Citations

Transplantation of autologous mesenchymal stem cells (MSCs) may be a viable option for treatment of several diseases. MSCs efficacy depends on adequate function of their mitochondria, which might be impaired in a noxious milieu. We hypothesized that obesity compromises MSCs mitochondrial structure and function, possibly via micro‐RNA (miRNA)‐based mechanisms. MSCs were collected from swine abdominal adipose tissue after 16 weeks of Lean or Obese diet (n = 7 each). Mitochondrial structure was assessed by electron microscopy and function by membrane potential and cytochrome‐c oxidase (COX)‐IV activity. Oxidative stress was assessed by Mito‐SOX and dihydroethidium staining. Next‐generation sequencing (RNA‐seq) was performed to identify miRNAs expression in MSCs, and predicted mitochondrial target genes were then identified (MitoCarta). Compared to Lean‐MSCs, mitochondria from Obese‐MSCs were smaller and showed cristae remodeling and loss. Mitochondrial membrane potential and COX‐IV activity decreased in Obese‐MSCs, associated with increased mitochondrial oxidative stress. RNA‐seq generated reads for 413 miRNAs, of which 5 miRNAs were upregulated in Obese‐MSCs (fold change >2, p < 0.05) and found to target 43 specific mitochondrial genes. Obesity impairs MSC mitochondrial structure and function, possibly mediated partly through miRNA‐induced mitochondrial gene regulation, leading to increased oxidative stress. Importantly, these alterations may limit the therapeutic use of autologous MSCs in subjects with obesity.

Adult gliomas are aggressive brain tumours associated with low patient survival rates and limited life expectancy. The most important hallmark of this type of tumour is its invasive behaviour, characterized by a markedly phenotypic plasticity, infiltrative tumour morphologies and the ability of malignant progression from low- to high-grade tumour types. Indeed, the widespread infiltration of healthy brain tissue by glioma cells is largely responsible for poor prognosis and the difficulty of finding curative therapies. Meanwhile, mathematical models have been established to analyse potential mechanisms of glioma invasion. In this review, we start with a brief introduction to current biological knowledge about glioma invasion, and then critically review and highlight future challenges for mathematical models of glioma invasion.

Background— Atherosclerotic renal artery stenosis reduces renal blood flow (RBF) and amplifies stenotic kidney hypoxia. Revascularization with percutaneous transluminal renal angioplasty (PTRA) and stenting often fails to recover renal function, possibly because of ischemia/reperfusion injury developing after PTRA. Elamipretide is a mitochondrial-targeted peptide that binds to cardiolipin and stabilizes mitochondrial function. We tested the hypothesis that elamipretide plus PTRA would improve renal function, oxygenation, and RBF in patients with atherosclerotic renal artery stenosis undergoing PTRA. Methods and Results— Inpatient studies were performed in patients with severe atherosclerotic renal artery stenosis scheduled for PTRA. Patients were treated before and during PTRA with elamipretide (0.05 mg/kg per hour intravenous infusion, n=6) or placebo (n=8). Stenotic kidney cortical/medullary perfusion and RBF were measured using contrast-enhanced multidetector CT, and renal oxygenation by 3-T blood oxygen level−dependent magnetic resonance imaging before and 3 months after PTRA. Age and basal glomerular filtration rate did not differ between groups. Blood oxygen level−dependent imaging demonstrated increased fractional hypoxia 24 hours after angiography and stenting in placebo (+47%) versus elamipretide (−6%). These were reverted to baseline 3 months later. Stenotic kidney RBF rose (202±29–262±115 mL/min; P =0.04) 3 months after PTRA in the elamipretide-treated group only. Over 3 months, systolic blood pressure decreased, and estimated glomerular filtration rate increased ( P =0.003) more in the elamipretide group than in the placebo group ( P =0.11). Conclusions— Adjunctive elamipretide during PTRA was associated with attenuated postprocedural hypoxia, increased RBF, and improved kidney function in this pilot trial. These data support a role for targeted mitochondrial protection to minimize procedure-associated ischemic injury and to improve outcomes of revascularization for human atherosclerotic renal artery stenosis. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT01755858.

AbstractAutologous transplantation of mesenchymal stem cells (MSCs) is a viable option for the treatment of several diseases. Evidence indicates that MSCs release extracellular vesicles (EVs) and that EVs shuttle miRNAs to damaged parenchymal cells to activate an endogenous repair program. We hypothesize that comorbidities may interfere with the packaging of cargo in MSC‐derived EVs. Therefore, we examined whether metabolic syndrome (MetS) modulates the miRNA content packed within MSC‐derived EVs. MSCs were collected from swine abdominal adipose tissue after 16 weeks of lean or obese diet (n = 7 each). Next‐generation RNA sequencing of miRNAs (miRNA‐seq) was performed to identify miRNAs enriched in MSC‐derived EVs and their predicted target genes. Functional pathway analysis of the top 50 target genes of the top 4 miRNAs enriched in each group was performed using gene ontology analysis. Lean‐ and MetS‐EVs were enriched in, respectively, 14 and 8 distinct miRNAs. Target genes of miRNAs enriched in MetS‐EVs were implicated in the development of MetS and its complications, including diabetes‐related pathways, validated transcriptional targets of AP1 family members Fra1 and Fra2, Class A/1 (Rhodopsin‐like receptors), and Peptide ligand‐binding receptors. In contrast, miRNAs enriched in Lean EVs target primarily EphrinA‐EPHA and the Rho family of GTPases. MetS alters the miRNA content of EVs derived from porcine adipose tissue MSCs. These alterations could impair the efficacy and limit the therapeutic use of autologous MSCs in subjects with MetS. Our findings may assist in developing adequate regenerative strategies to preserve the reparative potency of MSCs in individuals with MetS. © 2017 International Society for Advancement of Cytometry

AbstractBackgroundWe report the accumulated experience with ventral intermediate nucleus deep brain stimulation for medically refractory orthostatic tremor.MethodsData from 17 patients were reviewed, comparing presurgical, short‐term (0‐48 months), and long‐term (≥48 months) follow‐up. The primary end point was the composite activities of daily living/instrumental activities of daily living score. Secondary end points included latency of symptoms on standing and treatment‐related complications.ResultsThere was a 21.6% improvement (P = 0.004) in the composite activities of daily living/instrumental activities of daily living score, which gradually attenuated (12.5%) in the subgroup of patients with an additional long‐term follow‐up (8 of 17). The latency of symptoms on standing significantly improved, both in the short‐term (P = 0.001) and in the long‐term (P = 0.018). Three patients obtained no/minimal benefit from the procedure.ConclusionsDeep brain stimulation of the ventral intermediate nucleus was, in general, safe and well tolerated, yielding sustained benefit in selected patients with medically refractory orthostatic tremor. © 2017 International Parkinson and Movement Disorder Society