Brain Iron Assessment after Ferumoxytol-enhanced MRI in Children and Young Adults with Arteriovenous Malformations: A Case-Control Study.
Background Iron oxide nanoparticles are an alternative contrast agent for MRI. Gadolinium deposition has raised safety concerns, but it is unknown whether ferumoxytol administration also deposits in the brain. Purpose To investigate whether there are signal intensity changes in the brain at multiecho gradient imaging following ferumoxytol exposure in children and young adults. Materials and Methods This retrospective case-control study included children and young adults, matched for age and sex, with brain arteriovenous malformations who received at least one dose of ferumoxytol from January 2014 to January 2018. In participants who underwent at least two brain MRI examinations (subgroup), the first and last available examinations were analyzed. Regions of interests were placed around deep gray structures on quantitative susceptibility mapping and R2* images. Mean susceptibility and R2* values of regions of interests were recorded. Measurements were assessed by linear regression analyses: a between-group comparison of ferumoxytol-exposed and unexposed participants and a within-group (subgroup) comparison before and after exposure. Results Seventeen participants (mean age ± standard deviation, 13 years ± 5; nine male) were in the ferumoxytol-exposed (case) group, 21 (mean age, 14 years ± 5; 11 male) were in the control group, and nine (mean age, 12 years ± 6; four male) were in the subgroup. The mean number of ferumoxytol administrations was 2 ± 1 (range, one to four). Mean susceptibility (in parts per million [ppm]) and R2* (in inverse seconds [sec-1]) values of the dentate (case participants: 0.06 ppm ± 0.04 and 23.87 sec-1 ± 4.13; control participants: 0.02 ppm ± 0.03 and 21.7 sec-1 ± 5.26), substantia nigrae (case participants: 0.08 ppm ± 0.06 and 27.46 sec-1 ± 5.58; control participants: 0.04 ppm ± 0.05 and 24.96 sec-1 ± 5.3), globus pallidi (case participants: 0.14 ppm ± 0.05 and 30.75 sec-1 ± 5.14; control participants: 0.08 ppm ± 0.07 and 28.82 sec-1 ± 6.62), putamina (case participants: 0.03 ppm ± 0.02 and 20.63 sec-1 ± 2.44; control participants: 0.02 ppm ± 0.02 and 19.65 sec-1 ± 3.6), caudate (case participants: -0.1 ppm ± 0.04 and 18.21 sec-1 ± 3.1; control participants: -0.06 ppm ± 0.05 and 18.83 sec-1 ± 3.32), and thalami (case participants: 0 ppm ± 0.03 and 16.49 sec-1 ± 3.6; control participants: 0.02 ppm ± 0.02 and 18.38 sec-1 ± 2.09) did not differ between groups (susceptibility, P = .21; R2*, P = .24). For the subgroup, the mean interval between the first and last ferumoxytol administration was 14 months ± 8 (range, 1-25 months). Mean susceptibility and R2* values of the dentate (first MRI: 0.06 ppm ± 0.05 and 25.78 sec-1 ± 5.9; last MRI: 0.06 ppm ± 0.02 and 25.55 sec-1 ± 4.71), substantia nigrae (first MRI: 0.06 ppm ± 0.06 and 28.26 sec-1 ± 9.56; last MRI: 0.07 ppm ± 0.06 and 25.65 sec-1 ± 6.37), globus pallidi (first MRI: 0.13 ppm ± 0.07 and 27.53 sec-1 ± 8.88; last MRI: 0.14 ppm ± 0.06 and 29.78 sec-1 ± 6.54), putamina (first MRI: 0.03 ppm ± 0.03 and 19.78 sec-1 ± 3.51; last MRI: 0.03 ppm ± 0.02 and 19.73 sec-1 ± 3.01), caudate (first MRI: -0.09 ppm ± 0.05 and 21.38 sec-1 ± 4.72; last MRI: -0.1 ppm ± 0.05 and 18.75 sec-1 ± 2.68), and thalami (first MRI: 0.01 ppm ± 0.02 and 17.65 sec-1 ± 5.16; last MRI: 0 ppm ± 0.02 and 15.32 sec-1 ± 2.49) did not differ between the first and last MRI examinations (susceptibility, P = .95; R2*, P = .54). Conclusion No overall significant differences were found in susceptibility and R2* values of deep gray structures to suggest retained iron in the brain between ferumoxytol-exposed and unexposed children and young adults with arteriovenous malformations and in those exposed to ferumoxytol over time. © RSNA, 2020.
View details for DOI 10.1148/radiol.2020200378
View details for PubMedID 32930651
Locoregional delivery of stem cell-based therapies.
