tbuckley/cabot-search huggingface dataset:
Abstract 13956: Nalfurafine, an Orally Active, G Protein-Biased Kappa Opioid Receptor Agonist, Increases the Diuretic Response to Loop and Thiazide Diuretics and Limits Electrolyte Losses
Authors: Jacob Meariman, Jane Sutphen, Juan Gao, Daniel R Kapusta
Journal: Circulation (2021)

Nalfurafine, a G protein-biased kappa opioid receptor (KOR) agonist that produces analgesia and is devoid of CNS adverse effects, is used in Japan to treat pruritis in dialysis patients. Our lab has shown that in rats, IV nalfurafine produces a marked diuresis, antinatriuresis, antikaliuresis, and decrease in blood pressure. Here, we examined the cardiovascular and renal responses to IV and oral nalfurafine in combination with furosemide or hydrochlorothiazide (HCTZ). We hypothesized that combining nalfurafine with these diuretics would increase urine output, given its distinct mechanism of vasopressin inhibition, and limit electrolyte loss. Following chronic catheterization, conscious Sprague-Dawley rats received an isotonic saline infusion, and after stabilization, were administered an IV bolus diuretic alone or in combination with nalfurafine. Mean arterial pressure (MAP), heart rate (HR), and urine output were recorded for 90-min. In a separate study, rats were placed in metabolic cages, and following 2-hour acclimation, were administered drug in a volume load (20 cc/kg) via oral gavage. Hourly urine samples were then collected for five hours. When compared to diuretic treatment alone, IV co-administration with nalfurafine significantly increased total urine output to furosemide and HCTZ while reducing the amount of sodium and potassium excreted (Table 1). Notably, MAP was reduced with nalfurafine/diuretic combination therapy compared to diuretics alone. Similarly, oral co-administration of nalfurafine significantly increased the urine output to HCTZ and reduced the amount of sodium and potassium excreted, whereas combination with furosemide only limited the amount of sodium excreted (Table 1). Together, these findings demonstrate that nalfurafine enhances the diuresis to standard-of-care diuretics without causing an excessive loss of electrolytes, which may offer a new approach to treat several cardiovascular conditions.
Liver Transplantation for Intrahepatic Cholangiocarcinoma: Ready for Prime Time?
Authors: Gonzalo Sapisochin, Tommy Ivanics, Julie Heimbach
Journal: Hepatology (2021)

Cholangiocarcinoma (CCA) represents the second-most common primary liver malignancy after HCC and has risen in incidence globally in the past decades. Intrahepatic cholangiocarcinoma (iCCA) comprises 20% of all CCAs, with the rest being extrahepatic (including perihilar [pCCA] and distal CCA). Though long representing an absolute contraindication for liver transplantation (LT), recent analyses of outcomes of LT for iCCA have suggested that iCCA may be a potentially feasible option for highly selected patients. This has been motivated both by successes noted in outcomes of LT for other malignancies, such as HCC and pCCA, and by several retrospective reviews demonstrating favorable results with LT for a selected group of iCCA patients with small lesions. LT for iCCA is primarily relevant within two clinical scenarios. The first includes patients with very early disease (single tumor, ≤2 cm) with cirrhosis and are not candidates for liver resection (LR). The second scenario is patients with locally advanced iCCA, but where the extent of LR would be too extensive to be feasible. Preliminary single-center reports have described LT in a selected group of patients with locally advanced tumors who have responded to neoadjuvant therapy and have a period of disease stability. Currently, there are three prospective trials underway that will help clarify the role of LT in iCCA. This review seeks to explore the available studies involving LT for iCCA, the challenges of ongoing trials, and opportunities for the future.
