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Clinical Trial in a Dish: Personalized Stem Cell-Derived Cardiomyocyte Assay Compared With Clinical Trial Results for Two QT-Prolonging Drugs.
Blinova, K, Schocken, D, Patel, D, Daluwatte, C, Vicente, J, Wu, JC, Strauss, DG
Clinical and translational science. 2019;(6):687-697
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Abstract
Induced pluripotent stem cells (iPSCs) have shown promise in investigating donor-specific phenotypes and pathologies. The iPSC-derived cardiomyocytes (iPSC-CMs) could potentially be utilized in personalized cardiotoxicity studies, assessing individual proarrhythmic risk. However, it is unclear how closely iPSC-CMs derived from healthy subjects can recapitulate a range of responses to drugs. It is well known that QT-prolonging drugs induce subject-specific clinical response and that all healthy subjects do not necessarily develop arrhythmias or exhibit similar amounts of QT prolongation. We previously reported this variability in a study of four human ether-a-go-go-related gene (hERG) potassium channel-blocking drugs in which each subject underwent intensive pharmacokinetic and pharmacodynamic sampling such that subjects had 15 time-matched plasma drug concentration and electrocardiogram measurements throughout 24 hours after dosing in a phase I clinical research unit. In this study, iPSC-CMs were generated from those subjects. Their drug-concentration-dependent QT prolongation response from the clinic was compared with in vitro drug-concentration-dependent action potential duration (APD) prolongation response to the same two hERG-blocking drugs, dofetilide and moxifloxacin. Comparative results showed no significant correlation between the subject-specific APD response slopes and clinical QT response slopes to either moxifloxacin (P = 0.75) or dofetilide (P = 0.69). Similarly, no significant correlation was found between baseline QT and baseline APD measurements (P = 0.93). This result advances our current understanding of subject-specific iPSC-CMs and facilitates discussion into factors obscuring correlation and considerations for future studies of subject-specific phenotypes in iPSC-CMs.
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Sex, Age, and BMI Modulate the Association of Physical Examinations and Blood Biochemistry Parameters and NAFLD: A Retrospective Study on 1994 Cases Observed at Shuguang Hospital, China.
Tang, Z, Pham, M, Hao, Y, Wang, F, Patel, D, Jean-Baptiste, L, Fan, L, Wang, W, Wang, Y, Cheng, F
BioMed research international. 2019;:1246518
Abstract
OBJECTIVE Previous studies have shown that some metabolic risk factors are related to nonalcoholic fatty liver disease (NAFLD). This retrospective study was performed to investigate the associations between physical examinations and blood biochemistry parameters and NAFLD status and to identify possible risk factors of NAFLD. METHODS Study participants underwent general physical examinations, blood biochemistry, and abdominal ultrasound evaluations. In addition, data regarding sex, age, ethnicity, medical history, and alcohol consumption of participants were recorded. Among the study participants (N=1994), 57.8% were male, 41.2% over the age of 50, and 52.6% with BMI≥24. 986 patients had NAFLD and 1008 had no NAFLD. We used effect size analysis and logistic regression to determine which physical examinations and blood biochemistry parameters were significant for the association between these parameters and NAFLD status. RESULTS Both the effect size and logistic regression indicated that BMI, diastolic blood pressure (DBP), triglycerides (TG), and serum uric acid (SUA) show a significant association with NAFLD. Females are overall at a higher risk of NAFLD, but factors such as high BMI, DBP, TG, and SUA increase the associated risk for both sexes. Compared with males, females have a higher risk of NAFLD given that they are over 50, overweight and obese (BMI at or over 24), or have high SUA. In terms of age, people older than 50 with high SUA, and people younger than 50 with high DBP and low-density lipoprotein cholesterol (LDL-C) all increase the risk of NAFLD. For BMI, high DBP and low high-density lipoprotein cholesterol (HDL-C) are risk factors for NAFLD in overweight and obese people (BMI at or over 24), whereas in normal weight and underweight people (BMI under 24), elevated LDL-C increases the risk of NAFLD. CONCLUSIONS Our results revealed sex, age, and BMI modulate the association of physical examinations and blood biochemistry parameters and NAFLD, which may facilitate the development of personalized early warning and prevention strategies of NAFLD for at-risk populations.
