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Pubblicazioni recenti - cardiac stem
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A chitosan-vitamin C based injectable hydrogel improves cell survival under oxidative stress.
Int J Biol Macromol2022 Jan;():. doi: S0141-8130(22)00037-X.
Guo Yueping, Qu Youyang, Yu Jiaqi, Song Lili, Chen Simin, Qin Zhenmiao, Gong Jingwen, Zhan Haihe, Gao Yanan, Zhang Junqing,
Abstract
Stem cell transplantation technology provides the cell reconstruction of damaged heart a completely new therapy approach. Due to the inappropriate microenvironment such as reactive oxygen radicals caused by ischemic infarct, the survival and retention rates of cell transplantation are not desirable. A thermo sensitive chitosan-vitamin C (CSVC) hydrogel scaffold was developed to reduce oxidative stress injury after myocardial infarction, thereby increasing the cell survival rate of cell transplantation. Vitamin C was conjugated on the chitosan chain by electrostatic adsorption. Compared to chitosan, CSVC complex had a higher solubility and stronger antioxidant property. CSVC hydrogel has suitable gelation time and injectable properties. Scanning electron microscopy showed that chitosan hydrogels had three-dimensional porous structure with irregular pores interconnected throughout the construct. Live/dead and H&E staining results showed that CSVC hydrogel can support the survival and adhesion of cardiomyocytes. Compared with chitosan hydrogel, CSVC hydrogel can clearly improve the survival of cardiomyocytes and reduce the ROS level under HO-induced oxidative stress conditions. These results suggest that CSVC hydrogel has the potential to support the survival of cardiomyocytes in tissue engineering.
Copyright © 2021. Published by Elsevier B.V.
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Homologous cardiac calcium pump regulators phospholamban and sarcolipin adopt distinct oligomeric states in the membrane.
Comput Struct Biotechnol J2022 ;20():380-384. doi: 10.1016/j.csbj.2021.12.031.
Liu Andy Y, Aguayo-Ortiz Rodrigo, Guerrero-Serna Guadalupe, Wang Nulang, Blin Muriel G, Goldstein Daniel R, Michel Espinoza-Fonseca L,
Abstract
Phospholamban (PLN) and Sarcolipin (SLN) are homologous membrane proteins that belong to the family of proteins that regulate the activity of the cardiac calcium pump (sarcoplasmic reticulum Ca-ATPase, SERCA). PLN and SLN share highly conserved leucine zipper motifs that control self-association; consequently, it has been proposed that both PLN and SLN assemble into stable pentamers in the membrane. In this study, we used molecular dynamics (MD) simulations and Western blot analysis to investigate the precise molecular architecture of the PLN and SLN oligomers. Analysis showed that the PLN pentamer is the predominant oligomer present in mouse ventricles and ventricle-like human iPSC-derived cardiomyocytes, in agreement with the MD simulations showing stable leucine zipper interactions across all protomer-protomer interfaces and MD replicates. Interestingly, we found that the PLN pentamer populates an asymmetric structure of the transmembrane region, which is likely an intrinsic feature of the oligomer in a lipid bilayer. The SLN pentamer is not favorably formed across MD replicates and species of origin; instead, SLN from human and mouse atria primarily populate coexisting dimeric and trimeric states. In contrast to previous studies, our findings indicate that the SLN pentamer is not the predominant oligomeric state populated in the membrane. We conclude that despite their structural homology, PLN and SLN adopt distinct oligomeric states in the membrane. We propose that the distinct oligomeric states populated by PLN and SLN may contribute to tissue-specific SERCA regulation via differences in protomer-oligomer exchange, oligomer-SERCA dynamics, and noise filtering during ?-adrenergic stimulation in the heart.
© 2021 The Authors.
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Clinical results of short external rotators preserving posterolateral approach for hemiarthroplasty after femoral neck fractures in elderly patients.
Injury2022 Jan;():. doi: S0020-1383(21)01066-4.
Yoo Je-Hyun, Kwak Daekyung, Lee Yongmin, Ma Xiao, Yoon Joonhyeok, Hwang Jihyo,
Abstract
INTRODUCTION:
Even though the dislocation rate is lower in the hemiarthroplasty (HA) than total hip arthroplasty, it has still developed as one of serious complications in elderly patients. We have used short external rotators (SER) preserving posterolateral approach to reduce dislocation after hip arthroplasty, especially in elderly patients. The present study was conducted to introduce SER preserving posterolateral approach and report the dislocation rate after HA via this approach in elderly patients with femoral neck fractures.
