tbuckley/cabot-search huggingface dataset:
Amelioration of Ductular Reaction by Stem Cell Derived Extracellular Vesicles in MDR2 Knockout Mice via Lethal‐7 microRNA
Authors: Kelly McDaniel, Nan Wu, Tianhao Zhou, Li Huang, Keisaku Sato, Julie Venter, Ludovica Ceci, Demeng Chen, Sugeily Ramos‐Lorenzo, Pietro Invernizzi, Francesca Bernuzzi, Chaodong Wu, Heather Francis, Shannon Glaser, Gianfranco Alpini, Fanyin Meng
Journal: Hepatology (2019)

Cholangiopathies are diseases that affect cholangiocytes, the cells lining the biliary tract. Liver stem cells (LSCs) are able to differentiate into all cells of the liver and possibly influence the surrounding liver tissue by secretion of signaling molecules. One way in which cells can interact is through secretion of extracellular vesicles (EVs), which are small membrane-bound vesicles that contain proteins, microRNAs (miRNAs), and cytokines. We evaluated the contents of liver stem cell-derived EVs (LSCEVs), compared their miRNA contents to those of EVs isolated from hepatocytes, and evaluated the downstream targets of these miRNAs. We finally evaluated the crosstalk among LSCs, cholangiocytes, and human hepatic stellate cells (HSCs). We showed that LSCEVs were able to reduce ductular reaction and biliary fibrosis in multidrug resistance protein 2 (MDR2)-/- mice. Additionally, we showed that cholangiocyte growth was reduced and HSCs were deactivated in LSCEV-treated mice. Evaluation of LSCEV contents compared with EVs derived from hepatocytes showed a large increase in the miRNA, lethal-7 (let-7). Further evaluation of let-7 in MDR2-/- mice and human primary sclerosing cholangitis samples showed reduced levels of let-7 compared with controls. In liver tissues and isolated cholangiocytes, downstream targets of let-7 (identified by ingenuity pathway analysis), Lin28a (Lin28 homolog A), Lin28b (Lin28 homolog B), IL-13 (interleukin 13), NR1H4 (nuclear receptor subfamily 1 group H member 4) and NF-κB (nuclear factor kappa B), are elevated in MDR2-/- mice, but treatment with LSCEVs reduced levels of these mediators of ductular reaction and biliary fibrosis through the inhibition of NF-κB and IL-13 signaling pathways. Evaluation of crosstalk using cholangiocyte supernatants from LSCEV-treated cells on cultured HSCs showed that HSCs had reduced levels of fibrosis and increased senescence. Conclusion: Our studies indicate that LSCEVs could be a possible treatment for cholangiopathies or could be used for target validation for future therapies.
Sensitization to food allergens in allergic asthmatic patients: association between cockroach and shrimp sensitization
Authors: Raisa Borges Castro, Gabriella M.F.S. Dias, Joao Paulo de Assis, Rebeca M. Brugnolli, Jorge Kalil, Pedro Giavina-Bianchi, Rosana C. Agondi
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 18108: A Rapid Effect of Rosuvastatin and Atorvastatin on Myocardial Damage, as Measured by High Sensitivity Cardiac Troponin-I in Subjects With Stable Cardiovascular Disease, Results From the RADAR Substudy
Authors: Mathijs C Bodde, Paul Welsh, Sandrin C Bergheanu, Willem M Lijfering, Bart Mertens, Anho Liem, Naveed Sattar, Wouter J Jukema
Journal: Circulation (2017)

Introduction: Elevated troponin within the normal range is an emerging independent predictor of cardiovascular (CV) mortality. Recently, a randomized trial showed that troponin levels were lowered ...
Circulating proteomic panels for diagnosis and risk stratification of acute-on-chronic liver failure in patients with viral hepatitis B
Authors: Zeyu Sun, Xiaoli Liu, Daxian Wu, Hainv Gao, Jing Jiang, Ying Yang, Jie Wu, Qikang Gao, Jie Wang, Zhengyi Jiang, Youping Xu, Xiao Xu, Lanjuan Li
Journal: Theranostics (2019)

