tbuckley/cabot-search huggingface dataset:
Abstract 514: Proteomic Characterization of Extracellular Matrix Regulation in Human Aortic Valve Development and Disease
Authors: Cassandra L Clift, Jennifer Bethard, Susana Comte-Walters, Lauren E Ball, David Bichell, Yan R Su, Anand Mehta, Richard R Drake, Peggi M Angel
Journal: Circulation Research (2019)

We present the first report of the collagen protein interactome in human aortic valve (AV) development and disease. AV disease affects up to 13% of the world population. As no therapies are available, patients must “watch and wait” until surgical valve replacement is necessary to prevent heart failure. Extracellular matrix (ECM) forms the basis for correct valve function but alterations of the ECM scaffold during development and disease are not well defined. Here, we report ECM protein regulation from a cohort of 26 valvular tissues in four pathological categories: normal functioning AVs, pediatric end-stage congenital aortic valve stenosis (CAVS), adult end-stage fibrocalcific aortic valve stenosis (FAVS), and a pulmonic Ross operation valve. A novel proteomic method was used to target ECM proteins, primarily collagens, for sequence analysis from FFPE 5-μm thin tissue sections. Collagens represented 19/49 proteins identified (39%); A total of 46/49 ECM proteins (94%) were implicated in direct interactions in collagen synthesis, regulation or modification. Data suggested dynamic regulation of collagen types during age and disease, e.g., Col15a1 was found only in normal AV, whereas Col4a1 was reported only in patients younger than 5 years. Upstream regulators of the collagen interactome included COLQ1, IGFBP2, and SPARC. Detailed peptide sequence analysis reported 70 specific collagen peptide sequences containing up to multiple hydroxylated prolines (HYP), a post-translational modification critical to stabilizing the collagen triple helix. Quantitative data analysis on HYP peptides reported differential regulation across patient categories – i.e., Col3a1 peptides show 52% increased HYP in CAVS compared to age matched normal valve. Interestingly, the pulmonic Ross valve represented unique collagen HYP signatures distinct from all other aortic valve tissues. Tissue from pediatric end-stage CAVS patients showed a higher percentage of hydroxylated peptides compared to non-hydroxylated peptides (33%) as compared to normal (25%) or adult end-stage FAVS (16%). We anticipate that the completed study will be useful to targeted therapies aiming to inhibit fibrosis and ECM remodeling, and may better inform engineered options for valve replacement.
Anti-CD20 Chimeric Antigen Receptor (CAR) Modified Expanded Natural Killer (NK) Cells Significantly Mediate Burkitt Lymphoma (BL) Regression and Improve Survival In Human BL Xenografted NSG Mice
Authors: Yaya Chu, Ashlin Yahr, Janet Ayello, Carmella van de Ven, Xianzheng Zhou, Mitchell S. Cairo
Journal: Blood (2013)
Phase I Trial of CCI-779 (Temsirolimus) and Weekly Bortezomib in Relapsed and/or Refractory Multiple Myeloma
Authors: Irene M. Ghobrial, Nikhil Munshi, Robert Schlossman, Stacey Chuma, Renee Leduc, Marybeth Nelson, Amy Sam, Kelly O’Connor, Brianna Harris, Diane Warren, Akari M. Dollard, Jacob Laubach, Ravi Vij, Erica Campagnaro, Ann Birner, Virginia Dixon-Lipscomb, Kenneth C. Anderson, Paul G. Richardson
Journal: Blood (2008)
Abstract 250: Smad3-Mediated Induction of Smad7 in Activated Myofibroblasts Protects the Remodeling Myocardium
Authors: Claudio D Humeres, Arti Shinde, Nikolaos G Frangogiannis
Journal: Circulation Research (2019)