METHODS:
Between January 2015 and July 2019, 307 consecutive elderly patients aged over 70 years who underwent cementless bipolar HA for femoral neck fractures and were followed up for at least one year, were enrolled in this study. All surgeries were performed using the SER preserving posterolateral approach. The demographic and perioperative data were examined and the complications including dislocation were investigated.
RESULTS:
Mean operation time was 54.3 min, and mean estimated blood loss was 252.4 cc. The mean follow-up time was 22.1 months, HHS was 67.5 points at the final examination Dislocation following HA developed in only one patient (0.3%) with dementia during hospital stay, which was reduced closely with no subsequent recurrence. Periprosthetic femoral fracture occurred in two patients, which was treated with internal fixation in one patient and with stem revision in the other patient. There was no surgical site infection or periprosthetic infection as complications.
CONCLUSION:
The SER preserving technique in posterolateral approach effectively can be effective for reducing the dislocation after HA in elderly patients with femoral neck fracture. It can be encouraged in posterolateral approach for HA, especially in elderly patients under the risk of dislocation.
Copyright © 2022. Published by Elsevier Ltd.
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Establishment of an induced pluripotent stem cell line DHMi005-A from a healthy male proband.
Stem Cell Res2022 Jan;59():102662. doi: S1873-5061(22)00011-3.
Dreßen M, Luzius T, Lahm H, Neb I, Doppler S A, Schneider S, Dzilic E, Lange R, Krane M,
Abstract
We generated an induced pluripotent stem cell (iPSC) line from a healthy male 29-year-old proband. Adipose fibroblasts (AFs) were reprogrammed using Sendai virus. Generated iPSCs showed typical stem cell morphology. From passage 9 on, iPSCs were free of virus. Pluripotency in the iPSCs was verified and spontaneous differentiation showed expression of all three germ layers. Karyotyping indicated no anomalies for the generated iPSCs. Many patient-specific iPSCs are generated from subcutaneous fat fibroblasts obtained during surgical procedure. The described control iPSC line was generated equally and therefore serves as an ideal control for adipose-fibroblast-based patient-specific iPSC lines in disease modeling.
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
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Direct comparison of different therapeutic cell types susceptibility to inflammatory cytokines associated with COVID-19 acute lung injury.
Stem Cell Res Ther2022 Jan;13(1):20. doi: 10.1186/s13287-021-02699-7.
Vaka Ramana, Khan Saad, Ye Bin, Risha Yousef, Parent Sandrine, Courtman David, Stewart Duncan J, Davis Darryl R,
Abstract
BACKGROUND:
Although 90% of infections with the novel coronavirus 2 (COVID-19) are mild, many patients progress to acute respiratory distress syndrome (ARDS) which carries a high risk of mortality. Given that this dysregulated immune response plays a key role in the pathology of COVID-19, several clinical trials are underway to evaluate the effect of immunomodulatory cell therapy on disease progression. However, little is known about the effect of ARDS associated pro-inflammatory mediators on transplanted stem cell function and survival, and any deleterious effects could undermine therapeutic efficacy. As such, we assessed the impact of inflammatory cytokines on the viability, and paracrine profile (extracellular vesicles) of bone marrow-derived mesenchymal stromal cells, heart-derived cells, and umbilical cord-derived mesenchymal stromal cells.
METHODS:
All cell products were manufactured and characterized to established clinical release standards by an accredited clinical cell manufacturing facility. Cytokines and Extracellular vesicles in the cell conditioned media were profiled using proteomic array and nanoparticle tracking analysis. Using a survey of the clinical literature, 6 cytotoxic cytokines implicated in the progression of COVID-19 ARDS. Flow cytometry was employed to determine receptor expression of these 6 cytokines in three cell products. Based on clinical survey and flow cytometry data, a cytokine cocktail that mimics cytokine storm seen in COVID-19 ARDS patients was designed and the impact on cytokine cocktail on viability and paracrine secretory ability of cell products were assessed using cell viability and nanoparticle tracking analysis.
RESULTS:
Flow cytometry revealed the presence of receptors for all cytokines but IL-6, which was subsequently excluded from further experimentation. Despite this widespread expression, exposure of each cell type to individual cytokines at doses tenfold greater than observed clinically or in combination at doses associated with severe ARDS did not alter cell viability or extracellular vesicle character/production in any of the 3 cell products.
