tbuckley/cabot-search huggingface dataset:
Toward Automated Insulin Delivery
Authors: Daniela Bruttomesso
Journal: New England Journal of Medicine (2019)

For patients with type 1 diabetes, achieving the glycemic target recommended by the American Diabetes Association remains challenging, despite the use of insulin pumps, sensors for continuous glucose monitoring, the combination of these technologies (sensor-augmented pump), and systems that automatically suspend insulin delivery when glucose values fall below or are about to reach a prespecified threshold (low-glucose and predicted-low-glucose suspend features, respectively).1 The artificial pancreas, also called the closed-loop system, is a further step toward automated insulin delivery, addressing both hypoglycemia and hyperglycemia. It consists of an insulin pump, a glucose sensor, and an algorithm that continuously modifies the rate . . .
Abstract 408: <i>Mir148a</i> Family Regulates Cardiac Differentiation of Human Embryonic Stem Cells by Inhibiting The <i>Dll1</i> -mediated Notch Signaling Pathway
Authors: Shumei Miao, Xing Fang, You Yu, Xinglong Han, Hongchun Wu, Zhen-Ao Zhao, Yongming Wang, Wei Lei, Shijun Hu
Journal: Circulation Research (2019)

Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) can differentiate into spontaneously beating cardiomyocytes in vitro, and hold great promise for cardiovascular disease modeling, therapy and drug discovery. However, these applications were hampered by low yield and purity of the in vitro differentiated cardiomyocytes. Although miRNAs represent a type of potential candidates to promote cardiac differentiation, most of cardiomyocyte-enriched miRNAs have not been functionally investigated until now. This study investigated the roles of MIR148A family in cardiac differentiation from hESCs. The MIR148A family is composed of MIR148A , MIR148B and MIR152 , three highly conserved miRNAs sharing same seed sequences. The expression levels of all MIR148A family members were progressively increased during cardiac differentiation in vitro. By using CRISPR-Cas9-mediated knockout, we demonstrated that triple knockout of MIR148A family ( MIR148A -TKO), rather than individual knockout of each members, could grossly inhibited TNNT2 + cardiomyocyte generation. Ectopic expression of MIR152 significantly restored the cardiac differentiation efficiency of MIR148A -TKO hESCs. The transcriptome analysis identified a total of 1071 upregulated genes and 766 down-regulated genes in the MIR148A -TKO hESC-derived cells compared to wild-type hESC-derived cells at day 4 of cardiac differentiation. Gene Ontology analysis revealed that most genes down-regulated in MIR148A -TKO hESC-derived cells were involved in the events of lateral/cardiac mesoderm development, while the up-regulated genes were mainly involved in the events of paraxial/somitic development. Furthermore, the NOTCH ligand Delta-like1 ( DLL1 ) was validated as the target gene of MIR148A family, and the knockdown of DLL1 could inhibit target gene expression of Notch signaling pathway, and promote cardiac differentiation of MIR148A -TKO hESCs. Our findings demonstrate a new function of MIR148A family during cardiac differentiation. Synergistic inhibition of DLL1 -mediated Notch signaling represents a major mechanism for the MIR148A family to inhibit undesired lineage formation and promote hESC differentiation into cardiomyocytes.
Bone and Soft‐Tissue Sarcoma Risk in Long‐Term Survivors of Hereditary Retinoblastoma Treated With Radiation
Authors: Ruth A. Kleinerman, Sara J. Schonfeld, Byron S. Sigel, Jeannette R. Wong-Siegel, Ethel S. Gilbert, David H. Abramson, Johanna M. Seddon, Margaret A. Tucker, Lindsay M. Morton
Journal: Journal of Clinical Oncology (2019)

