tbuckley/cabot-search huggingface dataset:
Fish Oil–Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring
Authors: Hans Bisgaard, Jakob Stokholm, Bo L. Chawes, Nadja H. Vissing, Elin Bjarnadóttir, Ann-Marie M. Schoos, Helene M. Wolsk, Tine M. Pedersen, Rebecca K. Vinding, Sunna Thorsteinsdóttir, Nilofar V. Følsgaard, Nadia R. Fink, Jonathan Thorsen, Anders G. Pedersen, Johannes Waage, Morten A. Rasmussen, Ken D. Stark, Sjurdur F. Olsen, Klaus Bønnelykke
Journal: New England Journal of Medicine (2016)

Reduced intake of n−3 long-chain polyunsaturated fatty acids (LCPUFAs) may be a contributing factor to the increasing prevalence of wheezing disorders. We assessed the effect of supplementation with n−3 LCPUFAs in pregnant women on the risk of persistent wheeze and asthma in their offspring.
Abstract 223: Histone Deacetylase Inhibition Mediated Macrophage Polarization Suppresses Matrix Metalloproteinase-9 Upregulation Post Myocardial Infarction
Authors: Denise M Kimbrough, Santhosh K Mani, Chistine B Kern, Harinath Kasiganesan, Donald R Menick
Journal: Circulation Research (2013)

Background: Following a myocardial infarction (MI) the extracellular matrix (ECM) undergoes massive remodeling to prevent rupture and maintain cardiac output. Large increases in matrix metalloproteinase-9 (MMP-9) are associated with adverse ECM remodeling. We found that treatment with an HDAC inhibitor repressed post-MI upregulation of MMP-9. Significant sources of MMP-9 in the post-MI LV are M1 macrophages. Both phenotypes (M1 and M2) can contribute to MMP expression, but this is dependant on the phase of ECM remodeling. We hypothesize that HDAC inhibition regulates the post-MI expression of MMP-9 by mediating the M1 to M2 macrophage polarization. Methods: CD1 and MMP-9 β-gal reporter mice were induced with MI by LAD ligation then administered HDAC inhibitors: trichostatin A (TSA; class I and IIb), PD106 (class I), or Tubastatin A (HDAC 6) until termination at 5 or 7 days post-MI. Heart function evaluated by echocardiogram and cells or tissue by immunohistochemistry and immunoblotting. Results: The post-MI change in LV end-diastolic volume (49±9%) is significantly lower and ejection fraction (-44±8%) is improved with treatment of TSA vs. control (69±12%; -59±6%) respectively [n=28]. Immunohistochemical analysis revealed that infiltrating macrophages express MMP-9 at 5 and 7 days post-MI. HDAC inhibition decreases this expression and did so without reducing presence of macrophages within infarct. Immunoblotting shows that expression of all class I HDACs are increased following MI; however, in cultured macrophages only HDAC2 and HDAC3 are increased. TSA and PD106, inhibit control levels and lipopolysacharide (LPS) stimulated upregulation of MMP-9 in cultured RAW264.7 and bone marrow derived macrophages. Immunofluorescence revealed that treatment with PD106, Tub A, and TSA leads to M1 to M2 morphology specific polarization and maintenance of anti-inflammatory, M2, phenotype even with LPS stimulation in culture. However, only PD106 and TSA reduced MMP-9 expression in cultured macrophages. Conclusions: Macrophage mediated secretion of MMP-9 contributes to adverse ECM remodeling and loss of LV function post-MI. Class I HDAC inhibition promotes both M2 macrophage polarization and attenuates adverse remodeling by reducing MMP-9 expression.
Hunt says health spending must rise as part of GDP over coming decades
Authors: Adrian O’Dowd
Journal: BMJ (2016)

The amount that the government spends on the NHS will have to rise in coming years as the population lives longer, grows older, and needs more care for multi-morbidities, peers have been told by England’s health secretary, Jeremy Hunt.

Hunt, appearing before the House of Lords NHS sustainability committee on 13 December during an evidence session, spoke of his views on the NHS in the long term and also said that it was time for radical thinking on how people could start saving for social care costs for their old age in the same way as saving for pensions.

Peers asked about the long term sustainability of the NHS in light of predictions …
211. CD2, the First Identified T cell Co-Stimulator, Demonstrates More Effective Chimeric Antigen Receptor Activity Over CD28 and 4-1BB
Authors: Avery D. Posey, Carl H. June
Journal: Molecular Therapy (2015)

