Evan T. Hall

Measuring lung water: ex vivo validation of multi-image gradient echo MRI.

To validate a fast gradient echo sequence for rapid (9 s) quantitative imaging of lung water.

Is there a sweet spot for Nrf2 activation in the treatment of diabetic kidney disease

Diabetes-associated chronic kidney disease (CKD) continues to be a major contributor to morbidity and mortality in the U.S. and the world. Diabetic kidney disease is the most common reason that Americans are started on renal replacement therapy (1), and as the incidence of diabetes continues to increase, the health and economic consequences of nephropathy and other complications will rise in parallel (2). Unfortunately, there are no known treatments to reverse or arrest progression of diabetic kidney disease. Current treatment guidelines recently published by the National Kidney Foundation demonstrate the paucity of targeted therapies (3). The main recommendations include treatment of hyperglycemia, hypertension, and dyslipidemia, and use of inhibitors of the renin-angiotensin system if the patient has significant albuminuria. Thus, there is significant interest in identifying new therapeutic targets to prevent both development and progression of diabetic kidney disease. Oxidative stress and inflammation have been implicated as contributors to the progression of CKD from a variety of causes, including diabetes. Recently, a particularly active area of investigation has focused on modulation of the transcription factor Nrf2 (nuclear factor erythroid 2−related factor 2). Nrf2 induces protective, so-called phase 2 antioxidant genes by interacting with cis -acting response elements in their respective promoters (4). This transcription factor is degraded by a ubiquitin ligase complex, which includes Keap1 (Kelch-like ECH-associated protein 1). A series …

Racial/ethnic differences in multiple-gene sequencing results for hereditary cancer risk

PurposeWe examined racial/ethnic differences in the usage and results of germ-line multiple-gene sequencing (MGS) panels to evaluate hereditary cancer risk.MethodsWe collected genetic testing results and clinical information from 1,483 patients who underwent MGS at Stanford University between 1 January 2013 and 31 December 2015.ResultsAsians and Hispanics presented for MGS at younger ages than whites (48 and 47 vs. 55; P = 5E-16 and 5E-14). Across all panels, the rate of pathogenic variants (15%) did not differ significantly between racial groups. Rates by gene did differ: in particular, a higher percentage of whites than nonwhites carried pathogenic CHEK2 variants (3.8% vs. 1.0%; P = 0.002). The rate of a variant of uncertain significance (VUS) result was higher in nonwhites than whites (36% vs. 27%; P = 2E-4). The probability of a VUS increased with increasing number of genes tested; this effect was more pronounced for nonwhites than for whites (1.1% absolute difference in VUS rates testing BRCA1/2 vs. 8% testing 13 genes vs. 14% testing 28 genes), worsening the disparity.ConclusionIn this diverse cohort undergoing MGS testing, pathogenic variant rates were similar between racial/ethnic groups. By contrast, VUS results were more frequent among nonwhites, with potential significance for the impact of MGS testing by race/ethnicity.

Murine glomerular transcriptome links endothelial cell-specific molecule-1 deficiency with susceptibility to diabetic nephropathy

Diabetic nephropathy (DN) is the leading cause of kidney disease; however, there are no early biomarkers and no cure. Thus, there is a large unmet need to predict which individuals will develop nephropathy and to understand the molecular mechanisms that govern this susceptibility. We compared the glomerular transcriptome from mice with distinct susceptibilities to DN at four weeks after induction of diabetes, but before histologic injury, and identified differential regulation of genes that modulate inflammation. From these genes, we identified endothelial cell specific molecule-1 (Esm-1), as a glomerular-enriched determinant of resistance to DN. Glomerular Esm-1 mRNA and protein were lower in DN-susceptible, DBA/2, compared to DN-resistant, C57BL/6, mice. We demonstrated higher Esm-1 secretion from primary glomerular cultures of diabetic mice, and high glucose was sufficient to increase Esm-1 mRNA and protein secretion in both strains of mice. However, induction was significantly attenuated in DN-susceptible mice. Urine Esm-1 was also significantly higher only in DN-resistant mice. Moreover, using intravital microscopy and a biomimetic microfluidic assay, we showed that Esm-1 inhibited rolling and transmigration in a dose-dependent manner. For the first time we have uncovered glomerular-derived Esm-1 as a potential non-invasive biomarker of DN. Esm-1 inversely correlates with disease susceptibility and inhibits leukocyte infiltration, a critical factor in protecting the kidney from DN.

