Publications by authors named "Ronald Baxter"

18 Publications

  • Page 1 of 1

Liver stiffness and prediction of cardiac outcomes in patients with acute decompensated heart failure.

Clin Transplant 2021 Nov 24:e14545. Epub 2021 Nov 24.

Baylor Scott & White Research Institute, Baylor University Medical Center, Dallas, TX, USA.

Background: In acute decompensated heart failure (ADHF), noninvasive markers that predict morbidity and mortality are limited. Liver stiffness measurement (LSM) increases with hepatic fibrosis; however it may be falsely elevated in patients with ADHF in the absence of liver disease. We investigated whether elevated LSM predicts cardiac outcomes in ADHF.

Methods: In a prospective study, we examined 52 ADHF patients without liver disease between 2016 and 2017. Patients underwent liver 2D shear wave elastography (SWE) and were followed for 12 months to assess the outcomes of left ventricular assist device (LVAD), heart transplant (HT) or death.

Results: The median LSM was elevated in patients who received an LVAD or HT within 30-days compared to those who did not (median [IQR]: 55.6 [22.5 - 63.4] vs 13.8 [9.5 - 40.3] kPa, p = 0.049). Moreover, the risk of composite outcome was highest in the 3rd tertile (>39.8 kPa compared to 1 and 2 combined, HR 2.83, 95% CI 1.20- 6.67, p = 0.02). Each 1-kPa increase in LSM was associated with a 1%-increase in the incidence rate of readmissions (IRR 1.01, 95% CI 1.00-1.02, p = 0.01).

Conclusions: LSM may serve as a novel noninvasive tool to determine LVAD, HT or death in patients with ADHF. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/ctr.14545DOI Listing
November 2021

Machine learning analysis of multispectral imaging and clinical risk factors to predict amputation wound healing.

J Vasc Surg 2021 Jul 24. Epub 2021 Jul 24.

Department of Cardiothoracic Surgery, Baylor Scott & White The Heart Hospital, Plano, Tex; Department of Vascular Surgery, Baylor Scott & White The Heart Hospital, Plano, Tex. Electronic address:

Objective: Prediction of amputation wound healing is challenging due to the multifactorial nature of critical limb ischemia and lack of objective assessment tools. Up to one-third of amputations require revision to a more proximal level within 1 year. We tested a novel wound imaging system to predict amputation wound healing at initial evaluation.

Methods: Patients planned to undergo amputation due to critical limb ischemia were prospectively enrolled. Clinicians evaluated the patients in traditional fashion, and all clinical decisions for amputation level were determined by the clinician's judgement. Multispectral images of the lower extremity were obtained preoperatively using a novel wound imaging system. Clinicians were blinded to the machine analysis. A standardized wound healing assessment was performed on postoperative day 30 by physical exam to determine whether the amputation site achieved complete healing. If operative revision or higher level of amputation was required, this was undertaken based solely upon the provider's clinical judgement. A machine learning algorithm combining the multispectral imaging data with patient clinical risk factors was trained and tested using cross-validation to measure the wound imaging system's accuracy of predicting amputation wound healing.

Results: A total of 22 patients undergoing 25 amputations (10 toe, five transmetatarsal, eight below-knee, and two above-knee amputations) were enrolled. Eleven amputations (44%) were non-healing after 30 days. The machine learning algorithm had 91% sensitivity and 86% specificity for prediction of non-healing amputation sites (area under curve, 0.89).

Conclusions: This pilot study suggests that a machine learning algorithm combining multispectral wound imaging with patient clinical risk factors may improve prediction of amputation wound healing and therefore decrease the need for reoperation and incidence of delayed healing. We propose that this, in turn, may offer significant cost savings to the patient and health system in addition to decreasing length of stay for patients.
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http://dx.doi.org/10.1016/j.jvs.2021.06.478DOI Listing
July 2021

Comparison of the Bentall procedure versus valve-sparing aortic root replacement.

Proc (Bayl Univ Med Cent) 2020 Jun 22;33(4):524-528. Epub 2020 Jun 22.

Department of Cardiothoracic Surgery, Baylor Scott & White-The Heart Hospital, Plano, Texas.