CONCLUSIONS:
The paracrine production and viability of the three leading cell products under clinical evaluation for the treatment of severe COVID-19 ARDS are not altered by inflammatory mediators implicated in disease progression.
© 2022. The Author(s).
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Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study.
Lancet Haematol2022 Jan;():. doi: S2352-3026(21)00381-1.
Schjesvold Fredrik H, Dimopoulos Meletios-Athanasios, Delimpasi Sosana, Robak Pawel, Coriu Daniel, Legiec Wojciech, Pour Lud?k, ?pi?ka Ivan, Masszi Tamas, Doronin Vadim, Minarik Jiri, Salogub Galina, Alekseeva Yulia, Lazzaro Antonio, Maisnar Vladimir, Mikala Gábor, Rosiñol Laura, Liberati Anna Marina, Symeonidis Argiris, Moody Victoria, Thuresson Marcus, Byrne Catriona, Harmenberg Johan, Bakker Nicolaas A, Hájek Roman, Mateos Maria-Victoria, Richardson Paul G, Sonneveld Pieter, ,
Abstract
BACKGROUND:
Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma.
METHODS:
In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ?18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0-2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing.
FINDINGS:
Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60-72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61-72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0-8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2-5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64-0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4-22·8) in the melflufen group and 16·3 months (10·1-23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1-25·6) at a median follow-up of 19·8 months (IQR 12·0-25·0) in the melflufen group and 25·0 months (95% CI 18·1-31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8-23·7; HR 1·10 [95% CI 0·85-1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia).
INTERPRETATION:
Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma.
FUNDING:
Oncopeptides AB.
Copyright © 2022 Elsevier Ltd. All rights reserved.
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Comprehensive analyses of the inotropic compound omecamtiv mecarbil in rat and human cardiac preparations.
Am J Physiol Heart Circ Physiol2022 Jan;():. doi: 10.1152/ajpheart.00534.2021.
Rhoden Alexandra, Schulze Thomas, Pietsch Niels, Christ Torsten, Hansen Arne, Eschenhagen Thomas,
Abstract
Omecamtiv mecarbil (OM), a myosin activator, was reported to induce complex concentration- and species-dependent effects on contractile function and clinical studies indicated a low therapeutic index with diastolic dysfunction at concentrations above 1 µM. To further characterize effects of OM in a human context and under different preload conditions, we constructed a setup that allows isometric contractility analyses of human induced pluripotent stem cell (hiPSC)-derived engineered heart tissues (EHTs). The results were compared to effects of OM on the very same EHTs measured under auxotonic conditions. OM induced a sustained, concentration-dependent increase in time-to-peak under all conditions (maximally 2-3 fold). Peak force, in contrast, was increased by OM only in human, but not rat EHTs and only under isometric conditions, varied between hiPSC lines and showed a biphasic concentration-dependency with maximal effects at 1 µM. Relaxation time tended to fall under auxotonic and strongly increase under isometric conditions, again with biphasic concentration-dependency. Diastolic tension concentration-dependently increased under all conditions. The latter was reduced by an inhibitor of the mitochondrial sodium calcium exchanger (CGP-37157). OM induced increases in mitochondrial oxidation in isolated cardiomyocytes, indicating that OM, an inotrope that does not increase intracellular and mitochondrial Ca, can induce mismatch between an increase in ATP and ROS production and unstimulated mitochondrial redox capacity. Taken together, we developed a novel setup well suitable for isometric measurements of EHTs. The effects of OM on contractility and diastolic tension are complex with concentration-, time-, species- and loading-dependent differences. Effects on mitochondrial function require further studies.
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Phenotypic, trophic, and regenerative properties of mesenchymal stem cells from different osseous tissues.
Cell Tissue Res2022 Jan;():. doi: 10.1007/s00441-021-03563-z.