CD2, first identified as T11 sheep erythrocyte receptor protein, was originally classified as the trigger for an alternative T cell activation pathway and later as a costimulatory molecule that synergized with CD3 activation. Co-stimulation of T cells with CD2 augments CD3-mediated signaling cascades, IL-2 production, and proliferation. The field dedicated to the development of novel second- and third-generation chimeric antigen receptors (CARs) has focused on the inclusion endodomains from CD28 superfamily and TNFRSF members as costimulation, but the use of CD2/SLAM family of costimulatory molecules has not been explored. Here, we report the development of an anti-mesothelin (SS1) chimeric antigen receptor co-stimulated with the endodomain of CD2 juxtaposed to the CD3z activation domain (SS1CD2z). Human T cells modified with SS1CD2z demonstrate comparable cytotoxicity of tumor cell lines in vitro as SS1z, SS1BBz, and SS128z. SS1CD2z T cells proliferation similar to SS128z and better than SS1BBz in vitro. SS1CD2z T cells exhibit a calcium flux in response to antigen that is half the amplitude of the response seen for SS128z, while no calcium flux is observed for SS1BBz. Similarly, all three CARs exhibit differential signaling profiles, consistent with the signaling of CD28 superfamily, TNFRSF, and CD2/SLAM superfamily pathways. Luminex analysis revealed that IL-2 production is superior among SS128z and SS1CD2z, while SS1BBz T cells produce less. IFNγ production is comparable between all CAR groups. Importantly, SS1CD2z cells produce minimal quantities TNFα similar to SS1BBz cells; contrary to SS128z cells, which produce large quantities of the neurotoxic cytokine. SS1CD2z T cells exhibited a fast and durable anti-tumor response against a subcutaneous mesothelioma xenograft model, while both SS128z and SS1BBz T cells lagged in terms of response rate. These results suggest that CAR co-stimulation via CD2 can produce potent antitumor activity, T cell proliferation and favorable cytokine profiles. Exploration of other CD2/SLAM superfamily members for CAR co-stimulation could be beneficial to cancer patients and the cellular therapy community.
A Phase I/II Study of the Combination of Oral Rigosertib and Azacitidine in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML)
Authors: Shyamala C. Navada, Guillermo Garcia-Manero, Francois Wilhelm, Katherine Hearn, Rosalie Odchimar-Reissig, Erin P. Demakos, Yesid Alvarado, Naval Daver, Courtney D. DiNardo, Marina Konopleva, Gautam Borthakur, Nozar Azarnia, Lewis R. Silverman
Journal: Blood (2014)
Abstract 2380: Integrin αv is necessary for skin tissue generation and SCC tumor invasion, but dispensable for tissue maintenance
Authors: Elizabeth K. Duperret, Ankit Dahal, Todd W. Ridky
Journal: Cancer Research (2015)

Abstract Integrin heterodimers play crucial roles in epithelial adhesion, proliferation, differentiation, wound healing and tumorigenesis. However, the effects of acute loss of many of the 26 integrin subunits in epidermis have not been determined. This information is critical since many inhibitors for specific integrin heterodimers are entering clinical trials for various cancers. We performed an shRNA-based multiplexed screen to define roles for each integrin subunit in a 3-dimensional in vitro organotypic skin model. In this screen, we transduced individual populations of human keratinocytes with shRNAs against each integrin subunit. We then quantitatively determined the fitness of each cell population in a competition assay in reconstituted human skin. This screen identified the integrin αv class of heterodimers as essential for generation of human skin tissue: the population of keratinocytes lacking αv was selected against 125-fold compared to non-silencing control cells (p&amp;lt;0.001). An identical screen in human melanocytes showed no change in fitness upon loss of integrin αv, indicating cell-intrinsic functions for this subunit. Loss of integrin αv alone in keratinocytes leads to cell cycle arrest with a 4-5 fold increase in the G1/S ratio. Surprisingly, we found that integrin αv is not localized within focal adhesions in human keratinocytes and does not control focal adhesion dynamics in this cell type. Instead, it forms an independent signaling complex at the cellular membrane that controls keratinocyte growth through a FAK c-myc signaling axis. Both FAK and c-myc total protein levels are lost upon αv knock down, and re-expression of c-myc in αv-null keratinocytes is sufficient to completely rescue the cell cycle defects and skin tissue phenotypes. The effects of integrin αv loss are dependent on αv's binding partners β5 and β6, but not β1 or β8. Using a doxycycline-inducible system, we show that αv loss plays a crucial role in tissue generation and tumor invasion, but is not necessary for epidermal tissue maintenance. Furthermore, both β5 and β6 binding partners are required for tumor invasion, thus identifying αvβ5 and αvβ6 as therapeutic targets for metastatic squamous cell carcinoma. Citation Format: Elizabeth K. Duperret, Ankit Dahal, Todd W. Ridky. Integrin αv is necessary for skin tissue generation and SCC tumor invasion, but dispensable for tissue maintenance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2380. doi:10.1158/1538-7445.AM2015-2380
228. Characterization of Hematopoietic Progenitors from Pyruvate Kinase Deficient (PKD) Patients and Transduction of PKD CD34+ Cells with a Therapeutic Lentiviral Vector
Authors: Susana Navarro, Maria Garcia-Gomez, Sergio Lopez-Manzaneda, Rebeca Sanchez-Dominguez, Maria Garcia-Bravo, Omaira Alberquilla, Maria M. Mañu, Manuela Muriel-Ramos, Joan Ll. Vives-Corrons, Julian Sevilla, Juan A. Bueren, Jose C. Segovia
Journal: Molecular Therapy (2016)