PURPOSE Survivors of hereditary retinoblastoma have excellent survival but substantially increased risks of subsequent bone and soft-tissue sarcomas, particularly after radiotherapy. Comprehensive investigation of sarcoma risk patterns would inform clinical surveillance for survivors. PATIENTS AND METHODS In a cohort of 952 irradiated survivors of hereditary retinoblastoma who were originally diagnosed during 1914 to 2006, we quantified sarcoma risk with standardized incidence ratios (SIRs) and cumulative incidence analyses. We conducted analyses separately for bone and soft-tissue sarcomas occurring in the head and neck (in/near the radiotherapy field) versus body and extremities (out of field). RESULTS Of 105 bone and 124 soft-tissue sarcomas, more than one half occurred in the head and neck (bone, 53.3%; soft tissue, 51.6%), one quarter in the body and extremities (bone, 29.5%; soft tissue, 25.0%), and approximately one fifth in unknown/unspecified locations (bone, 17.1%; soft tissue, 23.4%). We noted substantially higher risks compared with the general population for head and neck versus body and extremity tumors for both bone (SIR, 2,213; 95% CI, 1,671 to 2,873 v SIR, 169; 95% CI, 115 to 239) and soft-tissue sarcomas (SIR, 542; 95% CI, 418 to 692 v SIR, 45.7; 95% CI, 31.1 to 64.9). Head and neck bone and soft-tissue sarcomas were diagnosed beginning in early childhood and continued well into adulthood, reaching a 60-year cumulative incidence of 6.8% (95% CI, 5.0% to 8.7%) and 9.3% (95% CI, 7.0% to 11.7%), respectively. In contrast, body and extremity bone sarcoma incidence flattened after adolescence (3.5%; 95% CI, 2.3% to 4.8%), whereas body and extremity soft-tissue sarcoma incidence was rare until age 30, when incidence rose steeply (60-year cumulative incidence, 6.6%; 95% CI, 4.1% to 9.2%), particularly for females (9.4%; 95% CI, 5.1% to 13.8%). CONCLUSION Strikingly elevated bone and soft-tissue sarcoma risks differ by age, location, and sex, highlighting important contributions of both radiotherapy and genetic susceptibility. These data provide guidance for the development of a risk-based screening protocol that focuses on the highest sarcoma risks by age, location, and sex.
Extracellular Trap‐Mimicking DNA‐Histone Mesostructures Synergistically Activate Dendritic Cells
Authors: Priyan D. Weerappuli, Cameron Louttit, Taisuke Kojima, Luke Brennan, Srilakshmi Yalavarthi, Yao Xu, Lukasz J. Ochyl, Midori L. Maeda, Hong Sun Kim, Jason S. Knight, Shuichi Takayama, James J. Moon
Journal: Advanced Healthcare Materials (2019)

Abstract Extracellular traps (ETs), such as neutrophil extracellular traps, are a physical mesh deployed by immune cells to entrap and constrain pathogens. ETs are immunogenic structures composed of DNA, histones, and an array of variable protein and peptide components. While much attention has been paid to the multifaceted function of these structures, mechanistic studies of ETs remain challenging due to their heterogeneity and complexity. Here, a novel DNA‐histone mesostructure (DHM) formed by complexation of DNA and histones into a fibrous mesh is reported. DHMs mirror the DNA‐histone structural frame of ETs and offer a facile platform for cell culture studies. It is shown that DHMs are potent activators of dendritic cells and identify both the methylation state of DHMs and physical interaction between dendritic cells and DHMs as key tuning switches for immune stimulation. Overall, the DHM platform provides a new opportunity to study the role of ETs in immune activation and pathophysiology.
Early-life inhalant allergen exposure, filaggrin genotype, and the development of sensitization from infancy to adolescence
Authors: Angela Simpson, Helen A. Brough, Sadia Haider, Danielle Belgrave, Clare S. Murray, Adnan Custovic
Journal: Journal of Allergy and Clinical Immunology (2019)