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Absorption and Safety With Sustained Use of RELiZORB Evaluation (ASSURE) Study in Patients With Cystic Fibrosis Receiving Enteral Feeding.
Stevens, J, Wyatt, C, Brown, P, Patel, D, Grujic, D, Freedman, SD
Journal of pediatric gastroenterology and nutrition. 2018;(4):527-532
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Abstract
OBJECTIVES Pancreatic insufficiency (PI) and malabsorption of fats lead to reduced caloric intake, inability to maintain weight, and increased gastrointestinal symptoms. Thus, enteral nutrition (EN) is used in patients with cystic fibrosis (CF) and poor nutritional status. The current study evaluated safety, tolerability, and improvement of fatty acid (FA) status in red blood cell (RBC) membranes, a marker of long-term FA absorption, with an in-line digestive cartridge (RELiZORB) that hydrolyzes fat in enteral formula. METHODS Patients with CF receiving EN participated in a multicenter, 90-day open-label study during which RELiZORB was used with overnight EN. The primary endpoint was change over time in RBC uptake of docosahexaenoic acid (DHA)+ eicosapentaenoic acid (EPA). Gastrointestinal symptoms were collected to evaluate safety and tolerability. Several clinical and anthropometric parameters were also assessed throughout the study. RESULTS A total of 36 subjects completed the study with a mean age of 13.8 years, body mass index of 17.7 and 6.2 years mean use of overnight EN. Fat absorption significantly improved as shown by increased RBC levels of DHA+EPA, improved ω-6/ω-3 ratio, and increased plasma levels of DHA+EPA. RELiZORB use was not associated with any unanticipated adverse events. CONCLUSIONS RELiZORB use was found to be safe, well tolerated, and resulted in increased levels of FAs in RBCs and plasma. This is the first prospective study to show EN can improve FA abnormalities in CF. Because improvement in omega-3 levels has been shown to help pulmonary and inflammatory status as well as anthropometric parameters in CF, RELiZORB may have important long-term therapeutic benefits in patients with CF.
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A phase II trial of valproic acid in patients with advanced, radioiodine-resistant thyroid cancers of follicular cell origin.
Nilubol, N, Merkel, R, Yang, L, Patel, D, Reynolds, JC, Sadowski, SM, Neychev, V, Kebebew, E
Clinical endocrinology. 2017;(1):128-133
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Abstract
OBJECTIVE Valproic acid (VA) is a histone deacetylase (HDAC) inhibitor that has antiproliferative effects on several types of cancer, including thyroid cancer. In addition, VA has been reported to upregulate the sodium-iodine symporter in thyroid cancer cells and increases radioiodine uptake in preclinical studies. The aim of this study was to assess the antiproliferative effects of VA and to evaluate if VA can increase the radioiodine uptake in patients with advanced, radioiodine-negative thyroid cancer. DESIGN An open-label Simon two-stage phase II trial. PATIENTS AND MEASUREMENTS Valproic acid was administered orally, and doses were adjusted to maintain serum trough levels between 50 and 100 mg/l for 10 weeks, followed by injections of recombinant human thyroid-stimulating hormone and a radioiodine uptake scan. Anatomical imaging studies were performed at week 16 to assess tumour response and radioiodine therapy in patients with increased radioiodine uptake. RESULTS Thirteen patients with a median age of 66 years (50-78 years) were enrolled and evaluated. Seven patients had papillary thyroid cancer (PTC), two had follicular variant PTC, two had follicular thyroid cancer, and two had Hürthle cell carcinoma. None of the 10 patients who completed the 10-week treatment had increased radioiodine uptake at their tumour sites. Three patients were taken off the study prior to the 10-week radioiodine uptake scan: one with grade-3 hepatic toxicity, one with disease progression and one for noncompliance. Four of 13 patients had decreased stimulated serum thyroglobulin with VA treatment. None of the patients had complete or partial responses based on Response Evaluation Criteria in Solid Tumors (RECIST), and six patients had disease progression. CONCLUSIONS Valproic acid does not increase radioiodine uptake and does not have anticancer activity in patients with advanced, radioiodine-negative thyroid cancer of follicular cell origin.