Science translational medicine
2020; 12 (547)
Interventional regenerative medicine (IRM) uses image-guided, minimally invasive procedures for the targeted delivery of stem cell-based therapies to regenerate, replace, or repair damaged organs. Although many cellular therapies have shown promise in the preclinical setting, clinical results have been suboptimal. Most intravenously delivered cells become trapped in the lungs and reticuloendothelial system, resulting in little therapy reaching target tissues. IRM aims to increase the efficacy of cell-based therapies by locoregional stem cell delivery via endovascular, endoluminal, or direct injection into tissues. This review highlights routes of delivery, disease states, and mechanisms of action involved in the targeted delivery of stem cells.
View details for DOI 10.1126/scitranslmed.aba4564
View details for PubMedID 32522806
Effects of Age on White Matter Microstructure in Children With Neurofibromatosis Type 1.
Journal of child neurology
Children with neurofibromatosis type 1 (NF1) often report cognitive challenges, though the etiology of such remains an area of active investigation. With the advent of treatments that may affect white matter microstructure, understanding the effects of age on white matter aberrancies in NF1 becomes crucial in determining the timing of such therapeutic interventions. A cross-sectional study was performed with diffusion tensor imaging from 18 NF1 children and 26 age-matched controls. Fractional anisotropy was determined by region of interest analyses for both groups over the corpus callosum, cingulate, and bilateral frontal and temporal white matter regions. Two-way analyses of variance were done with both ages combined and age-stratified into early childhood, middle childhood, and adolescence. Significant differences in fractional anisotropy between NF1 and controls were seen in the corpus callosum and frontal white matter regions when ages were combined. When stratified by age, we found that this difference was largely driven by the early childhood (1-5.9 years) and middle childhood (6-11.9 years) age groups, whereas no significant differences were appreciable in the adolescence age group (12-18 years). This study demonstrates age-related effects on white matter microstructure disorganization in NF1, suggesting that the appropriate timing of therapeutic intervention may be in early childhood.
View details for DOI 10.1177/08830738211008736
View details for PubMedID 34048307
Association of Pediatric Acute-Onset Neuropsychiatric Syndrome With Microstructural Differences in Brain Regions Detected via Diffusion-Weighted Magnetic Resonance Imaging.
JAMA network open
2020; 3 (5): e204063
Epidemiological studies indicate a link between obsessive-compulsive disorder and infections, particularly streptococcal pharyngitis. Pediatric acute-onset neuropsychiatric syndrome (PANS) manifests suddenly with obsessions, compulsions, and other behavioral disturbances, often after an infectious trigger. The current working model suggests a unifying inflammatory process involving the central nervous system, particularly the basal ganglia.To investigate whether diffusion-weighted magnetic resonance imaging (DWI) detects microstructural abnormalities across the brain regions of children with PANS.Case-control study performed at a single-center, multidisciplinary clinic in the United States focusing on the evaluation and treatment of children with PANS. Sixty consecutive patients who underwent 3 Tesla (T) magnetic resonance imaging (MRI) before immunomodulation from September 3, 2012, to March 30, 2018, were retrospectively reviewed for study inclusion. Six patients were excluded by blinded investigators because of imaging or motion artifacts, 3 patients for major pathologies, and 17 patients for suboptimal atlas image registration. In total, 34 patients with PANS before initiation of treatment were compared with 64 pediatric control participants.Using atlas-based MRI analysis, regional brain volume, diffusion, and cerebral blood flow were measured in the cerebral white matter, cerebral cortex, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, nucleus accumbens, and brainstem. An age and sex-controlled multivariable analysis of covariance was used to compare patients with control participants.This study compared 34 patients with PANS (median age, 154 months; age range, 55-251 months; 17 girls and 17 boys) and 64 pediatric control participants (median age, 139 months; age range, 48-213 months); 41 girls and 23 boys). Multivariable analysis demonstrated a statistically significant difference in MRI parameters between patients with PANS and control participants (F21,74 = 6.91; P < .001; partial η2 = 0.662). All assessed brain regions had statistically significantly increased median diffusivity compared with 64 control participants. Specifically, the deep gray matter (eg, the thalamus, basal ganglia, and amygdala) demonstrated the most profound increases in diffusivity consistent with the cardinal clinical symptoms of obsessions, compulsions, emotional dysregulation, and sleep disturbances. No statistically significant differences were found regarding volume and cerebral blood flow.This study identifies cerebral microstructural differences in children with PANS in multiple brain structures, including the deep gray matter structures (eg, the thalamus, basal ganglia, and amygdala). Further study of MRI is warranted in prospective, clinical trials as a potential quantitative method for assessing patients under evaluation for PANS.
View details for DOI 10.1001/jamanetworkopen.2020.4063
View details for PubMedID 32364596
Cerebral volume and diffusion MRI changes in children with sensorineural hearing loss.