Bentall and valve-sparing root replacement (VSRR) procedures are established treatments for aortic root disease. We present a single-center retrospective analysis comparing outcomes of bioprosthetic Bentall (BB), mechanical Bentall (MB), and VSRR patients from November 2007 to October 2016. Survival analysis was performed to evaluate the composite endpoint of freedom from recurrent aortic insufficiency, reoperation, or death. Of the 170 patients, BB was performed in 36 patients, MB in 63 patients, and VSRR in 71 patients. For BB, MB, and VSRR, the mean age was 63.8, 45.5, and 49.2 years ( < 0.001), respectively. Additionally, significantly more patients in the MB group (n = 32, 50.8%,  < 0.001) than in the BB and VSRR groups had prior cardiac surgeries. Cardiopulmonary bypass time and cross-clamp time were significantly longer in the VSRR group ( = 0.04 and 0.0005, respectively). Despite the complexity of the procedure, VSRR patients had higher combined freedom from death and reoperation than patients in the BB or MB groups. Elective Bentall root replacement is an excellent option for patients with root disease. Patients undergoing Bentall tend to have more severe or emergent cases, making them unlikely candidates for VSRR. VSRR in experienced centers carries equivalent morbidity and mortality and improved survival.
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http://dx.doi.org/10.1080/08998280.2020.1771163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549908PMC
June 2020

Outcomes of Open Versus Percutaneous Access for Patients Enrolled in the GREAT Registry.

Ann Vasc Surg 2021 Jan 27;70:370-377. Epub 2020 Jun 27.

Division of Vascular Surgery, Baylor Scott and White Heart Hospital, Texas Vascular Associates, Plano, TX. Electronic address:

Background: Arterial access and device delivery in endovascular aortic repair (EVAR) and thoracic endovascular aortic repair (TEVAR) have evolved from open femoral or iliac artery exposure to selective percutaneous arterial access. Although regional application of percutaneous access for these 2 procedures varies widely, the use of this technique continues to increase. Currently, differences in the use of percutaneous access between EVAR and TEVAR have not been well explored. The Gore Global Registry for Endovascular Aortic Treatment (GREAT) registry collected relevant data for evaluation of these issues and the comparative results between open and percutaneous approaches in regard to complication rates and length of stay (LOS).

Methods: This study was performed via a retrospective review of patients from the GREAT registry (Clinicaltrials.gov no. NCT01658787). The primary variable of this study was access site complications including postoperative hematoma, vessel dissection, and pseudoaneurysm. Patients were categorized by abdominal (EVAR) and thoracic (TEVAR) aortic procedures using percutaneous-only, cutdown-only, and combined vascular access techniques for a total of 6 groups. Standard statistical methodology was used to perform single-variable and multivariable analysis of a variety of covariates including LOS, geographical location of procedure, procedural success rate, and access sheath size.

Results: Of 4,781 patients from the GREAT registry, 3,837 (80.3%) underwent EVAR and 944 (19.7%) underwent TEVAR with percutaneous-only access techniques being used in 2,017 (42.2%) and cutdown-only in 2,446 (51.2%). There was variable application of percutaneous access by geographic region with Australia and New Zealand using this technique more frequently and Brazil using percutaneous access the least. No significant difference in the rate of access site complications was detected between the 6 groups of patients in the study; however, significantly lower rates of access site complications were associated with percutaneous-only compared with both cutdown-only and combined techniques (P = 0.03). In addition, associated with significantly higher rates of access site complications was longer LOS (P < 0.01). Average LOS was 5.2 days and was higher in the TEVAR group (10.1 days) than that in EVAR (4.0 days, P < 0.05). Increased sheath size does not appear to increase the risk of access site complication.

Conclusions: There was no significant difference found in the complication rate between percutaneous and cutdown access techniques. This analysis demonstrates that percutaneous-only access is safe, has low complication rates, and has lower LOS compared with open access or combined access techniques.
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http://dx.doi.org/10.1016/j.avsg.2020.06.033DOI Listing
January 2021

Effect of new and persistent left bundle branch block after transcatheter aortic valve replacement on long-term need for pacemaker implantation.

Proc (Bayl Univ Med Cent) 2020 Apr 30;33(2):157-162. Epub 2020 Jan 30.

Department of Interventional Cardiology, Baylor Scott & White The Heart HospitalPlanoTexas.