TGFβs are induced in the infarcted and pressure-overloaded myocardium and play an essential role in repair and remodeling by activating Smad-dependent and Smad-independent cascades. Fibroblasts are major targets of TGFβs. Activation of Smad3 signaling in cardiac fibroblasts is crucial in post-infarction repair, mediating formation of aligned myofibroblast arrays. TGFβ responses are tightly regulated through induction of endogenous suppressive signals, such as the inhibitory Smads, that prevent excessive TGFβ signaling. We hypothesized that the inhibitory Smad7 may be induced in activated myofibroblasts infiltrating infarcted and pressure-overloaded hearts, protecting the myocardium from adverse remodeling and fibrosis by restraining TGFβ actions. Smad7 is markedly induced in infarcted and pressure-overloaded mouse hearts, and is localized in cardiomyocytes, myofibroblasts and activated macrophages. Induction of Smad7 in myofibroblasts is mediated through TGFβ/Smad3 signaling in vitro and in vivo. Mice lacking Smad7 in activated myofibroblasts (MFS7KO) and Smad7 fl/fl controls underwent non-reperfused myocardial infarction and transverse aortic constriction protocols. Following infarction, MFS7KO mice had higher mortality, worse systolic dysfunction and accentuated diastolic dysfunction when compared to Smad7 fl/fl. Following pressure overload, MFS7KO mice had accentuated interstitial and perivascular fibrosis and increased cardiomyocyte hypertrophy. In vitro, Smad7 overexpression attenuated myofibroblast conversion and reduced expression of profibrotic genes. Conversely, Smad7 knockdown promoted a matrix-synthetic fibroblast phenotype. Smad7 overexpression abrogated TGF-β-stimulated Smad2/3 and Erk activation without affecting TβRI and TβRII phosphorylation. Akt and p38 activation were unaffected by Smad7 overexpression. In conclusion, in remodeling hearts, Smad7 induction in activated myofibroblasts restrains fibrosis, negatively regulating Smad2/3 and Erk signaling through actions downstream of the TβRs. The protective effects of fibroblast Smad7 in cardiac remodeling may have important therapeutic implications for heart failure patients.
Splicesome Mutant MDS and AML Cells Activate Innate Immune Signaling By Regulating the Expression of Therapeutically Targetable IRAK4 Isoforms
Authors: Molly A Smith, Gaurav Choudhary, Andrea Pellagatti, Kwangmin Choi, Tushar Damodar Bhagat, Nathan Salomonis, Matthew J. Walter, Kakajan Komurov, Maria Elena S Sampson, Shanisha Gordon, Dagny Von Ahrens, Kith Pradhan, Ulrich G. Steidl, Robert Booher, Jacqueline Boultwood, Amit Verma, Daniel Starczynowski
Journal: Blood (2017)
Bias and stereotyping among research and clinical professionals: Perspectives on minority recruitment for oncology clinical trials.
Authors: Soumya J. Niranjan, Michelle Y. Martin, Mona N Fouad, Selwyn M. Vickers, Jennifer Wenzel, Elise D. Cook, Badrinath R. Konety, Raegan W Durant
Journal: Journal of Clinical Oncology (2019)

152 Background: Extensive attention has been paid in recent years to the possibility that bias among health care professionals contributes to health disparities. In its 2003 report, Unequal Treatment, the Institute of Medicine concluded that bias against racial minorities may affect communication or care offered. However, the role of bias in the context of recruitment of racial minorities in cancer clinical trials has not been explored. Therefore, we assessed clinical and research personnel’s experiences related to factors influencing recruitment of racial and ethnic minorities for cancer clinical trials. Methods: Ninety-one qualitative interviews were conducted at 5 U.S. cancer centers among 4 stakeholder groups: cancer center leaders, principal investigators, referring clinicians and research staff. Data analysis was conducted using a content analysis approach to generate themes from the transcribed interviews. Results: Five prominent themes emerged. 1) Recruitment interactions with potential minority participants were perceived to be challenging. 2) Potential minority participants were not perceived to be ideal study candidates. 3) A combination of clinic level barriers and negative perceptions of minority study participants led to providers withholding clinical trial opportunities from potential minority participants. 4) When clinical trial recruitment practices were tailored to minority patients, addressing research misconceptions to build trust was a common strategy. 5) For some respondents, race was perceived as irrelevant when screening and recruiting potential minority participants for clinical trials. Conclusions: Not only did some respondents view racial and ethnic minorities as less promising participants, some respondents reported withholding trial opportunities to minorities based on these perceptions. Some providers endorsed using tailored recruitment strategies while others eschewed race as a factor in trial recruitment. The presence of bias and stereotyping among clinical and research professionals recruiting for cancer clinical trials, should be considered when designing interventions to increase minority enrollment.
Allergy to prebiotic galacto-oligosaccharides: House dust mites—the putative primary sensitizer
Authors: Li Yuan Gabriella Nadine Lee, Youjia Zhong, Si Yuan Leow, Shan Chun Lim, Hongmei Wen, Jian Yi Soh, Wen Chin Chiang, Dianne J. Delsing, Bee Wah Lee, Chiung-Hui Huang
Journal: Journal of Allergy and Clinical Immunology (2019)
Malaria Eradication Is Within Reach
Authors: Bridget Kuehn
Journal: JAMA (2019)