Zou Douhong, Vigen Marina, Putnam Andrew J, Cao Chen, Tarlé Susan A, Guinn Tyler, Kaigler Darnell,
Abstract
Mesenchymal stem cells (MSCs) have broad-based therapeutic potential in regenerative medicine. However, a major barrier to their clinical utility is that MSCs from different tissues are highly variable in their regenerative properties. In this study, we defined the molecular and phenotypic identities of different MSC populations from different osseous tissue sites of different patients and, additionally, determined their respective regenerative properties. MSCs from 6 patients were isolated from either bone marrow of the iliac crest (BMSCs) or alveolar bone tissue (aBMSCs), and flow cytometry revealed that regardless of the tissue source, MSC immunotypes had the same expression of MSC markers CD73, CD90, and CD105. However, transcriptomic analyses revealed 589 genes differentially expressed (DE) between BMSCs and aBMSCs, including eightfold higher levels of bone morphogenetic protein 4 (BMP-4) in aBMSCs. In striking contrast, gene expression of MSCs derived from the same tissue, but between different patients (i.e., BMSCs to BMSCs, aBMSCs to aBMSCs), showed only 38 DE BMSC genes and 51 DE aBMSC genes. A protein array showed that aBMSC and BMSC produced equivalent levels of angiogenic cytokines; however, when placed in angiogenesis model systems, aBMSCs induced significantly more capillaries in vitro and in vivo. Finally, cell transplantation of MSCS into osseous defects showed that the bone regenerative capacity of aBMSCs was significantly greater than that of BMSCs. This study is the first to link the molecular, phenotypic, and regenerative properties of different MSCs from different patients and provides novel insights toward MSC differences based on the osseous tissue origin.
© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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Bone Marrow Aspirate in Spine Surgery: Case Series and Review of the Literature.
Cureus2021 Dec;13(12):e20309. doi: 10.7759/cureus.20309.
Noh Thomas, Zakaria Hesham, Massie Lara, Ogasawara Christian T, Lee Gunnar A, Chedid Mokbel,
Abstract
Background With the modernization of biotechnology, there has been a concerted effort to create novel biomaterials to promote arthrodesis for spine surgery. The novel use of the stem cells from bone marrow aspirate (BMA) to augment spine surgery is a burgeoning field because these cells are considered to be both osteoinductive and osteogenic. We sought to review the evidence behind the use of BMAs in spinal fusions and report the results of our own case series. Methods PubMed and EMBASE databases were searched for studies that investigated the use of stem cells for spine surgery. For our own case series, the medical records of 150 consecutive patients who underwent a lumbar spinal fusion with BMA were retrospectively reviewed for adverse events (AEs) for up to two years after surgery. Results In our case series, there were no AEs identified in 49% of our patients. Of the identified AEs, 61% were unrelated to the use of BMA (e.g., UTI and heart failure), with the remaining 39% likely unrelated to its use (e.g., back pain and anemia). There was a 92.8% arthrodesis rate with the use of BMA. Conclusions We reviewed the rationale, basic science, and clinical science for BMA usage in spine surgery and concluded that BMA is safe for use in spine surgery and is associated with a high rate of arthrodesis.
Copyright © 2021, Noh et al.
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Rosiglitazone Ameliorates Spinal Cord Injury Inhibiting Mitophagy and Inflammation of Neural Stem Cells.
Oxid Med Cell Longev2022 ;2022():5583512. doi: 10.1155/2022/5583512.
Meng Qingqi, Chen Zhiteng, Gao Qingyuan, Hu Liqiong, Li Qilong, Li Shutai, Cui Lili, Feng Zhencheng, Zhang Xingliang, Cui Shiyun, Zhang Haifeng,
Abstract
Background:
Neurodegenerative diseases, such as Alzheimer's disease, and traumatic brain and spinal cord injury (SCI) are prevalent in clinical practice. Inhibition of hyperactive inflammation and proliferation of endogenous neural stem cells (NSCs) is a promising treatment strategy for SCI. Our previous studies demonstrated the beneficial effects of rosiglitazone (Rosi) on SCI, but its roles in inflammation inhibition and proliferation of NSCs are unknown.
Methods:
SCI in a rat model was established, and the effects of Rosi on motor functions were assessed. The effects of Rosi on NSC proliferation and the underlying mechanisms were explored in details.
Results:
We showed that Rosi ameliorated impairment of moto functions in SCI rats, inhibited inflammation, and promoted proliferation of NSCs . Rosi increased ATP production through enhancing glycolysis but not oxidative phosphorylation. Rosi reduced mitophagy by downregulating PTEN-induced putative kinase 1 (PINK1) transcription to promote NSC proliferation, which was effectively reversed by an overexpression of PINK1 . Through KEGG analysis and experimental validations, we discovered that Rosi reduced the expression of forkhead box protein O1 (FOXO1) which was a critical transcription factor of PINK1. Three FOXO1 consensus sequences (FCSs) were found in the first intron of the PINK1 gene, which could be potentially binding to FOXO1. The proximal FCS (chr 5: 156680169-156680185) from the translation start site exerted a more significant influence on PINK1 transcription than the other two FCSs. The overexpression of FOXO1 entirely relieved the inhibition of PINK1 transcription in the presence of Rosi.