Cardiac conduction abnormalities, including left bundle branch block (LBBB), are common following transcatheter aortic valve replacement (TAVR). This study assessed the incidence and outcomes of new or widening persistent LBBB following TAVR. Data regarding 550 consecutive patients undergoing TAVR between 2012 and 2016 at our institution were retrospectively reviewed. Both 30-day and 1-year outcomes of patients with isolated new or worsening LBBB following TAVR were reviewed. Fifty-two patients (9.5%) developed new or worsening LBBB. Six of the 52 (11.5%) patients received a permanent pacemaker (PPM) for LBBB prior to discharge. For patients discharged home following TAVR without a PPM, the 1-year PPM requirement was 15.2% in patients with new or worsening LBBB compared to 4.5% in patients without new or worsening LBBB ( = 0.01). One-year mortality rates for patients who did not have a new PPM placed before discharge were 15.2% in patients with new or worsening LBBB, 13.9% in patients without new or worsening LBBB, and 11.9% in patients with preoperative PPMs ( = 0.81). Patients with new or worsening persistent LBBB discharged without a PPM experience a higher requirement for PPM implantation in the year following TAVR compared to patients without new or worsening persistent LBBB.
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http://dx.doi.org/10.1080/08998280.2020.1717906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155984PMC
April 2020

Digital Health Primer for Cardiothoracic Surgeons.

Ann Thorac Surg 2020 08 5;110(2):364-372. Epub 2020 Apr 5.

Sanger Heart and Vascular Institute, Atrium Health, Charlotte, North Carolina. Electronic address:

The burgeoning demands for quality, safety, and value in cardiothoracic surgery, in combination with the advancement and acceleration of digital health solutions and information technology, provide a unique opportunity to improve efficiency and effectiveness simultaneously in cardiothoracic surgery. This primer on digital health explores and reviews data integration, data processing, complex modeling, telehealth with remote monitoring, and cybersecurity as they shape the future of cardiothoracic surgery.
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http://dx.doi.org/10.1016/j.athoracsur.2020.02.072DOI Listing
August 2020

Extracorporeal Membrane Oxygenation Support for Vaping-Induced Acute Lung Injury.

Ann Thorac Surg 2020 09 27;110(3):e193-e194. Epub 2020 Feb 27.

The Heart Hospital Baylor, Plano, Texas.

Cases of vaporizer-induced acute lung injury are increasing in frequency as the use of these recreational products have become more popular. Such pathology can result in life-threatening conditions for otherwise healthy patients, with diagnostic difficulties and complex treatment plans. Presented is a case of severe acute lung injury caused by vaporizing substances in a young man requiring extracorporeal membranous oxygenation (ECMO) as a bridge to recovery. Recovery was successful despite rapid-onset of adult respiratory distress syndrome with prompt use of ECMO and appropriate lung-protective strategies.
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http://dx.doi.org/10.1016/j.athoracsur.2020.01.028DOI Listing
September 2020

A Newly Discovered Genetic Disorder Associated With Life-Threatening Aortic Disease in a 6-Year-Old Boy.

J Investig Med High Impact Case Rep 2020 Jan-Dec;8:2324709620909234

Baylor Scott and White-The Heart Hospital, Plano, TX, USA.

Aortic aneurysms in children are rare and when present are usually caused by a connective tissue disorder. In this article, we present a case of multiple aortic aneurysms in an adolescent with a novel finding of a gene variation that is associated with aortic disease.
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http://dx.doi.org/10.1177/2324709620909234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047236PMC
August 2021

Commentary: Molecular pathogenesis of aortic stenosis: Will the puzzle pieces ever fit together?

J Thorac Cardiovasc Surg 2019 Oct 15. Epub 2019 Oct 15.

Baylor Scott & White Research Institute, The Heart Hospital Plano, Plano, Tex; Department of Cardiothoracic Surgery, The Heart Hospital Plano, Plano, Tex. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2019.10.010DOI Listing
October 2019

Enhanced Recovery After Surgery: A Narrative Review of its Application in Cardiac Surgery.

Ann Thorac Surg 2020 06 23;109(6):1937-1944. Epub 2019 Dec 23.