2020; 27: 102328
Sensorineural hearing loss (SNHL) is the most prevalent congenital sensory deficit in children. Information regarding underlying brain microstructure could offer insight into neural development in deaf children and potentially guide therapies that optimize language development. We sought to quantitatively evaluate MRI-based cerebral volume and gray matter microstructure children with SNHL.We conducted a retrospective study of children with SNHL who obtained brain MRI at 3 T. The study cohort comprised 63 children with congenital SNHL without known focal brain lesion or structural abnormality (33 males; mean age 5.3 years; age range 1 to 11.8 years) and 64 age-matched controls without neurological, developmental, or MRI-based brain macrostructure abnormality. An atlas-based analysis was used to extract quantitative volume and median diffusivity (ADC) in the following brain regions: cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, brain stem, and cerebral white matter. SNHL patients were further stratified by severity scores and hearing loss etiology.Children with SNHL showed higher median ADC of the cortex (p = .019), thalamus (p < .001), caudate (p = .005), and brainstem (p = .003) and smaller brainstem volumes (p = .007) compared to controls. Patients with profound bilateral SNHL did not show any significant differences compared to patients with milder bilateral SNHL, but both cohorts independently had smaller brainstem volumes compared to controls. Children with unilateral SNHL showed greater amygdala volumes compared to controls (p = .021), but no differences were found comparing unilateral SNHL to bilateral SNHL. Based on etiology for SNHL, patients with Pendrin mutations showed higher ADC values in the brainstem (p = .029, respectively); patients with Connexin 26 showed higher ADC values in both the thalamus (p < .001) and brainstem (p < .001) compared to controls.SNHL patients showed significant differences in diffusion and volume in brain subregions, with region-specific findings for patients with Connexin 26 and Pendrin mutations. Future longitudinal studies could examine macro- and microstructure changes in children with SNHL over development and potential predictive role for MRI after interventions including cochlear implant outcome.
View details for DOI 10.1016/j.nicl.2020.102328
View details for PubMedID 32622314
Comparisons of dual isogenic human iPSC pairs identify functional alterations directly caused by an epilepsy associated SCN1A mutation
Neurobiology of Disease
2020; 134: 104627
View details for DOI 10.1016/j.nbd.2019.104627
Development and Validation of a Machine Learning Model to Explore Tyrosine Kinase Inhibitor Response in Patients With Stage IV EGFR Variant-Positive Non-Small Cell Lung Cancer.
JAMA network open
2020; 3 (12): e2030442
An end-to-end efficacy evaluation approach for identifying progression risk after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy in patients with stage IV EGFR variant-positive non-small cell lung cancer (NSCLC) is lacking.To propose a clinically applicable large-scale bidirectional generative adversarial network for predicting the efficacy of EGFR-TKI therapy in patients with NSCLC.This diagnostic/prognostic study enrolled 465 patients from January 1, 2010, to August 1, 2017, with follow-up from February 1, 2010, to June 1, 2020. A deep learning (DL) semantic signature to predict progression-free survival (PFS) was constructed in the training cohort, validated in 2 external validation and 2 control cohorts, and compared with the radiomics signature.An end-to-end bidirectional generative adversarial network framework was designed to predict the progression risk in patients with NSCLC.The primary end point was PFS, considering the time from the initiation of therapy to the date of recurrence, confirmed disease progression, or death.A total of 342 patients with stage IV EGFR variant-positive NSCLC receiving EGFR-TKI therapy met the inclusion criteria. Of these, 145 patients from 2 of the hospitals (n = 117 and 28) formed a training cohort (mean [SD] age, 61  years; 87 [60.0%] female), and the patients from 2 other hospitals comprised 2 external validation cohorts (validation cohort 1: n = 101; mean [SD] age, 57  years; 60 [59.4%] female; and validation cohort 2: n = 96, mean [SD] age, 58  years; 55 [57.3%] female). Fifty-six patients with advanced-stage EGFR variant-positive NSCLC (mean [SD] age, 52  years; 26 [46.4%] female) and 67 patients with advanced-stage EGFR wild-type NSCLC (mean [SD] age, 54  years; 10 [15.0%] female) who received first-line chemotherapy were included. A total of 90 (26%) receiving EGFR-TKI therapy with a high risk of rapid disease progression were identified (median [range] PFS, 7.3 [1.4-32.0] months in the training cohort, 5.0 [0.6-34.6] months in validation cohort 1, and 6.4 [1.8-20.1] months, in validation cohort 2) using the DL semantic signature.The PFS decreased by 36% (hazard ratio, 2.13; 95% CI, 1.30-3.49; P < .001) compared with that in other patients (median [range] PFS, 11.5 [1.5-64.2] months in the training cohort, 10.9 [1.1-50.5] in validation cohort 1, and 8.9 [0.8-40.6] months in validation cohort 2. No significant differences were observed when comparing the PFS of high-risk patients receiving EGFR-TKI therapy with the chemotherapy cohorts (median PFS, 6.9 vs 4.4 months; P = .08). In terms of predicting the tumor progression risk after EGFR-TKI therapy, clinical decisions based on the DL semantic signature led to better survival outcomes than those based on radiomics signature across all risk probabilities by the decision curve analysis.This diagnostic/prognostic study provides a clinically applicable approach for identifying patients with stage IV EGFR variant-positive NSCLC who are not likely to benefit from EGFR-TKI therapy. The end-to-end DL-derived semantic features eliminated all manual interventions required while using previous radiomics methods and have a better prognostic performance.