BackgroundWe hypothesized that filaggrin (FLG) loss-of-function mutations modify the effect of allergen exposure on the development of allergic sensitization.ObjectiveWe sought to determine whether early-life exposure to inhalant allergens increases the risk of specific sensitization and whether FLG mutations modulate these odds.MethodsIn a population-based birth cohort we measured mite, cat, and dog allergen levels in dust samples collected from homes within the first year of life. Sensitization was assessed at 6 time points between infancy and age 16 years. Genotyping was performed for 6 FLG mutations.ResultsIn the longitudinal multivariable model (age 1-16 years), we observed a significant interaction between FLG and Fel d 1 exposure on cat sensitization, with the effect of exposure being significantly greater among children with FLG mutations compared with those without (odds ratio, 1.36; 95% CI, 1.02-1.80; P = .035). The increase in risk of mite sensitization with increasing Der p 1 exposure was consistently greater among children with FLG mutations, but the interaction did not reach statistical significance. Different associations were observed for dogs: there was a significant interaction between FLG and dog ownership, but the risk of sensitization to any allergen was significantly lower among children with FLG mutations who were exposed to a dog in infancy (odds ratio, 0.16; 95% CI, 0.03-0.86; P = .03).ConclusionsFLG loss-of-function mutations modify the relationship between allergen exposure and sensitization, but effects differ at different ages and between different allergens.Graphical abstract
Racial/ethnic disparities in childhood cancer survival in the United States: Mediation effects of health insurance coverage and area-level social deprivation.
Authors: Jingxuan Zhao, Xuesong Han, Zhiyuan Zheng, Leticia Maciel Nogueira, Paul C. Nathan, Amy Lu, K Robin Yabroff
Journal: Journal of Clinical Oncology (2019)

143 Background: Childhood cancer survival varies by race/ethnicity in the United States. This study evaluated the impact of potentially modifiable characteristics - health insurance and area-level social deprivation - on racial/ethnic disparities in childhood cancer survival nationwide. Methods: We identified 65,113 childhood cancer patients aged &lt; 18 years newly diagnosed with any of 10 common cancer types (e.g. central nervous system (CNS) neoplasms, acute lymphoblastic leukemia (ALL), Hodgkin lymphoma) from the 2004-2014 National Cancer Database. Cox proportional hazard models were used to compare survival probabilities by race and ethnicity (non-Hispanic white (NHW) vs non-Hispanic black (NHB), Hispanic, and non-Hispanic other (NH other)) for each cancer type. We conducted mediation analyses by the mma R package to evaluate the racial/ethnic survival disparities mediated by health insurance (private, Medicaid, and uninsured) and social deprivation index (SDI) quartile. SDI is a composite measure of deprivation based on seven characteristics (e.g. income, education, employment). Results: Compared to NHW, worse survival were observed for NHB (HR (hazard ratio): 1.4, 95% CI: 1.3-1.5), Hispanic (HR: 1.2, 95% CI: 1.1-1.2), and NH other (HR: 1.2, 95% CI: 1.1-1.3) for all cancer sites combined after adjusting for sociodemographic characteristics other than health insurance and SDI. Health insurance explained 20% of the survival disparities and SDI explained 19% of the disparity between NHB vs NHW; health insurance explained 48% of the survival disparities and SDI explained 45% of the disparity between Hispanic vs NHW. For ALL, health insurance significantly explained 15% and 18% of the survival disparities between NHB and Hispanic vs NHW, respectively. SDI significantly explained 19% and 31% of the disparities, respectively. Conclusions: Health insurance and SDI mediated racial/ethnic survival disparities for several childhood cancers. Expanding insurance coverage and improving healthcare access in disadvantaged areas may effectively reduce disparities for these cancer sites.
Utilizaton of patient reported outcomes measures (PROM) to characterize symptom burden and adherence associated with oral oncolytic therapy.
Authors: Emily R. Mackler, Taylor Weis, Kelly Marie Procailo, Vincent D. Marshall, Karen B. Farris
Journal: Journal of Clinical Oncology (2019)

