuela Romano ◽

Monika Kusio-Kobialka ◽

Periklis G. Foukas ◽

Petra Baumgaertner ◽

Christiane Meyer ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Clinical Efficacy ◽

Mechanism Of Action ◽

Mononuclear Cells ◽

Ex Vivo ◽

Immune Checkpoints ◽

Peripheral Blood Mononuclear ◽

Dependent Cell

Enhancing immune responses with immune-modulatory monoclonal antibodies directed to inhibitory immune receptors is a promising modality in cancer therapy. Clinical efficacy has been demonstrated with antibodies blocking inhibitory immune checkpoints such as cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) or PD-1/PD-L1. Treatment with ipilimumab, a fully human CTLA-4–specific mAb, showed durable clinical efficacy in metastatic melanoma; its mechanism of action is, however, only partially understood. This is a study of 29 patients with advanced cutaneous melanoma treated with ipilimumab. We analyzed peripheral blood mononuclear cells (PBMCs) and matched melanoma metastases from 15 patients responding and 14 not responding to ipilimumab by multicolor flow cytometry, antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and immunohistochemistry. PBMCs and matched tumor biopsies were collected 24 h before (i.e., baseline) and up to 4 wk after ipilimumab. Our findings show, to our knowledge for the first time, that ipilimumab can engage ex vivo FcγRIIIA (CD16)-expressing, nonclassical monocytes resulting in ADCC-mediated lysis of regulatory T cells (Tregs). In contrast, classical CD14++CD16− monocytes are unable to do so. Moreover, we show that patients responding to ipilimumab display significantly higher baseline peripheral frequencies of nonclassical monocytes compared with nonresponder patients. In the tumor microenvironment, responders have higher CD68+/CD163+ macrophage ratios at baseline and show decreased Treg infiltration after treatment. Together, our results suggest that anti–CTLA-4 therapy may target Tregs in vivo. Larger translational studies are, however, warranted to substantiate this mechanism of action of ipilimumab in patients.

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CD49d provides access to “untouched” human Foxp3+ Treg free of contaminating effector cells

Blood ◽

10.1182/blood-2008-04-150524 ◽

2009 ◽

Vol 113 (4) ◽

pp. 827-836 ◽

Cited By ~ 92

Author(s):

Markus Kleinewietfeld ◽

Mireille Starke ◽

Diletta Di Mitri ◽

Giovanna Borsellino ◽

Luca Battistini ◽

...

Keyword(s):

Mononuclear Cells ◽

Treg Cells ◽

Interferon Γ ◽

Clinical Applications ◽

Interleukin 17 ◽

Peripheral Blood Mononuclear ◽

Effector Cells ◽

Ifn Γ

Abstract The adoptive transfer of regulatory Foxp3+ T (Treg) cells has been shown in various animal models to prevent inflammatory immune and autoimmune diseases. Translation into therapeutic applications, however, is hindered by the lack of suitable techniques and markers. CD25, commonly used to isolate Treg cells from mice, has only limited value in humans as it is also present on proinflammatory CD4+ effector cells. Here we show that clean populations of human Foxp3+ Treg cells can be obtained with antibodies directed against CD49d. The marker is present on proinflammatory peripheral blood mononuclear cells but is absent on immune-suppressive Treg cells. Depletion with α-CD49d removes contaminating interferon-γ (IFN-γ)– and interleukin-17 (IL-17)–secreting cells from Treg preparations of CD4+CD25high cells. More importantly, in combination with α-CD127 it allows the isolation of “untouched” Foxp3+ Treg (ie, cells that have not been targeted by an antibody during purification). The removal of CD49d+/CD127+ cells leaves a population of Foxp3+ Treg virtually free of contaminating CD25+ effector cells. The cells can be expanded in vitro and are effective suppressors both in vitro and in vivo. Thus, CD49d provides access to highly pure populations of untouched Foxp3+ Treg cells conferring maximal safety for future clinical applications.

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Influence of Prior Exposure to Zidovudine on Stavudine Phosphorylation In Vivo and Ex Vivo

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.2.577-582.2001 ◽

2001 ◽

Vol 45 (2) ◽

pp. 577-582 ◽

Cited By ~ 10

Author(s):

P. G. Hoggard ◽

S. D. Sales ◽

D. Phiboonbanakit ◽

J. Lloyd ◽

B. A. Maher ◽

...

Keyword(s):