View details for DOI 10.1001/jamanetworkopen.2020.30442
View details for PubMedID 33331920
Emerging role of stem cell-derived extravesicular microRNAs in age-associated human diseases and in different therapies of longevity.
Ageing Research Reviews
2020; 57: 100979
Organismal aging involves the progressive decline in organ function and increased susceptibility to age-associated diseases. This has been associated with the aging of stem cell populations within the body that decreases the capacity of stem cells to self-renew, differentiate, and regenerate damaged tissues and organs. This review aims to explore how aging is associated with the dysregulation of stem cell-derived extracellular vesicles (SCEVs) and their corresponding miRNA cargo (SCEV-miRNAs), which are short non-coding RNAs involved in post-transcriptional regulation of target genes. Recent evidence has suggested that in aging stem cells, SCEV-miRNAs may play a vital role regulating various processes that contribute to aging: cellular senescence, stem cell exhaustion, telomere length, and circadian rhythm. Hence, further clarifying the age-dependent molecular mechanisms through which SCEV-miRNAs exert their downstream effects may inform a greater understanding of the biology of aging, elucidate their role in stem cell function, and identify important targets for future regenerative therapies. Additionally, current studies evaluating therapeutic role of SCEVs and SCEV-miRNAs in treating several age-associated diseases are also discussed.
View details for DOI 10.1016/j.arr.2019.100979
Mesenchymal stem cells confer chemoresistance in breast cancer via a CD9 dependent mechanism.
2019; 10 (37): 3435–50
The development of chemotherapy drug resistance remains a significant barrier for effective therapy in several cancers including breast cancer. Bone marrow-derived mesenchymal stem cells (BMMSCs) have previously been shown to influence tumor progression and the development of chemoresistance. In the present study, we showed that when GFP labelled BMMSCs and RFP labelled HCC1806 cells are injected together in vivo, they create tumors which contain a new hybrid cell that has characteristics of both BMMSCs and HCC1806 cells. By labelling these cells prior to their injection, we were then able to isolate new hybrid cell from harvested tumors using FACS (DP-HCC1806:BMMSCs). Interestingly, when DP-HCC1806:BMMSCs were then injected into the mammary fat pad of NOD/SCID mice, they produced xenograft tumors which were smaller in size, and exhibited resistance to chemotherapy drugs (i.e. doxorubicin and 5-fluorouracil), when compared tumors from HCC1806 cells alone. This chemoresistance was shown to associated with an increased expression of tetraspanins (CD9, CD81) and drug resistance proteins (BCRP, MDR1). Subsequent siRNA-mediated knockdown of BMMSC-CD9 in DP-HCC1806:BMMSCs resulted in an attenuation of doxorubicin and 5-fluorouracil chemoresistance associated with decreased BCRP and serum cytokine expression (CCL5, CCR5, CXCR12). Our findings suggest that within the tumor microenvironment, CD9 is responsible for the crosstalk between BMMSCs and HCC1806 breast cancer cells (via CCL5, CCR5, and CXCR12) which contributes to chemoresistance. Hence, BMMSC-CD9 may serve as an important therapeutic target for the treatment of breast cancer.
View details for DOI 10.18632/oncotarget.26952
View details for PubMedID 31191817
View details for PubMedCentralID PMC6544397
Reproducible and efficient generation of functionally active neurons from human iPSCs for preclinical disease modeling.
Stem Cell Research
2018; 26: 84-94
View details for DOI 10.1016/j.scr.2017.12.003
Astrocyte-enriched feeder layers from cryopreserved cells support differentiation of spontaneously active networks of human iPSC-derived neurons.
Journal of Neuroscience Methods
2018; 294: 91-101
View details for DOI 10.1016/j.jneumeth.2017.07.019
Research Associates Program: Expanding clinical research productivity with undergraduate students.
SAGE Open Medicine
2017; 5: 1-7
View details for DOI 10.1177/2050312117730245