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A cranberry proanthocyanidin rich extract induces both apoptosis and autophagy in human SEG-1 esophageal adenocarcinoma cells
Authors: Laura Kresty, Amy Howell, Maureen Baird
Journal: Cancer Research (2008)

621  Esophageal adenocarcinoma and its only recognized precursor lesion, Barrett’s esophagus, has rapidly increased during the past three decades throughout much of the Westernized world. Increasing rates have been linked to chronic reflux, obesity, the presence of hiatal hernia, and multiple nutritional factors. Generally plant-based diets have been associated with reduction of risk for esophageal adenocarcinoma and those of animal origin with risk escalation. In turn, our laboratory has been evaluating the chemopreventive potential of fruits and fruit constituents against esophageal cancer and esophageal premalignancy. Cranberry proanthocyanidins are known to have a role in maintaining urinary tract health and recently limited in vivo anda number of in vitro investigations andhave reported that cranberry extracts impact multiple cancer-associated processes in breast, colon, prostate and esophageal cancer cell lines. This study sought to investigate the effects of a cranberry proanthocyanidin rich extract (PAC) on programmed cell death in human SEG-1 esophageal adenocarcinoma (EAC) cells. Preliminary work with PAC showed potent inhibition of cell proliferation and apoptosis induction at a single time-point and expression array studies supported that the effects were caspase independent. Thus, Seg-1 EAC cells were pretreated with PAC [25 or 50 μg/ml] and assessed for induction of apoptosis, autophagy, and expression of select proteins over-time utilizing flow cytometry and annexin V staining, transmission electron microscopy, and western blot methods, respectively. PAC treatment induced apoptosis in SEG-1 cells by 3.4, 6.3, 5.7, 4.6 and 2.5-fold following 2, 6, 12, 24 and 48 hours of treatment. PAC also increased levels of PARP cleavage in a time and a dose-dependent manner further supporting its pro-apoptotic effects. In addition, parallel increases in autophagy were noted following PAC treatment as evidenced by striking morphological changes which included focal chromatin condensation, increased autophagic vacuole formation as early as 3 hours post-treatment, as well as the presence of empty vacuoles and greater numbers of vacuoles filled with cellular debris compared to vehicle-treated cells at 12 and 24 hours. Levels of Beclin-1 did not appear to change with PAC treatment. P21 levels markedly increased following PAC treatment and modest increases were noted in cytochrome C levels. These findings support that PAC is a potent inducer of both apoptosis and autophagy and that further research is warranted to improve our understanding of the interplay between these two modes of programmed cell death and to assess other key molecules involved.
Abstract 115: Surgical Bilateral Stellate Ganglionectomy Reduces Mitochondrial Reactive Oxygen Species (mROS) and Prevents Sudden Cardiac Death (SCD) in Non-ischemic Heart Failure (HF)
Authors: Swati Dey, Brian O'Rourke, Deeptankar DeMazumder
Journal: Circulation Research (2019)