210 Background: The use of patient reported outcome measures (PROMs) to monitor cancer treatment tolerability has been shown to positively impact outcomes. The purpose of this study was to characterize the incidence and severity of side effects, patient self-management confidence, and medication adherence in patients receiving oral oncolytic therapy. Methods: This multicenter, cross-sectional, observational study was conducted across 6 Michigan oncology practices from July 2016-December 2018. Patients were eligible to complete PROMs during the course of their treatment if they were receiving an oral oncolytic medication (excluding endocrine therapy). Results: There were a total of 2252 PROMs completed in 695 patients. Patients were 48% female, a median age of 69 years, and most commonly receiving treatment with capecitabine (18%), palbociclib (10%), and lenalidomide (9%). 54% of PROMs had at least one Edmonton Symptom Assessment Scale (ESAS) symptom rated as moderate or severe. Patients indicated the presence of a most bothersome symptom (MBS) in 35% of PROMs. Most common MBSs were fatigue (26%), pain (16%), constitutional symptoms other than fatigue (15%), and nausea/vomiting (14%). Non-adherence was reported in 20% of PROMs. ESAS symptoms rated as moderate or severe, the presence of a MBS, and lower confidence scores all correlated with medication non-adherence. Conclusions: Patients taking oral oncolytics for their cancer treatment experience a high symptom burden with more than 50% experiencing a moderate to severe symptom. Optimizing symptom management and providing patient education that increases patient confidence in self-management may improve medication adherence and patient outcomes.
Low Vs. High Intensity BEAM Prior To Autologous Hematopoietic Cell Transplantation For Chemosensitive Lymphoma Patients - A Matched Cohort Analysis
Authors: Galit Perez Avraham, Moshe Yeshurun, Itai Levi, Corina Hershcovici, Ory Rouvio, Oleg Pikovsky, Ofer Shpilberg, Ron Ram
Journal: Blood (2013)
Correcting the Conclusion in a Study of Frameworks for Measurement of Absolute or Relative Clinical Survival Benefit
Authors: Urania Dafni, Nathan I. Cherny, Elisabeth G. E. de Vries
Journal: JAMA Oncology (2019)

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D-Dimer Levels and Risk of Recurrence Following Provoked Venous Thromboembolism: Findings from the Riete Registry
Authors: Martin Ellis, Martin Mar, Monreal Manuel, Orly Hamburger-Avnery, Alessandra Bura-Riviere, Giovanni Barillari, Lucia Mazzolai, Isabelle Mahe, Pablo Javier Marchena, Peter Verhamme
Journal: Blood (2018)
Abstract 151: Organized 3D Neo-Angiogenic and Neo-Lymphangiogenic Vascular Networks for Cardiac Regeneration
Authors: Xi Lou, Valarmathi T Thiruvanamalai, Jianyi Zhang
Journal: Circulation Research (2019)

Introduction: Cardiovascular tissue engineering has been an area of intense investigation. The major challenge to these approaches has been the inability to vascularize and perfuse the in vitro engineered tissue constructs. Engineering a tissue of clinically relevant magnitude requires the formation of extensive and stable microvascular networks within the tissue. Hypothesis: Functional vascularized cardiac graft can be generated by the interaction of multipotent human mesenchymal stem cells (hMSCs) and human induced pluripotent stem cell-derived embryonic cardiac myocytes (hiPSC-eCMs) in a 3D collagen cell carrier (CCC) scaffold. Methods and Results: To achieve the above aim, we have developed an in vitro 3D functional vascularized cardiac muscle construct using hiPSC-eCMs and hMSCs. Initially, to generate the prevascularized scaffold, human cardiac microvascular endothelial cells (hCMVECs) and hMSCs were co-cultured on CCCs for 7 days under vasculogenic culture conditions. hCMVECs/hMSCs underwent maturation and differentiation characteristic of microvessel morphogenesis and formed extensive plexuses of capillary networks. Next, the hiPSC-eCMs and hMSCs were co-cultured onto these generated prevascularized CCCs for further 7 or 14 days in myogenic culture conditions. hiPSC-eCMS/hMSCs underwent maturation and differentiation, and demonstrated spontaneous rhythmic beating. The vascular and cardiac phenotypic inductions were analyzed at the morphological, immunological, biochemical, molecular and functional levels. Expression analyses of the differentiated cells revealed neo-angiogenesis and/or neo-lymphangiogenesis as well as neo-cardiomyogenesis. Conclusions: Our unique 3D co-culture system provides us the apt in vitro functional prevascularized 3D cardiac graft that can be utilized for myocardial repair and/or regeneration.
A regimen containing bedaquiline and delamanid compared to bedaquiline in patients with drug-resistant tuberculosis
Authors: Olatunde Olayanju, Aliasgar Esmail, Jason Limberis, Keertan Dheda
Journal: European Respiratory Journal (2019)