Targeted Radiation Evokes Catecholamine Production Triggering Systemic Inflammatory Responses
Authors: Yuko Kawano, Daniel K. Byun, Hiroki Kawano, Mark W. LaMere, Elizabeth A. LaMere, Carl J. Johnston, Nicole Paris, Joe V. Chakkalakal, Jaqueline P. Williams, Benjamin J. Frisch, Laura M. Calvi
Journal: Blood (2021)
Abstract 11923: Ventricular Parasystole: An Under-Recognized Risk Factor for Ventricular Fibrillation in Patients With Implantable Cardioverter-Defibrillators
Authors: Kyle T OMeara, Scott Meyer, Duc H Do
Journal: Circulation (2021)

Introduction: Ventricular parasystole is an uncommon characteristic of ventricular ectopic beats characterized by cyclical depolarization that is independent of the dominant rhythm. The relationship between ventricular parasystole and ventricular arrhythmias including ventricular tachycardia (VT) and fibrillation (VF) is unknown. We sought to quantify the prevalence of ventricular parasystole in patients with implantable cardioverter defibrillators (ICDs) with VT and VF. Methods: We reviewed all inpatient ICD interrogations between June 2019 and August 2020 at a single tertiary care hospital and identified patients with VT/VF. For each patient, we fully evaluate all available electrocardiograms, daily 7-lead rhythm strips during hospitalization, Holter monitors, stress test electrocardiograms, and ICD interrogations to identify evidence of ventricular parasystole. Results: Out of 468 ICD interrogations, 129 patients with VT/VF were identified (mean age 55.1 ± 20.3 years; 14 (11%) single chamber, 57 (44%) dual chamber, 12 (9%) subcutaneous, 46 (36%) biventricular). Of these, 88 (68%) patients had VT only, 31 (24%) VF only, and 10 (8%) both VT and VF. Ventricular parasystole was identified in 2/88 (2%) VT only patients, 7/31 (23%) VF only patients, and 3/10 (30%) patients with VT and VF. Patients with VF were significantly more likely than those with VT to have parasystole (p&lt;0.001). Nine of the 10 patients with VF and parasystole (90%) had presumed premature ventricular contraction (PVC) induced VF of unclear etiology (no acute ischemia or channelopathy). Additionally, in 4 patients with VF and parasystole (3 with VF only, 1 VT and VF), all with dual chamber ICDs, we also identified intradevice interactions with ventricular parasystole which led to R-on-T pacing-induced VF episodes (this was the only cause of VF in 1 patient). Conclusions: Ventricular parasystole was found in 24% of ICD patients with VF, and was significantly more common in ICD patients with VF compared to VT. Ventricular parasystole can lead to pacing-induced VF due to intradevice interactions in dual chamber ICDs. The role of ventricular parasystole and PVC-induced VF requires further study to determine whether parasystole is a causative factor or an epiphenomenon.
QOLP-29. THE EFFECTS OF AN ONLINE, NURSE-LED NEEDS-BASED SUPPORT PROGRAM ON NEURO-ONCOLOGY FAMILY CAREGIVERS' DISTRESS: A RANDOMIZED CONTROLLED TRIAL
Authors: Florien Boele, Paula Sherwood, Jason Weimer, Judith Proudfoot, Anna Marsland, Terri Armstrong, Charles Given, Jan Drappatz, Heidi Donovan
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Patients with primary malignant brain tumors have high symptom burden and commonly rely on family caregivers for practical and emotional support. This can lead to negative mental and physical consequences for caregivers. We investigated effectiveness of an 8-week nurse-led online needs-based support program (SmartCare©) with and without online self-guided cognitive behavioral therapy (CBT) for depression compared to enhanced care as usual (ECAU) on depressive symptoms, caregiving-specific distress, anxiety, mastery, and burden. METHODS Family caregivers with depressive symptoms were randomized to three groups: SmartCare© plus/minus self-guided CBT, or ECAU. Primary outcomes (depressive symptoms (CES-D); caregiving-specific distress (Caregiver Needs Screen)) and secondary outcomes (anxiety (POMS-A), caregiver mastery (Caregiver Mastery Scale), and caregiver burden (Caregiver Reactions Assessment)) were assessed online. Intention to treat analyses of covariance corrected for baseline scores were performed for outcomes at four months. RESULTS In total, 120 family caregivers participated. Accrual and CBT engagement were lower than expected, therefore intervention groups were combined (n=80) and compared to ECAU (n=40). For depressive symptoms, no statistically significant group differences were found. Caregiving-specific distress decreased in the intervention group compared with ECAU (p=0.01, partial ɳ 2=0.08). Among secondary outcomes, there was a trend towards improvement in mastery for the intervention group compared with ECAU (p=0.08, partial ɳ 2=0.04). CONCLUSION SmartCare©, with or without self-guided CBT, reduced caregiving-specific distress with a trend towards improving mastery. SmartCare© has the potential to improve the lives of families coping with a brain tumor diagnosis.