The effect of supine exercise on the distribution of regional pulmonary blood flow measured using proton MRI

The Zone model of pulmonary perfusion predicts that exercise reduces perfusion heterogeneity because increased vascular pressure redistributes flow to gravitationally nondependent lung, and causes dilation and recruitment of blood vessels. However, during exercise in animals, perfusion heterogeneity as measured by the relative dispersion (RD, SD/mean) is not significantly decreased. We evaluated the effect of exercise on pulmonary perfusion in six healthy supine humans using magnetic resonance imaging (MRI). Data were acquired at rest, while exercising (∼27% of maximal oxygen consumption) using a MRI-compatible ergometer, and in recovery. Images were acquired in most of the right lung in the sagittal plane at functional residual capacity, using a 1.5-T MR scanner equipped with a torso coil. Perfusion was measured using arterial spin labeling (ASL-FAIRER) and regional proton density using a fast multiecho gradient-echo sequence. Perfusion images were corrected for coil-based signal heterogeneity, large conduit vessels removed and quantified (in ml·min(-1)·ml(-1)) (perfusion), and also normalized for density and quantified (in ml·min(-1)·g(-1)) (density-normalized perfusion, DNP) accounting for tissue redistribution. DNP increased during exercise (11.1 ± 3.5 rest, 18.8 ± 2.3 exercise, 13.2 ± 2.2 recovery, ml·min(-1)·g(-1), P < 0.0001), and the increase was largest in nondependent lung (110 ± 61% increase in nondependent, 63 ± 35% in mid, 70 ± 33% in dependent, P < 0.005). The RD of perfusion decreased with exercise (0.93 ± 0.21 rest, 0.73 ± 0.13 exercise, 0.94 ± 0.18 recovery, P < 0.005). The RD of DNP showed a similar trend (0.82 ± 0.14 rest, 0.75 ± 0.09 exercise, 0.81 ± 0.10 recovery, P = 0.13). In conclusion, in contrast to animal studies, in supine humans, mild exercise decreased perfusion heterogeneity, consistent with Zone model predictions.

Second malignancies in Ewing sarcoma survivors

We read the article by Marina et al on the long-term follow-up of Ewing sarcoma (ES) survivors with great interest because, with improving treatments, more and more patients are surviving this disease. It is interesting to compare their findings regarding the risk of second malignant neoplasms (SMNs) with those identified by Sultan et al, who used a population-based data set from the Surveillance, Epidemiology, and End Results (SEER) program to estimate the risk of SMNs in a cohort of 1166 ES patients identified between 1973 and 2005. Thirty-five of these patients developed SMNs (excluding nonmelanoma skin cancers), and this meant an observed-to-expected (O/E) ratio of 4.01 (95% confidence interval [CI], 2.80-5.58; excess risk [ER], 33.18 per 10,000 persons) for all cancers in ES patients. We updated the SEER analysis with the most recent data set (1973-2014). Sixty cases developed SMNs in a total cohort of 1431 ES patients with a similar risk (O/E, 3.64; 95% CI, 2.78-4.68; P < .05; ER, 35.64). Among these cases, 41 were diagnosed with solid SMNs, and 19 had hematologic SMNs. Bone tumors were the most common SMNs identified (n 5 8; O/E, 66.26; 95% CI, 28.6130.55; P < .05; ER, 6.46), and they were followed by soft-tissue sarcomas (n 5 7; O/E, 34.16; 95% CI, 13.7370.38; P < .05; ER, 5.57), breast cancer (n 5 8; O/E, 3.27; 95% CI, 1.41-6.45; P < .05; ER, 4.55), and leukemia (n 5 17; O/E, 30.03; 95% CI, 17.49-48.08; P< .05; ER, 13.46). There are obviously several key differences in the 2 analytical approaches. Marina et al chose to focus on the delayed incidence of SMNs (more than 5 years after the diagnosis), whereas in our analysis (and in Sultan et al’s analysis), a 5-year lag time before the development of an SMN was not allowed. We observed an increase in the O/E ratio for hematologic SMNs in the SEER cohort (O/E for acute myeloid leukemia, 71 vs 29). The difference may reflect the 5-year lag time implemented by Marina et al. The data used by Marina et al come from a retrospective cohort of patients treated at selected institutions. However, they were able to examine the effects of different treatments, such as chemotherapy and radiation therapy, and associated chronic medical conditions, none of which are available in the SEER database. Overall, the results are fairly consistent and demonstrate that survivors of ES have a significantly increased risk of both solid and hematologic SMNs.