High Performance ◽

Mononuclear Cells ◽

Ex Vivo ◽

Hiv Positive ◽

Peripheral Blood Mononuclear ◽

Significant Difference ◽

Immunodeficiency Virus ◽

Ex Vivo Study ◽

Level 2

ABSTRACT Intracellular phosphorylation of stavudine (d4T) and zidovudine (ZDV) was investigated in peripheral blood mononuclear cells (PBMCs) isolated from ZDV-naive and ZDV-experienced human immunodeficiency virus (HIV)-positive patients. An in vivo study measured the amount of d4T triphosphate (d4TTP), while an ex vivo study assessed the capacity of cells to phosphorylate added d4T. Endogenous dTTP was also measured. d4TTP and dTTP were determined in vivo using a reverse transcriptase chain termination assay. In ex vivo studies, d4T (1 μM) was incubated in resting and phytohemagglutinin-stimulated (10 μg ml−1; 72 h) PBMCs for 24 h. After washing and methanol extraction, radiolabeled anabolites were detected by high-performance liquid chromatography. d4TTP reached its highest level 2 to 4 h after dosing (0.21 ± 0.14 pmol/106cells; n = 27 [mean ± standard deviation]). Comparison of ZDV-naive and ZDV-experienced individuals showed no significant difference in levels of d4TTP (ZDV naive, 0.23 ± 0.17 pmol/106 cells [n = 7] versus ZDV experienced, 0.20 ± 0.14 pmol/106 cells [n = 20]; P = 0.473) or the d4TTP/dTTP ratio (0.14 ± 0.12 [n = 7] and 0.10 ± 0.08 [n = 20], respectively;p = 0.391). Ex vivo data demonstrated no significant difference in the formation of d4TTP or total d4T phosphates in naive and experienced patients (0.086 ± 0.055 pmol/106cells in ZDV-naive patients [n = 17] versus 0.081 ± 0.038 pmol/106 cells in ZDV-experienced patients [n = 22]; P = 0.767). The ability of HIV-infected patients to phosphorylate d4T in vivo and ex vivo was unchanged with increasing exposure to ZDV.

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Bovine Leukemia Virus-Induced Persistent Lymphocytosis in Cattle Does Not Correlate with Increased Ex Vivo Survival of B Lymphocytes

Journal of Virology ◽

10.1128/jvi.73.2.1127-1137.1999 ◽

1999 ◽

Vol 73 (2) ◽

pp. 1127-1137 ◽

Cited By ~ 18

Author(s):

Franck Dequiedt ◽

Glenn H. Cantor ◽

Valerie T. Hamilton ◽

Suzanne M. Pritchard ◽

William C. Davis ◽

...

Keyword(s):

Cell Death ◽

Cell Survival ◽

Bovine Leukemia Virus ◽

Mononuclear Cells ◽

Ex Vivo ◽

Leukemia Virus ◽

Spontaneous Apoptosis ◽

Persistent Lymphocytosis ◽

Peripheral Blood Mononuclear

ABSTRACT Bovine leukemia virus (BLV) is an oncogenic retrovirus associated with B-cell lymphocytosis, leukemia, and lymphosarcoma in the ovine and bovine species. We have recently reported that in sheep, BLV protects the total population of peripheral blood mononuclear cells (PBMCs) from ex vivo spontaneous apoptosis. This global decrease in the apoptosis rates resulted from both direct and indirect mechanisms which allow extension of cell survival. Although sheep are not natural hosts for BLV, these animals are prone to develop virus-induced leukemia at very high frequencies. Most infected cattle, however, remain clinically healthy. This difference in the susceptibilities to development of leukemia in these two species might be related to alterations of the apoptotic processes. Therefore, we designed this study to unravel the mechanisms of programmed cell death in cattle. We have observed that PBMCs from persistently lymphocytotic BLV-infected cows were more susceptible to spontaneous ex vivo apoptosis than cells from uninfected or aleukemic animals. These higher apoptosis rates were the consequence of an increased proportion of B cells exhibiting lower survival abilities. About one-third of the BLV-expressing cells did not survive the ex vivo culture conditions, demonstrating that viral expression is not strictly associated with cell survival in cattle. Surprisingly, culture supernatants from persistently lymphocytotic cows exhibited efficient antiapoptotic properties on both uninfected bovine and uninfected ovine cells. It thus appears that indirect inhibition of cell death can occur even in the presence of high apoptosis rates. Together, these results demonstrate that the protection against spontaneous apoptosis associated with BLV is different in cattle and in sheep. The higher levels of ex vivo apoptosis occurring in cattle might indicate a decreased susceptibility to development of leukemia in vivo.

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Treatment of cancer patients with ex vivo anti-CD3-activated killer cells and interleukin-2.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.4.652 ◽

1993 ◽

Vol 11 (4) ◽

pp. 652-660 ◽

Cited By ~ 29

Author(s):

B D Curti ◽

D L Longo ◽

A C Ochoa ◽

K C Conlon ◽

J W Smith ◽

...

Keyword(s):