Abstract 10716: Etanercept as an Adjunct Therapy for Acute Kawasaki Disease: A Long Term Follow Up
Authors: Eyal Sagiv, Ashley Buffone, Nadine Choueiter, Nagib Dahdah, Michael A Portman
Journal: Circulation (2021)

Introduction: Etanercept, a soluble TNF receptor, is beneficial when given as an adjunct to IVIg to children with acute Kawasaki disease (KD) and coronary artery (CA) involvement. A multi-center phase III trial, Etanercept as Adjunctive Treatment for Acute Kawasaki Disease (EATAK), showed that this TNF antagonist prevented progression of CA dilation over 6 weeks after acute KD. Aims: This study is aimed to test the long-term benefit of Etanercept in improving CA outcome. Methods: Patients enrolled in the placebo controlled double blind EATAK trial from 3 institutions (Seattle, Montreal, Bronx) who had CA dilation (z≥2.5) on initial presentation were included in this study ( n =40). The percent reduction in the size of affected vessels from echocardiogram at presentation to mid-year (4-8 months), 1-year (9-23 months) and ≥2 years after diagnosis were analyzed, and two-tailed t test used to compare Etanercept (0.8 mg/kg x3 doses) and placebo ( n =18) groups. Results: Both groups showed mean reduction (20%) in coronary artery diameter over a 2 year period (Figure). However, patients treated with Etanercept had accelerated and significantly greater improvement in diameter of affected vessels in the first 6 months after diagnosis [22% ( n =25) vs. 6.8% ( n =13), p =0.015]. The trend continued at 1-year follow up ([24.1% ( n =35) vs. 17.5% ( n =27), p =0.24], and by 2 years both groups showed similar overall change [19.6% ( n =31) vs. 24.7% ( n =24), p =0. 43]. Conclusions: Etanercept as an adjunct treatment to IVIg in acute KD with CA involvement accelerates regression of CA dilation over at least a 6 month period after acute inflammation. Etanercept is a potent anti-inflammatory agent that has both early and long-term benefit in CA remodeling in KD. Acceleration of CA healing by Etanercept may provide long term coronary artery benefit.