Chronic HBV infection (CHB) can lead to acute-on-chronic liver failure (HBV-ACLF) characterized by high mortality.This study aimed to reveal ACLF-related proteomic alterations, from which protein based diagnostic and prognostic scores for HBV-ACLF were developed.Methods: Ten healthy controls, 16 CHB, and 19 HBV-ACLF according to COSSH (Chinese group on the study of severe hepatitis B) criteria were enrolled to obtain the comprehensive proteomic portrait related to HBV-ACLF initiation and progression.Potential markers of HBV-ACLF were further selected based on organ specificity and functionality.An additional cohort included 77 healthy controls, 92 CHB and 71 HBV-ACLF was used to validate the proteomic signatures via targeted proteomic assays.Results: Significant losses of plasma proteins related to multiple functional clusters, including fatty acid metabolism/transport, immuno-response, complement and coagulation systems, were observed in ACLF patients.In the validation study, 28 proteins were confirmed able to separate ACLF, CHB patients.A diagnostic classifier P4 (APOC3, HRG, TF, KLKB1) was built to differentiate ACLF from CHB with high accuracy (auROC = 0.956).A prognostic model P8 (GC, HRG, HPR, SERPINA6, age, NEU, INR and total protein) was built to distinguish survivors from non-survivors in 28 and 90-days follow-up (auROC = 0.882, 0.871), and to stratify ACLF patients into risk subgroups showing significant difference in 28 and 90-days mortality (HR=7.77,7.45, both P<0.0001).In addition, P8 score correlated with ACLF grades and numbers of extra-hepatic organ failures in ACLF patients, and was able to predict ACLF-associated coagulation and brain failure within 90 days (auROC = 0.815, 0.842).Conclusions: Proteomic signatures developed in this study reflected the deficiency of key hematological functions in HBV-ACLF patients, and show potential for HBV-ACLF diagnosis and risk prediction in complementary to current clinical based parameters.
Abstract 17759: Bone Morphogenetic Protein 2/4 Stimulate Dendritic and T Cell Inflammatory Responses in Atherosclerosis
Authors: Jorge A Scutti
Journal: Circulation (2014)

Our previous results (Sato et al., Atherosclerosis, 2014) showed that Bone Morphogenetic Proteins (BMP) 2 and 4 and their endogenous antagonist, Gremlin, are overexpressed in human and animal ather...
Anti-EGF Receptor Aptamer-Guided Co-Delivery of Anti-Cancer siRNAs and Quantum Dots for Theranostics of Triple-Negative Breast Cancer
Authors: Min Woo Kim, Hwa Yeon Jeong, Seong Jae Kang, In Ho Jeong, Moon Jung Choi, Young Myoung You, Chan Su Im, In Ho Song, Tae Sup Lee, Jin Suk Lee, Aeju Lee, Yong Serk Park
Journal: Theranostics (2019)