Conclusions:
Besides inflammation inhibition, Rosi suppressed mitophagy by reducing FOXO1 to decrease the transcription of PINK1, which played a pivotal role in accelerating the NSC proliferation.
Copyright © 2022 Qingqi Meng et al.
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T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma.
Nat Med2022 Jan;():. doi: 10.1038/s41591-021-01623-z.
Lozano Alexander X, Chaudhuri Aadel A, Nene Aishwarya, Bacchiocchi Antonietta, Earland Noah, Vesely Matthew D, Usmani Abul, Turner Brandon E, Steen Chloé B, Luca Bogdan A, Badri Ti, Gulati Gunsagar S, Vahid Milad R, Khameneh Farnaz, Harris Peter K, Chen David Y, Dhodapkar Kavita, Sznol Mario, Halaban Ruth, Newman Aaron M,
Abstract
Severe immune-related adverse events (irAEs) occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). However, it is unknown whether a common baseline immunological state precedes irAE development. Here we applied mass cytometry by time of flight, single-cell RNA sequencing, single-cell V(D)J sequencing, bulk RNA sequencing and bulk T cell receptor (TCR) sequencing to study peripheral blood samples from patients with melanoma treated with anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combination ICIs. By analyzing 93 pre- and early on-ICI blood samples and 3 patient cohorts (n?=?27, 26 and 18), we found that 2 pretreatment factors in circulation-activated CD4 memory T cell abundance and TCR diversity-are associated with severe irAE development regardless of organ system involvement. We also explored on-treatment changes in TCR clonality among patients receiving combination therapy and linked our findings to the severity and timing of irAE onset. These results demonstrate circulating T cell characteristics associated with ICI-induced toxicity, with implications for improved diagnostics and clinical management.
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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Cardiac ischemia on-a-chip to investigate cellular and molecular response of myocardial tissue under hypoxia.
Biomaterials2021 Dec;281():121336. doi: S0142-9612(21)00692-X.
Veldhuizen Jaimeson, Chavan Ramani, Moghadas Babak, Park Jin G, Kodibagkar Vikram D, Migrino Raymond Q, Nikkhah Mehdi,
Abstract
Tissue engineering has enabled the development of advanced and physiologically relevant models of cardiovascular diseases, with advantages over conventional 2D in vitro assays. We have previously demonstrated development of a heart on-a-chip microfluidic model with mature 3D anisotropic tissue formation that incorporates both stem cell-derived cardiomyocytes and cardiac fibroblasts within a collagen-based hydrogel. Using this platform, we herein present a model of myocardial ischemia on-a-chip, that recapitulates ischemic insult through exposure of mature 3D cardiac tissues to hypoxic environments. We report extensive validation and molecular-level analyses of the model in its ability to recapitulate myocardial ischemia in response to hypoxia, demonstrating the 1) induction of tissue fibrosis through upregulation of contractile fibers, 2) dysregulation in tissue contraction through functional assessment, 3) upregulation of hypoxia-response genes and downregulation of contractile-specific genes through targeted qPCR, and 4) transcriptomic pathway regulation of hypoxic tissues. Further, we investigated the complex response of ischemic myocardial tissues to reperfusion, identifying 5) cell toxicity, 6) sustained contractile irregularities, as well as 7) re-establishment of lactate levels and 8) gene expression, in hypoxic tissues in response to ischemia reperfusion injury.
Copyright © 2021 Elsevier Ltd. All rights reserved.
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Cardiovascular events and treatment of children with high risk medulloblastoma.
EClinicalMedicine2022 Jan;43():101251. doi: 10.1016/j.eclinm.2021.101251.
Cuomo Alessandra, Mercurio Valentina, Pugliese Manuela, Capasso Maria, Ruotolo Serena, Antignano Anita, Tocchetti Carlo G, Passariello Annalisa,
Abstract
Background:
Children with high-risk medulloblastoma are treated with chemotherapeutic protocols which may affect heart function. We aimed to assesscardiovascular events (CVE) in children with medulloblastoma/primitive neuroectodermal tumors (PNET).