EXTH-21. MECHANISMS OF SYNERGISTIC GROWTH SUPPRESSION BY RADIOTHERAPY AND C-MET INHIBITION IN EXPERIMENTAL GLIOBLASTOMA
Authors: Manuela Silginer, Eleanna Papa, Emese Szabo, Flavio Vasella, Patrick Roth, Tobias Weiss, Michael Weller
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma remains to be one of the most lethal solid cancers and novel therapies are urgently needed. There is increasing interest in the role of the HGF/MET pathway in the response of glioblastoma to radiotherapy. c-MET-mediated radioresistance may be partially induced via proinvasive and DNA damageresponse pathways and HGF may be involved in the regulation of immune responses. Here, we explored the role of the c-MET pathway in response to radiotherapy and investigated potential modes of action that mediate synergistic effects of MET pathway inhibition and irradiation in syngeneic murine glioma models in vitro and in vivo. Murine glioma cells express HGF and c-MET and respond with c-MET phosphorylation upon exposure to exogenous HGF. In vitro, glioma cell viability and proliferation are not affected by pharmacological or genetic c-MET pathway interference, and the c-MET inhibitor tepotinib fails to sensitize glioma cells to irradiation. Conversely, in vivo c-MET inhibition combined with focal radiotherapy synergistically prolongs survival in two syngeneic orthotopic glioma models compared with either treatment alone. Complementary studies demonstrated that synergy was lost when gliomas were established and treated in immunodeficient mice, and importantly, also when c-MET gene expression was disrupted in the tumor. Thus, synergistic suppression of experimental syngeneic glioma growth by irradiation and c-MET inhibition requires at least two mechanisms, expression of c-MET in the tumor and a functional immune system. In summary, our data suggest clinical evaluation of c-MET pathway inhibition in combination with radiotherapy in human glioblastoma.
Risk Factors for Adverse Outcomes Following Haploidentical Hematopoietic Cell Transplantation with Posttransplant Cyclophosphamide: A Two-Center Analysis
Authors: Viviane De Jesus Torres Lima, Anderson Felipe Felipe Da Silva, Andreza Alice Feitosa Ribeiro, Mariana Nassif Kerbauy, Lucila Kerbauy, Cinthya Correa Silva, Leonardo Javier Arcuri, Nelson Hamerschlak
Journal: Blood (2021)
Abstract 11009: Aortic Valve Calcium Score and Mortality Risk Following Transcatheter Aortic Valve Replacement
Authors: Parth P Patel, Abdallah El Sabbagh, Rayan Suliman, Najiyah Salwa, Peter Pollak, Mohamad H Yamani, Pragnesh Parikh, Peter A Noseworthy, Carolyh Landolfo, Demilade A Adedinsewo
Journal: Circulation (2021)

Background: Transcatheter aortic valve replacement (TAVR) is an approved alternative to surgical aortic valve replacement. However, as the clinical indication and adoption of TAVR expands, it remains important to identify predictors of mortality after TAVR. We aimed to study the impact of aortic valve calcium score on long term mortality following TAVR in a large patient population. Methods: We included consecutive patients who successfully underwent TAVR from June 2010 – June 2019 across all Mayo Clinic sites. Patients were followed through February 2021. Aortic valve calcium scores were obtained from preoperative computed tomography angiography of the chest. Additional data was abstracted from medical records. Cox-proportional hazard regression models were employed to evaluate the independent effect of aortic valve calcium score on mortality. Results: A total of 1988 patients were evaluated in the final analysis. Forty-two percent were women, median age was 83 years (Q1: 77, Q3: 87), 16% received a permanent pacemaker following TAVR and 83% received an Edwards Sapien valve. We demonstrate an incremental increase in mortality risk as aortic valve calcium score values increased after adjusting for age, gender, pacemaker implantation, left bundle branch block, and Charlson Comorbidity Index. Selected calcium score cut-points with adjusted hazard ratios (aHR) are displayed: 1200 AU (aHR: 1.13, 95% CI 1.06, 1.20); 2000 AU (aHR: 1.22, 95% CI 1.09, 1.35); 3000 AU (aHR: 1.34, 95% CI: 1.14, 1.58). Conclusion: This study demonstrates an association between aortic valve calcium score and long-term mortality in a large patient population. This highlights the potential predictive value of the calcium score in preoperative planning and may provide clinicians with an additional measure for risk stratification prior to TAVR.