Many aptamers have been evaluated for their ability as drug delivery vehicles to target ligands, and a variety of small interfering RNAs (siRNAs) have been tested for their anti-cancer properties.However, since these two types of molecules have similar physicochemical properties, it has so far been difficult to formulate siRNA-encapsulating carriers guided by aptamers.Here, we propose aptamer-coupled lipid nanocarriers encapsulating quantum dots (QDs) and siRNAs for theragnosis of triple-negative breast cancer (TNBC).Methods: Hydrophobic QDs were effectively incorporated into lipid bilayers, and then therapeutic siRNAs were complexed with QD-lipid nanocarriers (QLs).Finally, anti-EGFR aptamer-lipid conjugates were inserted into the QLs for TNBC targeting (aptamo-QLs).TNBC-targeting aptamo-QLs were directly compared to anti-EGFR antibody-coupled immuno-QLs.The in vitro delivery of therapeutic siRNAs and QDs to target cells was assessed by flow cytometry and confocal microscopy.The in vivo targeting of siRNAs to tumors and their therapeutic efficacy were evaluated in mice carrying MDA-MB-231 tumors.Results: Both types of EGFR-targeting QLs showed enhanced delivery to target cancer cells, resulting in more effective gene silencing and enhanced tumor imaging compared to non-targeting control QLs.Moreover, combinatorial therapy with Bcl-2 and PKC-ι siRNAs loaded into the anti-EGFR QLs was remarkably effective in inhibiting tumor growth and metastasis. Conclusion:In general, the aptamo-QLs showed competitive in vivo delivery and therapeutic efficacy compared to immuno-QLs under the same experimental conditions.Our results show that the anti-EGFR aptamer-guided lipid carriers may be a potential theranostic delivery vehicle for RNA interference and fluorescence imaging of TNBCs.
Abstract 9899: Understanding the Venus and Mars Effect: Sex-Based Differences Across a Spectrum of Cardiovascular Biomarkers
Authors: Jeanney Lew, Anand Rohatgi, Darren K McGuire, Monika Sanghavi, Colby R Ayers, Maria O Gore, Jarrett D Berry, Amit Khera, James A de Lemos
Journal: Circulation (2015)

It is unknown whether sex-based differences in the prevalence and pathobiology of cardiovascular disease (CVD) can be informed by cardiovascular biomarker profiles. We analyzed sex-based differences in multiple biomarkers associated with CVD that reflect unique biological pathways, adjusting for differences in CVD risk factors and body composition. Methods: A cross-sectional analysis was performed using data from the Dallas Heart Study, a multi-ethnic probability based cohort study. Participants with existing CVD were excluded. Associations between sex and 26 distinct biomarkers were evaluated using multivariable linear regression adjusting for age, race, traditional CVD risk factors, MRI and DEXA measures of body composition and fat distribution, renal function, insulin resistance, LV mass by MRI, and menopausal status. Results: The study population included 3557 individuals, mean age 43, 56% women and 52% African American. Significant sex-based differences were seen in multiple categories of biomarkers, including lipids, adipokines, and biomarkers of inflammation, endothelial dysfunction, myocyte injury and stress, and renal dysfunction. In fully adjusted models, women had higher levels of HDL-C and HDL-p, leptin, d-dimer, osteoprotegerin (OPG), and NT-proBNP, and men had higher levels of lipoprotein-associated phospholipase A2 (LP-PLA2), monocyte chemoattractant protein-1 (MCP-1), soluble endothelial cell adhesion molecule (sESAM), symmetric dimethylarginine (SDMA), hs-cTnT, and cystatin C (Table). Conclusion: Even after accounting for sex-based differences in traditional CVD risk factors, body composition and insulin resistance, important differences in biomarker profiles exist between women and men without CVD in the population. Future studies are needed to characterize whether pathophysiological processes delineated by these biomarkers contribute to sex-based differences in the development and complications of CVD.
Predictive Response Biomarkers for BET Inhibitors in AML
Authors: Joseph J Saad, Juho Miettinen, Dimitrios Tsallos, Samuli Eldfors, Mika Kontro, Krister Wennerberg, Olli Kallioniemi, Kimmo Porkka, Jing Tang, Caroline A Heckman
Journal: Blood (2018)
Abstract 050: Phenome Wide Association Study of IL6R Variants Identifies a Drug Target for Cardiovascular Disease and Inflammation
Authors: Tianxi Cai, Yichi Zhang, Yuk-Lam Ho, Nicholas Link, Jie Huang, Yuri Ahuja, Tianrun A Cai, Jacqueline Honerlaw, Jie Huang, Lauren Costa, Jiehuan Sun, Chuan Hong, Scott Damrauer, Yan V Sun, David Gagnon, Michael Gaziano, Peter Wilson, Kelly Cho, Phillip Tsao, Christopher J O'Donnell, Katherine P Liao
Journal: Circulation (2018)

