Publications
Department of Medicine faculty members published more than 3,600 peer-reviewed articles in 2024.
2015
2015
OBJECTIVE
The hippocampus is crucial for paired-associate learning. Obesity is associated with increased mineralocorticoid receptor (MR) activity in peripheral and possibly central tissues, decreased hippocampal size in humans, and impaired hippocampal learning in rodents. The MR is expressed in hippocampal neurons, and MR blockade improves hippocampal learning in obese animals. The goal of the study was to determine whether MR blockade would modulate paired-associate learning in men and women with obesity.
METHODS
Men and women ages 20-61 years with BMI between 30-45 kg/m(2) were randomly assigned to placebo (n = 11; 7 women) or 50 mg spironolactone daily (n = 12; 7 women) for six weeks. At baseline and post-treatment, subjects underwent a clinical and hormonal evaluation. They also underwent a computerized task that assesses paired-associate learning and has been shown by functional magnetic resonance imaging to activate the hippocampus.
RESULTS
In an ANCOVA model that adjusted for baseline paired-associate learning, age, and race, spironolactone treatment was associated with a significant (P = 0.043) improvement in hippocampal memory as compared to placebo treatment.
CONCLUSIONS
Our findings demonstrate, for the first time, that blocking MR with chronic, low-dose spironolactone treatment improves paired-associate learning in individuals with obesity, suggesting that MR activation contributes to hippocampal memory modulation in humans.
View on PubMed2015
PURPOSE
Acute myeloid leukemia (AML) is the most common acute leukemia in adults and is often resistant to conventional therapies. The MYC oncogene is commonly overexpressed in AML but has remained an elusive target. We aimed to examine the consequences of targeting MYC both directly and indirectly in AML overexpressing MYC/Myc due to trisomy 8/15 (human/mouse), FLT3-ITD mutation, or gene amplification.
METHODS
We performed in vivo knockdown of Myc (shRNAs) and both in vitro and in vivo experiments using four drugs with indirect anti-MYC activity: VX-680, GDC-0941, artemisinin, and JQ1.
RESULTS
shRNA knockdown of Myc in mice prolonged survival, regardless of the mechanism underlying MYC overexpression. VX-680, an aurora kinase inhibitor, demonstrated in vitro efficacy against human MYC-overexpressing AMLs regardless of the mechanism of MYC overexpression, but was weakest against a MYC-amplified cell line. GDC-0941, a PI3-kinase inhibitor, demonstrated efficacy against several MYC-overexpressing AMLs, although only in vitro. Artemisinin, an antimalarial, did not demonstrate consistent efficacy against any of the human AMLs tested. JQ1, a bromodomain and extra-terminal bromodomain inhibitor, demonstrated both in vitro and in vivo efficacy against several MYC-overexpressing AMLs. We also confirmed a decrease in MYC levels at growth inhibitory doses for JQ1, and importantly, sensitivity of AML cell lines to JQ1 appeared independent of the mechanism of MYC overexpression.
CONCLUSIONS
Our data support growing evidence that JQ1 and related compounds may have clinical efficacy in AML treatment regardless of the genetic abnormalities underlying MYC deregulation.
View on PubMed2015
RATIONALE
Biomarkers for monitoring response to anti-tuberculosis treatment are needed. We explored immune markers previously published as having predictive capability for 8 week culture status in 39 adults enrolled in a clinical trial in Kampala, Uganda.
METHODS
We consecutively selected 20 HIV-negative pulmonary TB subjects with positive cultures, and 19 subjects with negative cultures at the end of intensive phase therapy. At baseline and after 8 weeks, serum was assayed for nine cytokines and soluble cytokine receptors using multiplexed platforms or ELISA. We evaluated their association with week 8 culture status first using single-variable logistic models, then using cross-validated estimates of the C-statistic, a measure of discrimination, of candidate models including 2 or 3 analytes in addition to age.
RESULTS
All but one analyte decreased from baseline to week 8 (all p < 0.01). Individual biomarkers were not associated with 8 week culture status. Logistic models including increasing age, higher baseline soluble tumor necrosis factor receptor alpha 1 (sTNF-R1), and higher week 8 C-reactive protein (CRP) concentration classified subjects by culture status with up to 85% accuracy and acceptable discrimination (cross-validated C-statistic 0.76) and calibration (Hosmer-Lemeshow P > 0.2).
CONCLUSION
Exploratory post-hoc models including sTNF-R1, CRP, and age, classified 8 week culture status with promising accuracy.
View on PubMed2015
PURPOSE
To develop a new spiral-in/out balanced steady-state free precession (bSSFP) pulse sequence for real-time cardiac MRI and compare it with radial and spiral-out techniques.
METHODS
Non-Cartesian sampling strategies are efficient and robust to motion and thus have important advantages for real-time bSSFP cine imaging. This study describes a new symmetric spiral-in/out sequence with intrinsic gradient moment compensation and SSFP refocusing at TE = TR/2. In vivo real-time cardiac imaging studies were performed to compare radial, spiral-out, and spiral-in/out bSSFP pulse sequences. Furthermore, phase-based fat/water separation taking advantage of the refocusing mechanism of the spiral-in/out bSSFP sequence was also studied.
RESULTS
The image quality of the spiral-out and spiral-in/out bSSFP sequences was improved with off-resonance and k-space trajectory correction. The spiral-in/out bSSFP sequence had the highest signal-to-noise ratio (SNR), contrast-to-noise ratio, and image quality ratings, with spiral-out bSSFP sequence second in each category and the radial bSSFP sequence third. The spiral-in/out bSSFP sequence provides separated fat and water images with no additional scan time.
CONCLUSIONS
In this study, a new spiral-in/out bSSFP sequence was developed and tested. The superiority of spiral bSSFP sequences over the radial bSSFP sequence in terms of SNR and reduced artifacts was demonstrated in real-time MRI of cardiac function without image acceleration.
View on PubMed2015
2015
2015