Continuous Infusion ◽

Adoptive Transfer ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Ex Vivo ◽

Interleukin 2 ◽

Clotting Factors ◽

Peripheral Blood Mononuclear ◽

Killer Cells

PURPOSE This study describes the physiologic and biologic effects resulting from the adoptive transfer of ex vivo anti-CD3-stimulated T-killer cells (T-AK) to patients with advanced cancer in combination with interleukin-2 (IL-2). METHODS Autologous peripheral-blood mononuclear cells were obtained by leukapheresis and stimulated ex vivo with anti-CD3. The stimulated cells were reinfused at one of three dose levels on the next day (5 x 10(9), 7.5 x 10(9), and 1 x 10(10)). Cell administration was followed by IL-2 given by bolus and continuous infusion (1.5 x 10(6) U/m2 and 3.0 x 10(6) U/m2, respectively) for 7 days, or continuous infusion alone (3.0 x 10(6) U/m2) for 14 days. RESULTS Pronounced leukocytosis and atypical lymphocytosis were observed with individual values as high as 80,000 and 50,000 cells/microL, respectively. The other major clinical sequelae included a marked lactic acidosis with bicarbonate levels as low as 4.0 mmol/L in some patients, and prolongation of the prothrombin time (PT) and partial thromboplastin time (PTT) due to decreases in clotting factors VII, IX, and X. Antithrombin III levels were also reduced. Hypotension associated with increased serum nitrate and neopterin levels was observed. These toxicities were accompanied by increases in hepatocellular enzymes and creatinine previously described with IL-2. These events occurred at a time when the number of circulating T-AK cells reached their peak. The amount of bolus IL-2 correlated with increases in WBC count (P = .0311), atypical lymphocytes (P = .0241), PT (P = .0006), and PTT (P = .0122). CONCLUSION Substantial in vivo expansion of activated T lymphocytes was induced by a protocol combining ex vivo activation of peripheral-blood cells with anti-CD3 antibody followed by adoptive transfer and IL-2 administration. The synchronous expansion of these T cells superimposed on diminished liver and kidney function from IL-2 can cause profound but reversible metabolic changes.

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Monitoring DNA Damage and Repair in Peripheral Blood Mononuclear Cells of Lung Cancer Radiotherapy Patients

Cancers ◽

10.3390/cancers12092517 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2517

Author(s):

Pavel N. Lobachevsky ◽

Nicholas W. Bucknell ◽

Joel Mason ◽

Diane Russo ◽

Xiaoyu Yin ◽

...

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Ex Vivo ◽

Predictive Biomarkers ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells

Thoracic radiotherapy (RT) is required for the curative management of inoperable lung cancer, however, treatment delivery is limited by normal tissue toxicity. Prior studies suggest that using radiation-induced DNA damage response (DDR) in peripheral blood mononuclear cells (PBMC) has potential to predict RT-associated toxicities. We collected PBMC from 38 patients enrolled on a prospective clinical trial who received definitive fractionated RT for non-small cell lung cancer. DDR was measured by automated counting of nuclear γ-H2AX foci in immunofluorescence images. Analysis of samples collected before, during and after RT demonstrated the induction of DNA damage in PBMC collected shortly after RT commenced, however, this damage repaired later. Radiation dose to the tumour and lung contributed to the in vivo induction of γ-H2AX foci. Aliquots of PBMC collected before treatment were also irradiated ex vivo, and γ-H2AX kinetics were analyzed. A trend for increasing of fraction of irreparable DNA damage in patients with higher toxicity grades was revealed. Slow DNA repair in three patients was associated with a combined dysphagia/cough toxicity and was confirmed by elevated in vivo RT-generated irreparable DNA damage. These results warrant inclusion of an assessment of DDR in PBMC in a panel of predictive biomarkers that would identify patients at a higher risk of toxicity.

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Ex vivo use of cell-permeable succinate prodrug attenuates mitochondrial dysfunction in blood cells obtained from carbon monoxide-poisoned individuals

AJP Cell Physiology ◽

10.1152/ajpcell.00539.2019 ◽

2020 ◽

Vol 319 (1) ◽

pp. C129-C135 ◽

Cited By ~ 2

Author(s):

Shawn Owiredu ◽

Abhay Ranganathan ◽

David M. Eckmann ◽

Frances S. Shofer ◽

Kevin Hardy ◽

...

Keyword(s):

Carbon Monoxide ◽

Blood Cells ◽

Mononuclear Cells ◽

Ex Vivo ◽

Mitochondrial Dynamics ◽

Control Group ◽

Co Poisoning ◽

Peripheral Blood Mononuclear ◽

Complex Ii

The purpose of this study was to evaluate a new pharmacological strategy using a first-generation succinate prodrug, NV118, in peripheral blood mononuclear cells (PBMCs) obtained from subjects with carbon monoxide (CO) poisoning and healthy controls. We obtained human blood cells from subjects with CO poisoning and healthy control subjects. Intact PBMCs from subjects in the CO and Control group were analyzed with high-resolution respirometry measured in pmol O2 per second per 10−6 PBMCs. In addition to obtaining baseline respiration, NV118 (100 μM) was injected, and the same parameters of respiration were obtained for comparison in PBMCs. We measured mitochondrial dynamics with microscopy with the same conditions. We enrolled 37 patients (17 in the CO group and 20 in the Control group for comparison) in the study. PMBCs obtained from subjects in the CO group had overall significantly lower respiration compared with the Control group ( P < 0.0001). There was a significant increase in respiration with NV118, specifically with an increase in maximum respiration and respiration from complex II and complex IV ( P < 0.0001). The mitochondria in PBMCs demonstrated an overall increase in net movement compared with the Control group. Our results of this study suggest that the therapeutic compound, NV118, increases respiration at complex II and IV as well as restoration of mitochondrial movement in PBMCs obtained from subjects with CO poisoning. Mitochondrial-directed therapy offers a potential future strategy with further exploration in vivo.

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