Background: Individuals with an interleukin 6 receptor (IL6R) genetic variant not on IL6R blocking therapy have biomarker profiles similar to those treated with IL6R blockers. Thus, studying whether the IL6R variant is protective for a phenotype can inform which diseases may benefit from treatment with IL6R blockade. To test this hypothesis, we performed a Phenome-Wide Association Study (PheWAS) to screen for associations between an IL6R variant and a broad range of phenotypes in the electronic health records (EHR). Methods: We studied veteran participants in the Veteran’s Affairs Million Veteran’s Project using genomic data linked to EHR. We extracted all diagnoses codes and mapped them to phenotype groups using published PheWAS methods. Routine laboratory measurements, e.g. liver function tests, were also extracted. A PheWAS was performed by constructing logistic regression models testing associations between the IL6R variant (Asp358Ala, rs2228145) and 1,866 phenotype groups; linear regression models were constructed to screen for associations between IL6R and 26 routine laboratory measurements. All models were adjusted for age, gender, and race. Significance was reported using false discovery rate ≤0.05 and Bonferroni correction. Results: We studied 342,529 participants; the minor allele frequency of the IL6R variant was 35.3%. IL6R was most strongly associated with a reduced risk of aortic aneurysm (OR 0.91-0.92, 95% CI 0.89, 0.94) (Figure 1). We observed the expected association between IL6R and reduced C-reactive protein. We also observed known side effects of IL6R blockade, elevated transaminases, as well as elevated triglycerides, an initially unexpected result in the early clinical trials. Conclusion: In this proof of concept study, we demonstrate the utility of PheWAS to inform drug effects using the largest US-based biobank study. The strong association with aortic aneurysm corresponded with the newest indication for IL6R blockade to prevent aortic aneurysms due to large vessel vasculitis.
High Resolution Donor/Recipient HLA Matching Level in Unrelated Hematopoietic Stem Cell Transplantation and Impact on the Transplant Outcome: The Italian Experience on Behalf of GITMO, IBMDR and Aibt
Authors: Alessandra Picardi, Nicoletta Sacchi, Valeria Miotti, Francesca Lorentino, Elena Oldani, Alessandro Rambaldi, Mariarosaria Sessa, Benedetto Bruno, Michela Cerno, Paolo Bernasconi, Luca Vago, William Arcese, Fabio Benedetti, Pietro Pioltelli, Lucia Farina, Giorgia Saporiti, Patrizia Chiusolo, Francesco Zallio, Franca Fagioli, Gabriele Papalinetti, Carlo Borghero, Angelo M. Carella, Franco Narni, Domenico Russo, Attilio Olivieri, Teresa Lamparelli, Giorgina Specchia, Stefano Guidi, Anna Paola Iori, Giuseppe Milone, Marco Andreani, Anna Maria Gallina, Francesca Patriarca, Sonia Mammoliti, Fabio Ciceri, Francesca Bonifazi
Journal: Blood (2018)
Bobblehead-Doll Syndrome
Authors: Nitish Agarwal, Amol Raheja
Journal: New England Journal of Medicine (2019)

A 5-year-old girl presented with a 2-year history of excessive head nodding. MRI of the head revealed a suprasellar arachnoid cyst and ventriculomegaly. A video shows the child displaying movements typical of the bobblehead-doll syndrome.
A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer
Authors: Lucia D’Amico, Ulrike Menzel, Michael Prummer, Philipp Müller, Mélanie Buchi, Abhishek Kashyap, Ulrike Haessler, Alexander Yermanos, Rémy Gébleux, Manfred Briendl, Tamara Hell, Fabian I. Wolter, Roger R. Beerli, Iva Truxova, Špíšek Radek, Tatjana Vlajnic, Ulf Grawunder, Sai Reddy, Alfred Zippelius
Journal: Journal for ImmunoTherapy of Cancer (2019)