Department of Surgery, Baylor Scott and White, The Heart Hospital, Plano, Texas. Electronic address:

Background: Enhanced Recovery After Surgery (ERAS) is a perioperative patient management strategy that is being adopted rapidly across surgical specialties worldwide. Components of ERAS work collaboratively throughout the perioperative course to achieve significant benefits for both the patient and the entire health care system. The use of ERAS in cardiac surgery (ERAS-C) could lead to similar improvements, but currently, use of ERAS-C programs is lacking and not well defined.

Methods: A literature search was performed of the Medline database to capture relevant studies discussing ERAS-C. Key concepts were extracted from these articles and grouped according to appropriate perioperative stages. Supporting literature was also included, briefly discussing the historical progression of cardiac surgery to enhanced recovery pathways, potential limitations to these pathways in cardiac surgery, and the first studies evaluating the use of an ERAS program with cardiac surgery patients.

Results: Initial results of ERAS-C studies have shown similar benefits to those of other surgical fields, including decreased hospital and intensive care unit lengths of stay (1-4 days and 4-20 hours, respectively), improved perioperative pain control (25%-60% decreased opioid usage), and improvements in early postoperative mobility and oral diets. Results especially beneficial to cardiac surgery have also been reported, such as an 8% to 14% decreased incidence of postoperative atrial fibrillation.

Conclusions: This review presents pertinent current research related to the implementation of ERAS programs in the field of cardiac surgery and provides a call to action for further investigation and adaption of ERAS in cardiac surgery.
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http://dx.doi.org/10.1016/j.athoracsur.2019.11.008DOI Listing
June 2020

Predictors and impact of right heart failure severity following left ventricular assist device implantation.

J Thorac Dis 2019 Apr;11(Suppl 6):S864-S870

Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, TX, USA.

Background: Right heart failure (RHF) is a well-known consequence of left ventricular assist device (LVAD) placement, and has been linked to negative surgical outcomes. However, little is known regarding risk factors associated with RHF. This article delineates pre- and intra-operative risk factors for RHF following LVAD implantation and demonstrates the effect of RHF severity on key surgical outcomes.

Methods: We performed a retrospective analysis of consecutive LVAD patients treated at our center between 2008 and 2016. RHF was categorized using the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) definition of none/mild, moderate, severe, and acute-severe. We constructed a predictive model using multivariable logistic regression and performed a competing risks analysis for survival stratified by RHF severity.

Results: Of 202 subjects, 52 (25.7%) developed moderate or worse RHF. Cardiopulmonary bypass (CPB) time and nadir hematocrit contributed jointly to the model of RHF severity (moderate or worse none/mild; area under the curve =0.77). Postoperative length of stay (LOS) was shortest in the non/mild group and longest in the acute-severe group (median 13 29.5 days; P<0.001). Stage 2/3 acute kidney injury (range, 26-57%, P=0.002), respiratory failure (13-94%, P<0.001), stroke (0-32%, P=0.02), and 1-year mortality (19-64%, P=0.002) differed by severity. Those with acute-severe RHF had 5.4 [95% confidence interval (CI), 2.5-11.8] times the risk of 1-year mortality compared to those who did not have RHF.

Conclusions: RHF remains a postoperative threat and is associated with worsened surgical outcomes. Ongoing research will reveal further opportunities to mitigate RHF post-LVAD.
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http://dx.doi.org/10.21037/jtd.2018.09.155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535485PMC
April 2019

Papillary Fibroelastoma of the Ascending Aorta.

J Investig Med High Impact Case Rep 2019 Jan-Dec;7:2324709619840377

2 Geisinger Medical Center, Danville, PA, USA.

Papillary fibroelastomas are rare benign primary cardiac tumors. They are typically found on valvular surfaces, most commonly, the aortic valve. In this article, we report a case of papillary fibroelastoma arising from the sinotubular junction of the ascending aorta, a rare and unusual site causing an embolic stroke.
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http://dx.doi.org/10.1177/2324709619840377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480984PMC
June 2020

Commentary: Off-pump mitral repair-Augmenting the future.

J Thorac Cardiovasc Surg 2019 10 30;158(4):e137. Epub 2019 Mar 30.

Department of Cardiothoracic Surgery, The Heart Hospital Baylor Plano, Plano, Tex. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2019.03.051DOI Listing
October 2019

Outcomes of Moderate-to-Severe Acute Kidney Injury following Left Ventricular Assist Device Implantation.

Cardiorenal Med 2019 23;9(2):100-107. Epub 2019 Jan 23.

Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, Texas, USA,

Background: Although acute kidney injury (AKI) is a common complication following cardiac surgery, less is known about the occurrence and consequences of moderate/severe AKI following left ventricular assist device (LVAD) implantation.

Methods: All patients who had an LVAD implanted at our center from 2008 to 2016 were reviewed to determine the incidence of, and risk factors for, moderate/severe (stage 2/3) AKI and to compare postoperative complications and mortality rates between those with and those without moderate/severe AKI.

Results: Of 246 patients, 68 (28%) developed moderate/severe AKI. A multivariable logistic regression comprising body mass index and prior sternotomy had fair predictive ability (area under the curve = 0.71). A 1-unit increase in body mass index increased the risk of moderate/severe AKI by 7% (odds ratio = 1.07; 95% confidence interval: 1.03-1.11); a prior sternotomy increased the risk more than 3-fold (odds ratio = 3.4; 95% confidence interval: 1.84-6.43). The group of patients with moderate/severe AKI had higher rates of respiratory failure and death than the group of patients with mild/no AKI. Patients with moderate/severe AKI were at 3.2 (95% confidence interval: 1.2-8.2) times the risk of 30-day mortality compared to those without. Even after adjusting for age and Interagency Registry for Mechanically Assisted Circulatory Support profile, those with moderate/severe AKI had 1.75 (95% confidence interval: 1.03-3.0) times the risk of 1-year mortality compared to those without.

Discussion: Risk-stratifying patients prior to LVAD placement in regard to AKI development may be a step toward improving surgical outcomes.
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http://dx.doi.org/10.1159/000492476DOI Listing
June 2019

Durable left ventricular assist device implantation in extremely obese heart failure patients.

Artif Organs 2019 Mar 3;43(3):234-241. Epub 2019 Jan 3.

Baylor University Medical Center, Center for Advanced Heart and Lung, Dallas, TX.

Left ventricular assist devices (LVADs) have improved clinical outcomes and quality of life for those with end-stage heart failure. However, the costs and risks associated with these devices necessitate appropriate patient selection. LVAD candidates are becoming increasingly more obese and there are conflicting reports regarding obesity's effect on outcomes. Hence, we sought to evaluate the impact of extreme obesity on clinical outcomes after LVAD placement. Consecutive LVAD implantation patients at our center from June 2008 to May 2016 were studied retrospectively. We compared patients with a body mass index (BMI) ≥40 kg/m (extremely obese) to those with BMI < 40 kg/m with respect to patient characteristics and surgical outcomes, including survival. 252 patients were included in this analysis, 30 (11.9%) of whom met the definition of extreme obesity. We found that patients with extreme obesity were significantly younger (47[33, 57] vs. 60[52, 67] years, P < 0.001) with fewer prior sternotomies (16.7% vs. 36.0%, P = 0.04). They had higher rates of pump thrombosis (30% vs. 9.0%, P = 0.003) and stage 2/3 acute kidney injury (46.7% vs. 27.0%, P = 0.003), but there were no differences in 30-day or 1-year survival, even after adjusting for age and clinical factors. Extreme obesity does not appear to place LVAD implantation patients at a higher risk for mortality compared to those who are not extremely obese; however, extreme obesity was associated with an increased risk of pump thrombosis, suggesting that these patients may require additional care to reduce the need for urgent device exchange.
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http://dx.doi.org/10.1111/aor.13380DOI Listing
March 2019

Determinants and Outcomes of Vasoplegia Following Left Ventricular Assist Device Implantation.

J Am Heart Assoc 2018 05 17;7(11). Epub 2018 May 17.

Department of Cardiology, Baylor University Medical Center, Dallas, TX

Background: Vasoplegia is associated with adverse outcomes following cardiac surgery; however, its impact following left ventricular assist device implantation is largely unexplored.

