Research Spotlight

Baylor Health Sciences Library brings to you each month the latest published research from the Baylor Scott & White community. Each newly published article features the researcher, the abstract, and link to the full text. For information on including your own research, please contact John Fullinwider, john.fullinwider@baylorhealth.edu. 214-828-8989.


Posted June 15th 2018

Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial.

Cara East M.D.

Cara East M.D.

Kandzari, D. E., M. Bohm, F. Mahfoud, R. R. Townsend, M. A. Weber, S. Pocock, K. Tsioufis, D. Tousoulis, J. W. Choi, C. East, S. Brar, S. A. Cohen, M. Fahy, G. Pilcher and K. Kario (2018). “Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial.” Lancet. 391(10137): 2346-2355. Epub 2018 May 23

Full text of this article.

BACKGROUND: Previous catheter-based renal denervation studies have reported variable efficacy results. We aimed to evaluate safety and blood pressure response after renal denervation or sham control in patients with uncontrolled hypertension on antihypertensive medications with drug adherence testing. METHODS: In this international, randomised, single-blind, sham-control, proof-of-concept trial, patients with uncontrolled hypertension (aged 20-80 years) were enrolled at 25 centres in the USA, Germany, Japan, UK, Australia, Austria, and Greece. Eligible patients had an office systolic blood pressure of between 150 mm Hg and 180 mm Hg and a diastolic blood pressure of 90 mm Hg or higher; a 24 h ambulatory systolic blood pressure of between 140 mm Hg and 170 mm Hg at second screening; and were on one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned to undergo renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were masked to randomisation assignments. The primary efficacy endpoint was blood pressure change from baseline (measured at screening visit two), based on ambulatory blood pressure measurements assessed at 6 months, as compared between treatment groups. Drug surveillance was used to assess medication adherence. The primary analysis was done in the intention-to-treat population. Safety events were assessed through 6 months as per major adverse events. This trial is registered with ClinicalTrials.gov, number NCT02439775, and follow-up is ongoing. FINDINGS: Between July 22, 2015, and June 14, 2017, 467 patients were screened and enrolled. This analysis presents results for the first 80 patients randomly assigned to renal denervation (n=38) and sham control (n=42). Office and 24 h ambulatory blood pressure decreased significantly from baseline to 6 months in the renal denervation group (mean baseline-adjusted treatment differences in 24 h systolic blood pressure -7.0 mm Hg, 95% CI -12.0 to -2.1; p=0.0059, 24 h diastolic blood pressure -4.3 mm Hg, -7.8 to -0.8; p=0.0174, office systolic blood pressure -6.6 mm Hg, -12.4 to -0.9; p=0.0250, and office diastolic blood pressure -4.2 mm Hg, -7.7 to -0.7; p=0.0190). The change in blood pressure was significantly greater at 6 months in the renal denervation group than the sham-control group for office systolic blood pressure (difference -6.8 mm Hg, 95% CI -12.5 to -1.1; p=0.0205), 24 h systolic blood pressure (difference -7.4 mm Hg, -12.5 to -2.3; p=0.0051), office diastolic blood pressure (difference -3.5 mm Hg, -7.0 to -0.0; p=0.0478), and 24 h diastolic blood pressure (difference -4.1 mm Hg, -7.8 to -0.4; p=0.0292). Evaluation of hourly changes in 24 h systolic blood pressure and diastolic blood pressure showed blood pressure reduction throughout 24 h for the renal denervation group. 3 month blood pressure reductions were not significantly different between groups. Medication adherence was about 60% and varied for individual patients throughout the study. No major adverse events were recorded in either group. INTERPRETATION: Renal denervation in the main renal arteries and branches significantly reduced blood pressure compared with sham control with no major safety events. Incomplete medication adherence was common. FUNDING: Medtronic.


Posted June 15th 2018

Mechanistic insights into anticancer properties of oligomeric proanthocyanidins from grape seeds in colorectal cancer.

Ajay Goel Ph.D.

Ajay Goel Ph.D.