Increasing evidence suggests that antibody-drug conjugates (ADCs) can enhance anti-tumor immunity and improve clinical outcome. Here, we elucidate the therapeutic efficacy and immune-mediated mechanisms of a novel HER2-targeting ADC bearing a potent anthracycline derivate as payload (T-PNU) in a human HER2-expressing syngeneic breast cancer model resistant to trastuzumab and ado-trastuzumab emtansine. Mechanistically, the anthracycline component of the novel ADC induced immunogenic cell death leading to exposure and secretion of danger-associated molecular signals. RNA sequencing derived immunogenomic signatures and TCRβ clonotype analysis of tumor-infiltrating lymphocytes revealed a prominent role of the adaptive immune system in the regulation of T-PNU mediated anti-cancer activity. Depletion of CD8 T cells severely reduced T-PNU efficacy, thus confirming the role of cytotoxic T cells as drivers of the T-PNU mediated anti-tumor immune response. Furthermore, T-PNU therapy promoted immunological memory formation in tumor-bearing animals protecting those from tumor rechallenge. Finally, the combination of T-PNU and checkpoint inhibition, such as α-PD1, significantly enhanced tumor eradication following the treatment. In summary, a novel PNU-armed, HER2-targeting ADC elicited long-lasting immune protection in a murine orthotopic breast cancer model resistant to other HER2-directed therapies. Our findings delineate the therapeutic potential of this novel ADC payload and support its clinical development for breast cancer patients and potentially other HER2 expressing malignancies.
Abstract 19672: Contemporary Outcomes of Cardioembolic Stroke in the United States
Authors: Sami Aljohani, Fahad Alqahtani, Ahmad Almustafa, Ali Hama Amin, Tatiana Busu, Akram Kawsara, Mohamad Adnan Alkhouli
Journal: Circulation (2017)

Introduction: atrial fibrillation (Afib) is the main cause of Cardioembolic stroke, and has historically been associated with worse outcomes than acute ischemic stroke (AIS) of other etiologies. Method: we utilized the national inpatient sample to examine contemporary trends in the prevalence of Afib and it associated in-hospital outcomes in patients admitted with AIS. Results: between 2003-2014, 930,010 patients were admitted with AIS, of whom 168,806 (18.2%) had Afib. The prevalence of Afib among AIS patients increased by 24% (Figure 1). Patients with Afib were older (82±10 vs. 70±15 year, p<0.001), had more females (56.6% vs. 47.9%, p<0.001) and less black patients (9.1% vs. 18.8%, p<0.001). Afib patients were more likely to receive lytics and mechanical thrombectomy than non-Afib patients (5.1% vs. 3.5%, and 0.9% vs. 0.4%, p<0.001). In-hospital mortality was significantly higher in Afib patients and this was constant throughout the study period (adjusted mortality 9.9% vs. 6.1%, p<0.001). Bleeding com...
The analytic utility of distinguishing fighting from dying
Authors: Ian Grant Hansen
Journal: Behavioral and Brain Sciences (2018)

Abstract Fighting and dying, or what Whitehouse calls “out-group hostility” and “extreme self-sacrifice,” are not conceptually overlapping, but in fact are highly distinguishable, both theoretically and empirically. I present empirical evidence from a reanalysis of Ginges et al. (2009, Study 4), demonstrating the potentially inverse relationship between “parochial hostility” – fighting and “sacrificial altruism” – “and” dying.
Heat Shock Factor 1 Reprograms the DLBCL Microenvironment to Evade Immune Surveillance and Support Tumor Growth
Authors: Jude M Phillip, Maria Nieves Calvo Vidal, Maria Victoria Revuelta, Nahuel Zamponi, Stephen Sloan, Benet Pera Gresely, Tharu Fernando, Wayne Tam, Giorgio Inghirami, Lawrence Bonassar, Ari M. Melnick, Leandro Cerchietti
Journal: Blood (2018)
Quality of Life and Psychological Distress in Patients with Acute Myeloid Leukemia (AML)
Authors: Areej El-Jawahri, Lauren Waldman, Joseph Greer, Gregory A. Abel, David P. Steensma, Andrew M. Brunner, Amir T. Fathi, Daniel J. DeAngelo, Martha Wadleigh, Gabriela S. Hobbs, Philip C. Amrein, Richard M. Stone, Jennifer S Temel
Journal: Blood (2018)
Stereotactic body radiation therapy for hepatocellular carcinoma with macrovascular invasion.
Authors: Pablo Munoz-Schuffenegger, Aisling S Barry, Eshetu G. Atenafu, John Kim, James D. Brierley, Jolie Ringash, Anthony M. Brade, Robert Edward Dinniwell, Rebecca Wong, Charles Cho, Gonzalo Sapisochin, Laura A. Dawson
Journal: Journal of Clinical Oncology (2019)