Methods And Results: In 252 consecutive patients receiving a left ventricular assist device, vasoplegia was defined as the occurrence of normal cardiac function and index but with the need for intravenous vasopressors within 48 hours following surgery for >24 hours to maintain a mean arterial pressure >70 mm Hg. We further categorized vasoplegia as ; , requiring 1 vasopressor (vasopressin, norepinephrine, or high-dose epinephrine [>5 μg/min]); or , requiring ≥2 vasopressors. Predictors of vasoplegia severity were determined using a cumulative logit (ordinal logistic regression) model, and 1-year mortality was evaluated using competing-risks survival analysis. In total, 67 (26.6%) patients developed mild vasoplegia and 57 (22.6%) developed moderate to severe vasoplegia. The multivariable model for vasoplegia severity utilized preoperative Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile, central venous pressure, systolic blood pressure, and intraoperative cardiopulmonary bypass time, which yielded an area under the curve of 0.76. Although no significant differences were noted in stroke or pump thrombosis rates (=0.87 and =0.66, respectively), respiratory failure and major bleeding increased with vasoplegia severity (<0.01). Those with moderate to severe vasoplegia had a significantly higher risk of mortality than those without vasoplegia (adjusted hazard ratio: 2.12; 95% confidence interval, 1.08-4.18; =0.03).

Conclusions: Vasoplegia is predictive of unfavorable outcomes, including mortality. Risk factors for future research include preoperative INTERMACS profile, central venous pressure, systolic blood pressure, and intraoperative cardiopulmonary bypass time.
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http://dx.doi.org/10.1161/JAHA.117.008377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015358PMC
May 2018

MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis.

Nat Commun 2017 06 22;8:15877. Epub 2017 Jun 22.

Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK.

Current treatments for rheumatoid arthritis (RA) do not reverse underlying aberrant immune function. A genetic predisposition to RA, such as HLA-DR4 positivity, indicates that dendritic cells (DC) are of crucial importance to pathogenesis by activating auto-reactive lymphocytes. Here we show that microRNA-34a provides homoeostatic control of CD1c DC activation via regulation of tyrosine kinase receptor AXL, an important inhibitory DC auto-regulator. This pathway is aberrant in CD1c DCs from patients with RA, with upregulation of miR-34a and lower levels of AXL compared to DC from healthy donors. Production of pro-inflammatory cytokines is reduced by ex vivo gene-silencing of miR-34a. miR-34a-deficient mice are resistant to collagen-induced arthritis and interaction of DCs and T cells from these mice are reduced and do not support the development of Th17 cells in vivo. Our findings therefore show that miR-34a is an epigenetic regulator of DC function that may contribute to RA.
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http://dx.doi.org/10.1038/ncomms15877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489689PMC
June 2017

Fisetin, a phytochemical, potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells.

Oncotarget 2015 Sep;6(29):28296-311

Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.

Melanoma is the most deadly form of cutaneous malignancy, and its incidence rates are rising worldwide. In melanoma, constitutive activation of the BRAF/MEK/ERK (MAPK) and PI3K/AKT/mTOR (PI3K) signaling pathways plays a pivotal role in cell proliferation, survival and tumorigenesis. A combination of compounds that lead to an optimal blockade of these critical signaling pathways may provide an effective strategy for prevention and treatment of melanoma. The phytochemical fisetin is known to possess anti-proliferative and pro-apoptotic activities. We found that fisetin treatment inhibited PI3K signaling pathway in melanoma cells. Therefore, we investigated the effect of fisetin and sorafenib (an RAF inhibitor) alone and in combination on cell proliferation, apoptosis and tumor growth. Combination treatment (fisetin + sorafenib) more effectively reduced the growth of BRAF-mutated human melanoma cells at lower doses when compared to individual agents. In addition, combination treatment resulted in enhanced (i) apoptosis, (ii) cleavage of caspase-3 and PARP, (iii) expression of Bax and Bak, (iv) inhibition of Bcl2 and Mcl-1, and (v) inhibition of expression of PI3K, phosphorylation of MEK1/2, ERK1/2, AKT and mTOR. In athymic nude mice subcutaneously implanted with melanoma cells (A375 and SK-MEL-28), we found that combination therapy resulted in greater reduction of tumor growth when compared to individual agents. Furthermore, combination therapy was more effective than monotherapy in: (i) inhibition of proliferation and angiogenesis, (ii) induction of apoptosis, and (iii) inhibition of the MAPK and PI3K pathways in xenograft tumors. These data suggest that simultaneous inhibition of both these signaling pathways using combination of fisetin and sorafenib may serve as a therapeutic option for the management of melanoma.
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http://dx.doi.org/10.18632/oncotarget.5064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695061PMC
September 2015
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