Abstract 14479: Progress Towards A Peroxidase-free Catalase Mimic
Authors: Andrew G Tennyson
Journal: Circulation (2021)

Manganese complexes that exhibit catalase activity (i.e., catalyze the disproportionation of H 2 O 2 into ½ O 2 and H 2 O) are intrinsically also able to exhibit peroxidase activity (i.e., catalyze the oxidation of other molecules with H 2 O 2 as terminal oxidant). Both reactivity modes can be harnessed for therapeutically beneficial outcomes. For example, Mn-porphyrin complexes can both ( a ) protect healthy cells during radiotherapy by preventing a shift in cellular redox state to more oxidized potentials as well as (b) trigger cancer cell apoptosis by impelling a shift to more oxidized potentials. However, it is difficult to predict in advance which reactivity mode will predominate in a given biological environment. Herein we present a ruthenium complex with catalase activity 11.9-fold higher, stability to H 2 O 2 120-fold higher, and catalase/peroxidase selectivity 89.2-fold higher than the best values achieved by the synthetic MnSOD mimics.
Abstract 14015: Extracellular Vesicle-Associated microRNAs From the Plasma of HIV-Positive Individuals Enhance Atherosclerosis Burden
Authors: Andrea Da Fonseca Ferreira, Jianqin Wei, Lukun Zhang, Conrad Macon, Qianhuan Zhang, Dushyantha Jayaweera, Michael Bellio, Aisha Khan, Joshua M Hare, Derek Dykxhoorn, Liyong Wang, Chunming Dong
Journal: Circulation (2021)

Introduction: People living with HIV (PLHIV) have a higher risk of cardiovascular diseases (CVD) compared to HIV negative (HIV - ) individuals. The molecular mechanisms underlying the increased CVD risk remain elusive. Extracellular vesicles (EVs) mediate cell-to-cell communication through cargo transfer, including microRNAs (EV-miRs). Hypothesis: HIV infection results in modification of plasma EVs cargo and these HIV positive EVs (HIV posEVs ), specifically EV-miRs, recapitulate the effects of HIV infection on CVD development. Methods: Atherosclerosis burden was assessed by carotid ultrasound in 74 PLHIV treated with antiretroviral therapy (ART) with viral loads &lt;50 c/ml and 23 HIV - subjects. Circulating endothelial progenitor cell (EPC) levels were measured by colony forming unit (CFU) assay. PLHIV plasma was fractionated into plasma EVs (HIV posEVs ) and plasma-depleted of EVs (HIV plasmadepEVs ). These fractions, EVs from HIV - subjects (HIV negEVs ) and PBS were injected weekly into apoE -/- mice via tail vein for three months. Atherosclerosis burden (H&amp;E and Oil Red O staining), bone marrow (BM) EPC senescence (β-galactosidase staining), proliferation (MTT assay) and migration (“scratch” assay) were examined. RNASeq was used to identify EV-miRs that mediated the effects of HIV posEVs . Tailored EVs (TEVs) loaded with antagomirs for top EV-miRs were generated to determine their capacity to reverse the adverse effects of HIV posEVs in mouse EPCs in vitro . Results: PLHIV had higher atherosclerosis burden and lower circulating EPC numbers. Mice treated with HIV posEVs showed increased atherosclerotic burden, higher BM EPC senescence and lower functionality. HIV posEVs also negatively affected mouse BM EPC senescence in vitro . RNAseq identified four top candidate EV-miRs upregulated in HIV posEVs : let-7b-5p, miR-16-5p, miR-423-5p, and miR-103a-2. TEVs loaded with the antagomirs for let-7b and miR103a-2 counteracted the effects of HIV posEVs on the accelerated senescence of mouse BM EPCs. Conclusion: 1) Plasma EVs from PLHIV reconstitute the effects of HIV infection on accelerated atherosclerosis via negatively affects EPC functionality; and 2) TEVs, targeting candidate EV-miRs counteracts the effects of HIV infection on EPCs.