Methods:
We retrospectively collected data from a case series of 22 children with high-risk medulloblastoma/PNET admitted to the Santobono-Pausilipon Hospital, Naples, Italy from 2008 to 2016. All patients received the Milan HART protocol for high-risk brain malignancies as first line treatment (induction phase), followed by a consolidation phase with Thiotepa and hematopoietic stem cells transplantation, except for 1 patient who received the Milan HART as second line therapy. Four patients also received second line treatment, while 4 patients also received maintenance therapy. Patients underwent cardiac examination, including ECG, echocardiography and serum biomarkers, before antineoplastic treatment initiation and then when clinically needed. Six patients developed CVE (CVE group); 16 patients had no CVE (NO-CVE group).
Findings:
In the CVE group, 3 patients presented acute CVE during chemotherapy (2 patients with left ventricular (LV) dysfunction, 1 patient with arterial hypertension), while 3 patients presented chronic CVE after chemotherapy completion (2 patients with LV dysfunction, 1 patient with ectopic atrial tachycardia). After a 51 months median follow-up, 9 patients died: 4 from the CVE group (in 2 cases heart failure-related deaths) and 5 from the NO-CVE group (progression of disease).
Interpretation:
A relevant percentage of children treated for medulloblastoma/PNET develops CVE. Heart failure potentially due to chemotherapy may represent a cause of death. Hence, in these patients, strict cardiac surveillance is essential.
Funding:
No funding was associated with this study.
© 2021 The Author(s).
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Growing With the Flow: Insights Into How Flow Mediates Endocardial Fibroelastosis.
JACC Basic Transl Sci2021 Dec;6(12):1000-1002. doi: 10.1016/j.jacbts.2021.09.007.
Pek Nicole Min Qian, Gu Mingxia,
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Application of Mesenchymal Stem Cells During Machine Perfusion: An Emerging Novel Strategy for Organ Preservation.
Front Immunol2021 ;12():713920. doi: 10.3389/fimmu.2021.713920.
Li Jiale, Peng Qinbao, Yang Ronghua, Li Kunsheng, Zhu Peng, Zhu Yufeng, Zhou Pengyu, Szabó Gábor, Zheng Shaoyi,
Abstract
Although solid organ transplantation remains the definitive management for patients with end-stage organ failure, this ultimate treatment has been limited by the number of acceptable donor organs. Therefore, efforts have been made to expand the donor pool by utilizing marginal organs from donation after circulatory death or extended criteria donors. However, marginal organs are susceptible to ischemia-reperfusion injury (IRI) and entail higher requirements for organ preservation. Recently, machine perfusion has emerged as a novel preservation strategy for marginal grafts. This technique continually perfuses the organs to mimic the physiologic condition, allows the evaluation of pretransplant graft function, and more excitingly facilitates organ reconditioning during perfusion with pharmacological, gene, and stem cell therapy. As mesenchymal stem cells (MSCs) have anti-oxidative, immunomodulatory, and regenerative properties, mounting studies have demonstrated the therapeutic effects of MSCs on organ IRI and solid organ transplantation. Therefore, MSCs are promising candidates for organ reconditioning during machine perfusion. This review provides an overview of the application of MSCs combined with machine perfusion for lung, kidney, liver, and heart preservation and reconditioning. Promising preclinical results highlight the potential clinical translation of this innovative strategy to improve the quality of marginal grafts.
Copyright © 2021 Li, Peng, Yang, Li, Zhu, Zhu, Zhou, Szabó and Zheng.
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From heart to muscle: Pathophysiological mechanisms underlying long-term physical sequelae from SARS-CoV-2 infection.
J Appl Physiol (1985)2022 Jan;():. doi: 10.1152/japplphysiol.00734.2021.