Ravindranathan, P., D. Pasham, U. Balaji, J. Cardenas, J. Gu, S. Toden and A. Goel (2018). “Mechanistic insights into anticancer properties of oligomeric proanthocyanidins from grape seeds in colorectal cancer.” Carcinogenesis 39(6): 767-777.

Full text of this article.

Although the anticancer properties of oligomeric proanthocyanidins (OPCs) from grape seeds have been well recognized, the molecular mechanisms by which they exert anticancer effects are poorly understood. In this study, through comprehensive RNA-sequencing-based gene expression profiling in multiple colorectal cancer cell lines, we for the first time illuminate the genome-wide effects of OPCs from grape seeds in colorectal cancer. Our data revealed that OPCs affect several key cancer-associated genes. In particular, genes involved in cell cycle and DNA replication were most significantly and consistently altered by OPCs across multiple cell lines. Intriguingly, our in vivo experiments showed that OPCs were significantly more potent at decreasing xenograft tumor growth compared with the unfractionated grape seed extract (GSE) that includes the larger polymers of proanthocyanidins. These findings were further confirmed in colorectal cancer patient-derived organoids, wherein OPCs more potently inhibited the formation of organoids compared with GSE. Furthermore, we validated alteration of cell cycle and DNA replication-associated genes in cancer cell lines, mice xenografts as well as patient-derived organoids. Overall, this study provides an unbiased and comprehensive look at the mechanisms by which OPCs exert anticancer properties in colorectal cancer.


Posted June 15th 2018

Association of Opioid-Related Adverse Drug Events With Clinical and Cost Outcomes Among Surgical Patients in a Large Integrated Health Care Delivery System.

Shahid Shafi M.D.

Shahid Shafi M.D.

Shafi, S., A. W. Collinsworth, L. A. Copeland, G. O. Ogola, T. Qiu, M. Kouznetsova, I. C. Liao, N. Mears, A. T. Pham, G. J. Wan and A. L. Masica (2018). “Association of Opioid-Related Adverse Drug Events With Clinical and Cost Outcomes Among Surgical Patients in a Large Integrated Health Care Delivery System.” JAMA Surg. May 23. [Epub ahead of print].

Full text of this article.

Importance: Opioids are commonly used for pain control during and after invasive procedures. However, opioid-related adverse drug events (ORADEs) are common and have been associated with worse patient outcomes. Objectives: To examine the incidence of ORADEs in patients undergoing hospital-based surgical and endoscopic procedures and to evaluate the association of ORADEs with clinical and cost outcomes. Design, Setting, and Participants: In this retrospective study of clinical and administrative data, ORADEs were identified using International Classification of Diseases, Ninth Revision diagnosis codes for known adverse effects of opioids or by opioid antagonist use. Multivariable regression analysis was used to measure the association of ORADEs with outcomes after adjusting for potential confounding factors. The setting was 21 acute care hospitals in a large integrated health care delivery system. Participants were 135379 patients (aged >/=18 years, admitted from January 1, 2013, to September 30, 2015) who underwent surgical and endoscopic procedures and were given opioids. Exposure: Opioid use, reported as morphine milligram equivalent doses. Main Outcomes and Measures: Opioid-related adverse drug events and their association with inpatient mortality, discharge to another care facility, length of stay, cost of hospitalization, and 30-day readmission. Results: Among 135379 adult patients in this study (67.5% female), 14386 (10.6%) experienced at least one ORADE. Patients with ORADEs were more likely to be older, of white race/ethnicity, and male and have more comorbidities. Patients with ORADEs received a higher total dose of opioids (median morphine milligram equivalent dose, 46.8 vs 30.0 mg; P < .001) and for a longer duration (median, 3.0 vs 2.0 days; P < .001). In adjusted analyses, ORADEs were associated with increased inpatient mortality (odds ratio [OR], 28.8; 95% CI, 24.0-34.5), greater likelihood of discharge to another care facility (OR, 2.9; 95% CI, 2.7-3.0), prolonged length of stay (OR, 3.1; 95% CI, 2.8-3.4), high cost of hospitalization (OR, 2.7; 95% CI, 2.4-3.0), and higher rate of 30-day readmission (OR, 1.3; 95% CI, 1.2-1.4). ORADEs were associated with a 2.9% increase in absolute mortality, an $8225 increase in cost for the index hospitalization, and a 1.6-day increase in length of stay for the index hospitalization. Conclusions and Relevance: Opioid-related adverse drug events were common among patients undergoing hospital-based invasive procedures and were associated with significantly worse clinical and cost outcomes. Hospital-acquired harm from ORADEs in the surgical patient population is an important opportunity for health systems to improve patient safety and reduce cost.