There are limited data on combining delamanid and bedaquiline in drug-resistant tuberculosis (DR-TB) regimens. Prospective long-term outcome data, including in HIV-infected persons, are unavailable. We prospectively followed up 122 South African patients (52.5% HIV-infected) with DR-TB and poor prognostic features between 2014 and 2018. We examined outcomes and safety in those who received a bedaquiline-based regimen (n=82) compared to those who received a bedaquiline–delamanid combination regimen (n=40). There was no significant difference in 6-month culture conversion (92.5% versus 81.8%; p=0.26) and 18-month favourable outcome rate (63.4% versus 67.5%; p=0.66) in the bedaquiline versus the bedaquiline–delamanid combination group, despite the latter having more advanced drug resistance (3.7% versus 22.5% resistant to at least five drugs; p=0.001) and higher pre-treatment failure rates (12.2% versus 52.5% with pre-treatment multidrug-resistant TB therapy failure; p&lt;0.001). Although the proportion of prolongation of the QT interval corrected using Fridericia's formula was higher in the combination group (&gt;60 ms from baseline (p=0.001) or &gt;450 ms during treatment (p=0.001)), there were no symptomatic cases or drug withdrawals in either group. Results were similar in HIV-infected patients. A bedaquiline–delamanid combination regimen showed comparable long-term safety compared to a bedaquiline-based regimen in patients with DR-TB, irrespective of HIV status. These data inform regimen selection in patients with DR-TB from TB-endemic settings.
Abstract 803: Sepsis-induced Acute Heart Failure is Driven by MEF2D-dependent Transcription
Authors: Richard Schell, Felix Alban, Clemens Haslinger, Philipp Theis, Hugo A Katus, Johannes Backs
Journal: Circulation Research (2019)

Rationale: Our recent work unmasked an unexpected link between inflammation and adverse cardiac remodeling via activation of the transcription factor myocyte enhancer factor 2 (MEF2). We identified a signaling pathway consisting of PGE2, EP3-receptors, PKD and Rac1 leading to a nucleo-cytoplasmic shuttling of HDAC5 with subsequent activation of MEF2. Here, we aimed to elucidate the in vivo role of MEF2 in a model of acute inflammatory cardiomyopathy. Results: Exposure of BALB/c-mice to 7 mg/kg from E. coli derived lipopolysaccharide (LPS) led to severe depression of left-ventricular function and was accompanied by considerably increased levels of PGE2. Strikingly, cardiac myocyte-specific MEF2D deficient mice (MEF2D-KO) were largely protected from LPS-induced acute heart failure, as documented by preserved ejection fraction (LVEF after 24 hours: 49% in contrast to 31% in LPS-treated littermates). Moreover, expression of typical target genes of MEF2 (e.g. Myomaxin) were attenuated in MEF2D-KO, confirming that the loss of MEF2D contributed to reduced MEF2 activity. A cardiomyocyte-specific unbiased transcriptome-sequencing in the early stage of inflammation-induced acute heart failure revealed new MEF2D-dependent genes. Conclusion: Thus, we provide new conceptual insights into inflammation-induced acute heart failure and provide evidence that the transcription factor MEF2D mediates acute contractile dysfunction. We therefore propose that transcriptional therapies might represent a novel approach to combat not only chronic but also acute heart failure.
Cyclosporine May Inhibit the Effect of Extra-Physiologic Oxygen Shock/Stress on Peripheral Blood Stem Cells
Authors: Amro Elshoury, Hans Minderman, Alexis Conway, Paul K. Wallace, Charlie Mantel, Joseph Dennis Tario, Yeong Choi, Kieran O'Loughin, Carlos Cedeno, Jenna Nichols, Kahteong Soh, Philip L. McCarthy, George Chen
Journal: Blood (2018)
Rituximab for Immune Thrombocytopenia: A Retrospective Analysis on the Role of Prophylaxis Against Pneumocystis Jirovecii and Herpes Zoster Virus
Authors: Simona Raso, Mariasanta Napolitano, Melania Carlisi, Salvatrice Mancuso, Marco Santoro, Sergio Siragusa
Journal: Blood (2018)