Introduction: Current therapies for SCD are limited. Bilateral sympathetic stellate ganglionectomy ( BSG ) is a promising new adjunctive therapy in patients with ischemic HF who have incessant ventricular tachyarrhythmias ( VT/VF ) despite optimal medical management. The underlying mechanisms are unknown. The effect of BSG in non-ischemic HF is unclear. Hypothesis: BSG prevents VT/VF and SCD in non-ischemic HF by restoring sympathovagal balance and reducing mROS . METHODS: We used a unique pressure-overload guinea pig model that closely mimics human non-ischemic HF, including a high incidence of spontaneous VT/VF/SCD. We randomized the animals to non-failing controls, HF+Sham, or HF+BSG surgery. We used intention to treat analysis to evaluate VT/VF-free survival. We analyzed continuous ECG (VT/VF burden, heart rate variability, QT variability) and echo (cardiac function). In isolated left ventricular (LV) myocytes, we measured Ca 2+ transients and mitochondrial reactive oxygen species (mROS) using targeted ratiometric probes. Results: Half of the HF+Sham animals experienced SCD in 4 weeks. In contrast, BSG abolished SCD, reduced VT/VF, and increased parasympathetic tone (beyond corresponding reductions in sympathetic tone). Fractional shortening of the LV was markedly reduced in HF+Sham (0.28±0.02) vs. control (0.50±0.01), but preserved by BSG (0.45±0.02). Whereas HF+Sham increased mROS levels in LV myocytes (fractional oxidation, F ox : 0.53±0.015) compared to control (0.29±0.020), BSG reduced mROS (0.38±0.035). Mitochondrial antioxidant capacity, as indexed by H 2 O 2 challenge of LV myocytes, was compromised in HF+Sham (F ox : 0.81±0.040) compared to control (0.44±0.061), but preserved by BSG (0.48±0.023). Conclusions: Surgical BSG prevents SCD in non-ischemic HF by reducing mROS, decreasing sympathetic tone, and by increasing parasympathetic tone (possibly by facilitating cholinergic transdifferentiation). This promising new minimally-invasive surgical therapy may be particularly useful in patients with non-ischemic HF on optimal medical therapy who require recurrent ICD shocks to prevent SCD. Patients in the early stages of HF who are not eligible for ICDs but remain at higher SCD risk may also benefit from BSG surgery.
Abstract 775: Interaction of Phosphate Transport and Calcification in Placenta Vasculature
Authors: Ciara Benson, Nirmala Jayaraman, Ariel Mei, Mary C Wallingford
Journal: Circulation Research (2019)

Phosphate transport has been associated with pathological vascular calcification, but this relationship remains largely unexplored in placenta tissue. In this study we investigated the interaction of maternal-fetal phosphate transport and placental calcification using in vitro and in vivo models. Sodium-dependent phosphate transporter transcriptomics validated by quantitative RT-PCR revealed that the type III sodium-dependent phosphate transporter family members Slc20a1 and Slc20a2 are the predominant sodium-dependent symporters in both mouse and human placenta. Global loss of Slc20a2 generates multiple maternal and fetal phenotypes. We examined Slc20a2 promoter activity and protein localization of Slc20a2 throughout placentation. Slc20a2 was detected in embryonic structures that give rise to the maternal-fetal interface and in regions of the placenta that are susceptible to vascular calcification in the absence of Slc20a2. Pathologically, vascular malformations were found to precede calcium deposition in the absence of Slc20a2. Activation of osteocalcin in the placenta suggested that physiological calcification mechanisms may potentiate the mineral deposition observed with Slc20a2 loss. Histological analyses of human placenta revealed focal localization of Slc20a2 protein and distinct calcification deposition patterns. Lastly, the BeWo trophoblast model confirmed cellular competency for active, sodium-dependent phosphate symport as well as extracellular matrix calcification. Taken together, our findings support that normal growth and maintenance of the placenta requires Slc20a2. Moving forward, we now propose the working hypothesis that Slc20a2-mediated placental phosphate transport contributes to the energy requirements for rapid placental vascular development, enabling vascular patterning that maximizes surface area and minimizes tissue damage caused by aberrant flow, thereby promoting organ health and transport of nutrients, including phosphorus, across the placenta.
Abstract 923: Pharmacological Activation of Ampk With a Direct Pan-ampk Activator Results in a Worsening of a Hf Phenotype in Mice
Authors: Russell A Miller, Kimberly Cameron, Declan Flynn
Journal: Circulation Research (2019)