Posted June 15th 2018

hDNA2 nuclease/helicase promotes centromeric DNA replication and genome stability.

Ajay Goel Ph.D.

Ajay Goel Ph.D.

Li, Z., B. Liu, W. Jin, X. Wu, M. Zhou, V. Z. Liu, A. Goel, Z. Shen, L. Zheng and B. Shen (2018). “hDNA2 nuclease/helicase promotes centromeric DNA replication and genome stability.” EMBO Journal. May 17 [Epub ahead of print].

Full text of this article.

DNA2 is a nuclease/helicase that is involved in Okazaki fragment maturation, replication fork processing, and end resection of DNA double-strand breaks. Similar such helicase activity for resolving secondary structures and structure-specific nuclease activity are needed during DNA replication to process the chromosome-specific higher order repeat units present in the centromeres of human chromosomes. Here, we show that DNA2 binds preferentially to centromeric DNA The nuclease and helicase activities of DNA2 are both essential for resolution of DNA structural obstacles to facilitate DNA replication fork movement. Loss of DNA2-mediated clean-up mechanisms impairs centromeric DNA replication and CENP-A deposition, leading to activation of the ATR DNA damage checkpoints at centromeric DNA regions and late-S/G2 cell cycle arrest. Cells that escape arrest show impaired metaphase plate formation and abnormal chromosomal segregation. Furthermore, the DNA2 inhibitor C5 mimics DNA2 knockout and synergistically kills cancer cells when combined with an ATR inhibitor. These findings provide mechanistic insights into how DNA2 supports replication of centromeric DNA and give further insights into new therapeutic strategies.


Posted June 15th 2018

Proposed Standardized Neurological Endpoints for Cardiovascular Clinical Trials: An Academic Research Consortium Initiative.

Michael J. Mack M.D.

Michael J. Mack M.D.

Lansky, A. J., S. R. Messe, A. M. Brickman, M. Dwyer, H. Bart van der Worp, R. M. Lazar, C. G. Pietras, K. J. Abrams, E. McFadden, N. H. Petersen, J. Browndyke, B. Prendergast, V. G. Ng, D. E. Cutlip, S. Kapadia, M. W. Krucoff, A. Linke, C. Scala Moy, J. Schofer, G. A. van Es, R. Virmani, J. Popma, M. K. Parides, S. Kodali, M. Bilello, R. Zivadinov, J. Akar, K. L. Furie, D. Gress, S. Voros, J. Moses, D. Greer, J. K. Forrest, D. Holmes, A. P. Kappetein, M. Mack and A. Baumbach (2018). “Proposed Standardized Neurological Endpoints for Cardiovascular Clinical Trials: An Academic Research Consortium Initiative.” Eur Heart J 39(19): 1687-1697.

Full text of this article.

Surgical and catheter-based cardiovascular procedures and adjunctive pharmacology have an inherent risk of neurological complications. The current diversity of neurological endpoint definitions and ascertainment methods in clinical trials has led to uncertainties in the neurological risk attributable to cardiovascular procedures and inconsistent evaluation of therapies intended to prevent or mitigate neurological injury. Benefit-risk assessment of such procedures should be on the basis of an evaluation of well-defined neurological outcomes that are ascertained with consistent methods and capture the full spectrum of neurovascular injury and its clinical effect. The Neurologic Academic Research Consortium is an international collaboration intended to establish consensus on the definition, classification, and assessment of neurological endpoints applicable to clinical trials of a broad range of cardiovascular interventions. Systematic application of the proposed definitions and assessments will improve our ability to evaluate the risks of cardiovascular procedures and the safety and effectiveness of preventive therapies.