Abstract 13083: Circulating Androgen Levels and Risk of Incident Heart Failure in Older Men: The Cardiovascular Health Study (CHS)
Authors: Joyce N Njoroge, William Tressel, Mary Lou Biggs, Alvin Matsumoto, Nicholas L Smith, Emily Rosenberg, Calvin Hirsch, John S Gottdiener, Ken J Mukamal, Jorge R Kizer
Journal: Circulation (2021)

Introduction: Circulating androgen levels in men decline with advancing age and have been linked to diabetes and atherosclerotic cardiovascular disease (ASCVD). A similar relationship has been reported for low total testosterone (T) and incident heart failure (HF), but whether this differs for free T or the more potent androgen, dihydrotestosterone (DHT), remains unknown. Methods: We hypothesized that total and free T are inversely related and SHBG positively related to incident HF in older men, whereas, based on earlier data on ASCVD in CHS, total DHT bears a U-shaped relationship with this outcome. In a male sample from CHS without prevalent ASCVD or HF, serum T and DHT concentration were measured by liquid chromatography tandem mass spectrometry, and sex hormone-binding globulin (SHBG) by immunoassay. Free T was calculated from total T, SHBG and albumin. We used Cox regression to estimate relative risks of HF, adjusting for age, race, BMI, smoking, alcohol, physical activity, systolic BP, antihypertensive use, total and HDL cholesterol, and eGFR. Results: In 1061 men (age 76±5) followed for a median of 9.6 years, there were 368 HF events. Restricted cubic splines showed no meaningful departure from linearity, and relationships were expressed per SD decrement in androgen levels. After adjustment, lower free T was significantly associated with higher risk of HF (HR 1.14 [95% CI 1.01, 1.28]), p=0.03). Risk estimates for total T (HR 1.12 [0.99, 1.26], p=0.07), DHT (HR 1.10 [0.97, 1.24], p=0.14) and SHBG (HR 1.07 [0.95, 1.21], p=0.25) were directionally similar, but not statistically significant. The association of lower free T and HF was not altered after further adjustment for diabetes or atrial fibrillation. In a sensitivity analysis excluding participants with history of prostate cancer, findings were similar. Conclusion: Total T, free T, DHT and SHBG were inversely associated with incident HF, but only the association of free T was statistically significant. These findings suggest a contribution of androgen deficiency to HF incidence among men late in life, the segment of the population at highest risk of both conditions. Additional research is needed to determine whether androgen replacement therapy is an effective strategy to lower HF risk in older men.
S1pr2 is a key mediator of endoplasmic reticulum stress in NAFLD/ NASH pathogenesis
Authors: Luciana Petti, Ana Lleo, Silvia Restelli, Giusy Sammarco, Matteo Donadon, Giulia Rizzo, Vincenzo Arena, Guido Carpino, Paola Corsetto, Roberto Ceriani, Angela Maria Rizzo, Alessio Aghemo, Stefania Vetrano
Journal: Journal of Hepatology (2020)
Evaluating the Value of a New Prediction Model for Gastric Cancer
Authors: Jesse A. Berlin, Daniel V. Catenacci
Journal: JAMA Network Open (2021)

Dexin Chen, MD; Hao Chen, MD; Liangjie Chi, MD; Meiting Fu, MD; Guangxing Wang, MS; Zhida Wu, MD; Shuoyu Xu, PhD; Caihong Sun, MS; Xueqin Xu, MS; Liyan Lin, MD; Jiaxin Cheng, MD; Wei Jiang, MD; Xiaoyu Dong, MD; Jianping Lu, MD; Jixiang Zheng, MD; Gang Chen, MD; Guoxin Li, MD, PhD; Shuangmu Zhuo, PhD; Jun Yan, MD, PhD
Hikoboshi Study: Remaining Burden and Current Medical Care Status of Patients with Congenital Hemophilia a: A Study Using Two Japanese Medical Information Databases
Authors: Azusa Nagao, Akiko Ioka, Takao Nakamura, Yoichi Murakami, Misako Makishima, Norihiro Okada, Michio Sakai
Journal: Blood (2021)