The absence of effective therapeutic treatments that can restore function in patients with heart failure necessitates the identification of new mechanisms and strategies to improve outcomes. Strategies that directly target the cardiomyocyte and have potential to increase metabolic capacity hold promise as treatment modalities. We sought to evaluate direct activators of the AMP-Activated Protein Kinase (AMPK) in a model of HF to test for improvements. The pan-AMPK activator PF-739 resulted in activation of AMPK, phosphorylation of the downstream target ACC, and increases in glucose uptake after a single dose in vivo. PF-739 resulted in an increase in the gene expression of relevant transcriptional regulators PGC1α and NR4a1, suggesting potential for beneficial effects on substrate metabolism in a HF model. PF-739 and the ACE inhibitor Enalipril were used in a combined TAC/MI model of mouse HF. 4 weeks after injury the animals treated with PF-739 had an increase in end systolic and diastolic volume and ejection fraction compared to vehicle animals. Enalipril treatment resulted in modest improvements in echo heart assessments and a reduction in heart weight compared to vehicle animals. To understand the mechanism for impaired heart function in HF we assessed the impact of PF-739 on systemic blood pressure, reasoning this could impact HF progression in the model. PF-739 caused an increase in blood pressure after acute dosing in mice and rats. A small molecule analogue of PF-739 differing in one methyl group with dramatically reduced AMPK activity was shown to have no detectable blood pressure effect, suggesting the blood pressure effects are related to AMPK activity. Contrary to expectation, treatment with PF-739 caused impairment in heart function in a mouse model of HF, an effect that may be the result of a systemic blood pressure effect of the compound.
Abstract 802: Cardiomyocyte-derived Exosomal MicroRNAs Regulates Post-Infarction Inflammation and Myofibroblast Phenoconversion
Authors: Gaetano Santulli, Celestino Sardu, Jun Shu, Alessandro Matarese, Xujun Wang
Journal: Circulation Research (2019)

Background: The inclusion of microRNAs (miRNAs) in extracellular microvesicles/exosomes (named cardiosomes when deriving from cardiomyocytes) allows their active transportation and ensures cell-cell communication. Aim: We hypothesize that cardiosomal miRNAs play a pivotal role in the activation of myofibroblasts following ischemic injury. Methods: Using bioinformatic approaches and an established murine model of myocardial infarction (MI, achieved via ligation of the left anterior descending coronary artery), we tested our hypothesis by measuring in isolated fibroblasts and cardiosomes the expression levels of a set of miRNAs, upregulated in cardiomyocytes post-MI and involved in myofibroblast phenoconversion. Results: We found that miR-92a and miR-195 were significantly upregulated (absolute values) in cardiosomes as well as in fibroblasts isolated at different time points after MI compared with SHAM conditions. These miRs were demonstrated to be both predicted (bioinformatics) and biologically validated (luciferase assays) targets of SMAD7. Moreover, primary isolated cardiac fibroblasts were activated both when incubated with cardiosomes isolated from ischemic cardiomyocytes and when cultured in conditioned medium of post-MI cardiomyocytes, whereas no significant effects were observed following incubation with cardiosomes or medium from sham cardiomyocytes. Myofibroblast activation was assessed measuring the expression of aSMA, periostin, collagen I/III, FAP, fibronectin ED-A. Both miRs also regulated the inflammatory response (evaluated in terms of IL-6 and CXCL1). The addition of an inhibitor of exosome release (GW4869 10 μM for 12 h) significantly attenuated all these responses. The mechanistic contribution of miR-92a and miR-195 was further confirmed using specific miR mimics and inhibitors. Conclusions: Taken together, our findings indicate for the first time that two cardiomyocyte-specific miRNAs (miR-92a and miR-195), transferred to fibroblasts in form of exosomal cargo, are essential in the activation of myofibroblasts in MI.
Elevated High Sensitivity Troponin T (HsTnT) during Front-Line Therapy with Cyclophosphamide, Doxorubicin, Vincristine and Prednisone +/- Rituximab (CHOP+/-R) or Cyclophosphamide, Epirubicin, Vincristine and Prednisone +/- Rituximab (CEpOP+/-R) Correlates with a Decline in Left Ventricular Ejection Fraction (LVEF) in Patients with Aggressive B-Cell Lymphoma: Results from a Randomized Prospective Clinical Trial NCT00854568
Authors: Kai Xue, Juan J Gu, Qunling Zhang, Xiaojian Liu, Jiachen Wang, Jianfeng Luo, Francisco J. Hernandez-Ilizaliturri, Stanley F. Fernandez, Myron S. Czuczman, Junning Cao, Xiaonan Hong, Ye Guo
Journal: Blood (2014)