428 Background: In patients with hepatocellular carcinoma (HCC), macrovascular invasion (MVI) is associated with a poor prognosis. This study describes long-term outcomes of patients with HCC and MVI treated with stereotactic body radiation therapy (SBRT). Methods: Patients with HCC and MVI who were treated with SBRT from January 2003 to December 2016 were eligible for analysis. Patients who had extrahepatic disease or who had prior liver transplant were excluded. Demographical, clinical, and treatment variables were collected, under IRB approval. The degree of vascular invasion was quantified into two categories: main portal vein branch/IVC and distal portal/hepatic vein. Results: 128 eligible pts with HCC and MVI were treated with SBRT ( &gt; 4.5 Gy/fraction). The median age was 61 yrs (range: 39 to 90 yrs). Underlying liver disease was hepatitis B in 23%, hepatitis C in 45%, other in 20%; no known liver disease in 12%. Baseline Child-Pugh (CP) score was A5 in 67%, A6 in 20%, B7 or higher in 13%. 35% received previous liver-directed therapies. Median HCC volume was 153.7 mL (range: 3.9 to 1,813.5 mL). Median AFP was 205 ug/L (range: 1 to 171,154 ug/L). Median SBRT dose was 33.3 Gy (range: 27 to 54 Gy) in 6 fractions. Local control at 1 year was 87.4% (95% CI 78.6 to 96.1%). SBRT dose or HCC volume were not significant on univariate analysis. Median overall survival was 18.3 months (95% CI 11.2 to 21.4 months). ECOG PS &gt; 1 (HR:1.73, p = 0.03), CP score (HR: 1.67, p = 0.04), and treatment between 2004 and 2010 (HR: 2.28, p = 0.0009) were significant on multivariable analysis, while SBRT dose, HCC volume, and degree of vascular invasion were not. In 35 patients who received sorafenib following SBRT, median survival was 38.5 months (95% CI 17.23 to 43.16 months). 4/128 pts. developed GI bleeding and 35/112 patients with liver function evaluable at baseline and 3 months had a deterioration in CP class. Conclusions: SBRT was associated with excellent outcomes for patients with HCC and MVI. Randomized phase III trials of SBRT are warranted and ongoing.
A Randomized, Open-label, Parallel-group Clinical Study to Evaluate the Efficacy and Safety of Omalizumab in the Treatment of Persistent Moderate and Severe Allergic Asthma and Persistent Allergic Rhinitis in Pediatric Patients 6 to 17 years of age
Authors: Socorro Orozco Martinez, Alvaro Pedroza-Meléndez, Vania Trejo-Uribe, Sandra Bautista-García, Alberto Contreras-Verduzco, Enrique Ramírez-González, Leticia Hernández-Nieto
Journal: Journal of Allergy and Clinical Immunology (2019)
Initial Results of a Phase II Study of Sequential Chemotherapy and Lenalidomide Followed By Rituximab and Lenalidomide Maintenance for Untreated Mantle Cell Lymphoma
Authors: Anita Kumar, Andrew D. Zelenetz, Connie Lee Batlevi, Philip Caron, Ahmet Dogan, Pamela Drullinsky, John Gerecitano, Audrey Hamilton, Paul A. Hamlin, Leana Laraque, Matthew J Matasar, Susan Jennifer McCall, Alison J. Moskowitz, Craig H. Moskowitz, Colette Owens, Janine Pichardo, Heiko Schoder, Allison Sigler, David J. Straus, Anas Younes
Journal: Blood (2018)