Serviente Corinna, Decker Stephen T, Layec Gwenael,
Abstract
The long-term sequelae of the coronavirus disease 2019 (COVID-19) are multifaceted and, besides the lungs, impact other organs and tissues, even in cases of mild infection. Along with commonly reported symptoms such as fatigue and dyspnea, a significant proportion of those with prior COVID-19 infection also exhibit signs of cardiac damage, muscle weakness, and ultimately, poor exercise tolerance. This review provides an overview of evidence indicating cardiac impairments and persistent endothelial dysfunction in the peripheral vasculature of those previously infected with COVID-19, irrespective of the severity of the acute phase of illness. Additionally, VO appears to be lower in convalescent patients, which may stem, in part, from alterations in O transport such as impaired diffusional Oconductance. Together, the persistent multi-organ dysfunction induced by COVID-19 may set previously healthy individuals on a trajectory towards frailty and disease. Given the large proportion of individuals recovering from COVID-19, it is critically important to better understand the physical sequelae of COVID-19, the underlying biological mechanisms contributing to these outcomes, and the long-term effects on future disease risk. This review highlights relevant literature on the pathophysiology post-COVID-19 infection, gaps in the literature, and emphasizes the need for the development of evidence-based rehabilitation guidelines.
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Recapitulating human cardio-pulmonary co-development using simultaneous multilineage differentiation of pluripotent stem cells.
Elife2022 Jan;11():. doi: 10.7554/eLife.67872.
Ng Wai Hoe, Johnston Elizabeth K, Tan Jun Jie, Bliley Jacqueline M, Feinberg Adam W, Stolz Donna B, Sun Ming, Wijesekara Piyumi, Hawkins Finn, Kotton Darrell N, Ren Xi,
Abstract
The extensive crosstalk between the developing heart and lung is critical to their proper morphogenesis and maturation. However, there remains a lack of models that investigate the critical cardio-pulmonary mutual interaction during human embryogenesis. Here, we reported a novel stepwise strategy for directing the simultaneous induction of both mesoderm-derived cardiac and endoderm-derived lung epithelial lineages within a single differentiation of human induced pluripotent stem cells (hiPSCs) via temporal specific tuning of WNT and nodal signaling in the absence of exogenous growth factors. Using 3D suspension culture, we established concentric cardio-pulmonary micro-Tissues (mTs), and expedited alveolar maturation in the presence of cardiac accompaniment. Upon withdrawal of WNT agonist, the cardiac and pulmonary components within each dual-lineage mT effectively segregated from each other with concurrent initiation of cardiac contraction. We expect that our multilineage differentiation model will offer an experimentally tractable system for investigating human cardio-pulmonary interaction and tissue boundary formation during embryogenesis.
© 2022, Ng et al.
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MicroRNA-365 regulates human cardiac action potential duration.
Nat Commun2022 Jan;13(1):220. doi: 10.1038/s41467-021-27856-7.
Esfandyari Dena, Idrissou Bio Maria Ghéo, Hennis Konstantin, Avramopoulos Petros, Dueck Anne, El-Battrawy Ibrahim, Grüter Laurenz, Meier Melanie Annemarie, Näger Anna Christina, Ramanujam Deepak, Dorn Tatjana, Meitinger Thomas, Hagl Christian, Milting Hendrik, Borggrefe Martin, Fenske Stefanie, Biel Martin, Dendorfer Andreas, Sassi Yassine, Moretti Alessandra, Engelhardt Stefan,
Abstract
Abnormalities of ventricular action potential cause malignant cardiac arrhythmias and sudden cardiac death. Here, we aim to identify microRNAs that regulate the human cardiac action potential and ask whether their manipulation allows for therapeutic modulation of action potential abnormalities. Quantitative analysis of the microRNA targetomes in human cardiac myocytes identifies miR-365 as a primary microRNA to regulate repolarizing ion channels. Action potential recordings in patient-specific induced pluripotent stem cell-derived cardiac myocytes show that elevation of miR-365 significantly prolongs action potential duration in myocytes derived from a Short-QT syndrome patient, whereas specific inhibition of miR-365 normalizes pathologically prolonged action potential in Long-QT syndrome myocytes. Transcriptome analyses in these cells at bulk and single-cell level corroborate the key cardiac repolarizing channels as direct targets of miR-365, together with functionally synergistic regulation of additional action potential-regulating genes by this microRNA. Whole-cell patch-clamp experiments confirm miR-365-dependent regulation of repolarizing ionic current I. Finally, refractory period measurements in human myocardial slices substantiate the regulatory effect of miR-365 on action potential in adult human myocardial tissue. Our results delineate miR-365 to regulate human cardiac action potential duration by targeting key factors of cardiac repolarization.
© 2022. The Author(s).
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G3bp1 - microRNA-1 axis regulates cardiomyocyte hypertrophy.
Cell Signal2022 Jan;91():110245. doi: S0898-6568(22)00005-5.