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Amino acids in a targeted versus a non-targeted metabolomics LC-MS/MS assay. Are the results consistent?
Klepacki, J, Klawitter, J, Klawitter, J, Karimpour-Fard, A, Thurman, J, Ingle, G, Patel, D, Christians, U
Clinical biochemistry. 2016;(13-14):955-61
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Abstract
BACKGROUND The results of plasma amino acid patterns in samples from kidney transplant patients with good and impaired renal function using a targeted LC-MS/MS amino acid assay and a non-targeted metabolomics assay were compared. METHODS EDTA plasma samples were prospectively collected at baseline, 1, 2, 4 and 6months post-transplant (n=116 patients, n=398 samples). Each sample was analyzed using both a commercial amino acid LC-MS/MS assay and a non-targeted metabolomics assay also based on MS/MS ion transitions. The results of both assays were independently statistically analyzed to identify amino acids associated with estimated glomerular filtration rates using correlation and partial least squares-discriminant analysis. RESULTS Although there was overlap between the results of the targeted and non-targeted metabolomics assays (tryptophan, 1-methyl histidine), there were also substantial inconsistencies, with the non-targeted assay resulting in more "hits" than the targeted assay. Without further verification of the hits detected by the non-targeted discovery assay, this would have led to different interpretation of the results. There were also false negative results when the non-targeted assay was used (hydroxy proline). Several of said discrepancies could be explained by loss of sensitivity during analytical runs for selected amino acids (serine and threonine), retention time shifts, signals above the range of linear detector response and integration of peaks not separated from background and interferences (aspartate) when the non-targeted metabolomics assay was used. CONCLUSIONS Whenever assessment of a specific pathway such as amino acids is the focus of interest, a targeted seems preferable to a non-targeted metabolomics assay.
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Targeting Estrogen Receptor Beta in a Phase 2 Study of High-Dose Estradiol in Metastatic Triple-Negative Breast Cancer: A Wisconsin Oncology Network Study.
Wisinski, KB, Xu, W, Tevaarwerk, AJ, Saha, S, Kim, K, Traynor, A, Dietrich, L, Hegeman, R, Patel, D, Blank, J, et al
Clinical breast cancer. 2016;(4):256-61
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Abstract
BACKGROUND Estrogen receptor beta (ERβ) is expressed by 50% to 80% of triple-negative breast cancers (TNBC). Agonism of ERβ has antiproliferative effects in TNBC cells expressing ERβ. This phase 2 study evaluated single-agent high-dose estradiol in patients with advanced TNBC. PATIENTS AND METHODS Adult women with measurable advanced TNBC were treated with estradiol 10 mg oral 3 times daily provided continuously for 28-day cycles. A Simon optimal 2-stage design was used. The primary end point was objective response (OR). Secondary end points included progression-free survival (PFS), clinical benefit (CB), and safety. OR, CB, and PFS by ERβ status were also examined. RESULTS Seventeen evaluable women were enrolled. Median age was 58 years (range, 34-90 years); the median number of prior systemic therapies was 2 (range, 0-6). One patient had a confirmed partial response (OR rate, 5.9%) and remained on the study for > 24 weeks. Three patients had stable disease, with one lasting more than 16 weeks. ERβ expression was detected in 77% (13 patients). The CB rate at 16 weeks was 15% (2 of 13) in ERβ-positive patients and 0% (0 of 4) in ERβ-negative patients (P = 1). PFS was poor (median, 1.9 months) and not statistically significantly different between ERβ-positive versus -negative patients. No new adverse events from estradiol were identified. The study closed after the first stage as a result of limited responses in these unselected patients. CONCLUSION In unselected TNBC, high-dose estradiol has limited efficacy. However, further evaluation of ERβ selective agonists in TNBC selected by ERβ expression may be warranted.