Alikunju Saleena, Niranjan Nandita, Mohsin Maha, Sayed Nazish, Sayed Danish,
Abstract
Adaptation of gene expression is one of the most fundamental response of cardiomyocytes to hypertrophic stimuli. G3bp1, an RNA binding protein with site-specific endoribonuclease activity regulates the processing of pre-miR-1 stem-loop, and thus levels of cardiomyocyte -enriched mature miR-1. Here, we examine the role of G3bp1 in regulating gene expression in quiescent cardiomyocytes and those undergoing growth-factor induced hypertrophy. Further, we determine if these changes are facilitated through G3bp1-mediated regulation of miR-1 in these cardiomyocytes. Using isolated cardiomyocytes with knockdown of endogenous G3bp1, we performed high throughput RNA sequencing to determine the change in cardiac transcriptome. Then, using gain and loss of function approach for both, G3bp1 and miR-1, alone or in combination we examine the G3bp1-miR-1 signaling in regulating gene expression and Endothelin (ET-1) -induced cardiomyocyte hypertrophy. We show that knockdown of endogenous G3bp1 results in inhibition of genes involved in calcium handling, cardiac muscle contraction, action potential and sarcomeric structure. In addition, there is inhibition of genes that contribute to hypertrophic and dilated cardiomyopathy development. Conversely, an increase is seen in genes that negatively regulate the Hippo signaling, like Rassf1 and Arrdc3, along with inflammatory genes of TGF-? and TNF pathways. Knockdown of G3bp1 restricts ET-1 induced cardiomyocyte hypertrophy. Interestingly, concurrent silencing of G3bp1 and miR-1 rescues the change in gene expression and inhibition of hypertrophy seen with knockdown of G3bp1 alone. Similarly, expression of exogenous G3bp1 reverses the miR-1 induced inhibition of gene expression. Intriguingly, expression of Gfp tagged G3bp1 results in perinuclear accumulations of G3bp1-Gfp, resembling Stress Granules. Based on our results, we conclude that G3bp1 through its regulation of mature miR-1 levels plays a critical role in regulating the expression of essential cardiac-enriched genes and those involved in development of cardiomyocyte hypertrophy.
Copyright © 2022 Elsevier Inc. All rights reserved.
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Adverse outcomes in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: Follow-up of patients diagnosed 2002-2017 in a complete coverage and nationwide agnostic register study.
Am J Hematol2022 Jan;():. doi: 10.1002/ajh.26463.
Dahlén Torsten, Edgren Gustaf, Ljungman Per, Flygt Hjalmar, Richter Johan, Olsson-Strömberg Ulla, Wadenvik Hans, Dreimane Arta, Myhr-Eriksson Kristina, Zhao Jingcheng, Själander Anders, Höglund Martin, Stenke Leif,
Abstract
Tyrosine kinase inhibitors (TKIs) have profoundly improved the clinical outcome for patients with chronic myeloid leukemia (CML), but their overall survival it is still subnormal and the treatment is associated with adverse events. In a large cohort-study we assessed the morbidity in 1 328 Swedish CML chronic phase patients diagnosed 2002-2017 and treated with TKIs, as compared to that in carefully matched control individuals. Several Swedish patient registers with near complete nationwide coverage were utilized for data acquisition. Median follow-up was 6 (IQR, 3-10) years with total follow-up of 8510 person-years for the full cohort. Among 670 analyzed disease categories the patient cohort showed a significantly increased risk in 142 while, strikingly, no category was more common in controls. Increased incidence rate ratios/IRR (95% CI) for more severe events among patients included acute myocardial infarction (AMI) 2.0 (1.5-2.6), heart failure 2.6 (2.2-3.2), pneumonia 2.8 (2.3-3.5) and unspecified sepsis 3.5 (2.6-4.7). When comparing patients on 2nd generation TKIs vs. imatinib in a within-cohort analysis, nilotinib generated elevated IRRs for AMI (2.9; 1.5-5.6) and chronic ischemic heart disease (2.2; 1.2-3.9), dasatinib for pleural effusion (11.6; 7.6-17.7) and infectious complications, e.g. acute upper respiratory infections (3.0; 1.4-6.0). Our extensive real-world data reveal significant risk increases of severe morbidity in TKI-treated CML patients, as compared to matched controls, particularly for 2nd generation TKIs. Whether this increased morbidity may also translate into increased mortality, thus preventing CML patients to achieve a normalized overall survival, needs to be further explored. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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