Pyruvate kinase deficiency (PKD) is an autosomal recessive disorder caused by mutations in the PKLR gene. PKD is the most common erythroid inherited enzymatic defect causing chronic non-spherocytic hemolytic anemia, high reticulocytosis, acute splenomegaly and intense iron overload in the liver, being life-threatening in severe patients. Up to date allogeneic bone marrow transplant represents the only curative treatment of patients affected by the severe form of the disease (5-10% of PKD patients aprox.). Preclinical gene therapy studies conducted in pyruvate kinase deficient mice have shown the safety and the efficacy of a new PGK-coRPK-Wpre therapeutic lentiviral vector that provided the designation by the European Medicinal Agency (EMA) of this PGK-coRPK-Wpre vector as a new orphan drug (EU/3/14/1130). To continue with the preclinical studies required to develop a clinical trial for PKD we have characterized the hematopoietic progenitor's content and the erythroid progenitors' profile in peripheral blood (PB) from PKD patients, showing an increase in both types of cells. For transduction studies, CD34+ sorted cells from PKD PB were transduced with PGK-coRPK-Wpre viral vector supernatants. Hematopoietic progenitors' content and final yield of cells and CFCs was evaluated to analyze the toxicity of the vector. Percentage of transduction ranged from 31% to 100%, showing the efficacy of the transduction protocol and of the PGK-coRPK therapeutic vector. Vector copy number was quantified in both, individual CFUs and CD34+ cells maintained in liquid culture for 14 days, ranging from 0.1 to 3.0 VCN/cells. Additional studies are being conducted to demonstrate PGK-coRPK functionality in human PKD cells.
Abstract 2029: Mcph1/Brit1 deficiency promotes genomic instability and tumor formation in a mouse model
Authors: Yulong Liang, Hong Gao, Shiaw-Yih Lin, John A. Goss, Chunying Du, Kaiyi Li
Journal: Cancer Research (2015)

Abstract MCPH1, also known as BRIT1, has recently been identified as a novel key regulatory gene of the DNA damage response pathway. MCPH1 is located on human chromosome 8p23.1, where human cancers frequently show loss of heterozygosity. As such, MCPH1 is aberrantly expressed in many malignancies, including breast and ovarian cancers, and the function of MCPH1 has been implicated in tumor suppression. However, it remains poorly understood whether MCPH1 deficiency leads to tumorigenesis. Here, we generated and studied both Mcph1−/− and Mcph1−/−p53−/− mice; we showed that Mcph1−/− mice developed tumors with long latency, and that primary lymphoma developed significantly earlier in Mcph1−/−p53−/− mice than in Mcph11+/+p53−/− and Mcph1+/−p53−/- mice. The Mcph1−/−p53−/− lymphomas and derived murine embryonic fibroblasts (MEFs) were both more sensitive to irradiation. Mcph1 deficiency resulted in remarkably increased chromosome and chromatid breaks in Mcph1−/−p53−/− lymphomas and MEFs, as determined by metaphase spread assay and spectral karyotyping analysis. Additionally, Mcph1 deficiency significantly enhanced aneuploidy as well as abnormal centrosome multiplication in Mcph1−/−p53−/− cells. Meanwhile, Mcph1 deficiency impaired double strand break (DSB) repair in Mcph1−/−p53−/− MEFs as demonstrated by neutral Comet assay. Compared with Mcph1+/+p53−/− MEFs, homologous recombination and non-homologous end joining activities were significantly decreased in Mcph1−/−p53−/− MEFs. Notably, reconstituted MCPH1 rescued the defects of DSB repair and alleviated chromosomal aberrations in Mcph1−/−p53−/- MEFs. Taken together, our data demonstrate MCPH1 deficiency promotes genomic instability and increases cancer susceptibility. Our study using knockout mouse models provides convincing genetic evidence that MCPH1 is a bona fide tumor suppressor gene. Its deficiency leading to defective DNA repair in tumors can be utilized to develop novel targeted cancer therapies in the future. Citation Format: Yulong Liang, Hong Gao, Shiaw-Yih Lin, John A. Goss, Chunying Du, Kaiyi Li. Mcph1/Brit1 deficiency promotes genomic instability and tumor formation in a mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2029. doi:10.1158/1538-7445.AM2015-2029
Effects of a Home-Based Exercise Intervention Program on Physical Capacity and Fatigue in Patients with Myelodysplastic Syndrome (MDS) - a Feasibility Study
Authors: Markus K Schuler, Julia Goebel, Beate Hornemann, Julia Hoffmann, Michael Kramer, Martin Bornhäuser, Gerhard Ehninger, Uwe Platzbecker
Journal: Blood (2015)
Transcriptional programs that control expression of the autoimmune regulator gene Aire
Authors: Yonatan Herzig, Shir Nevo, Chamutal Bornstein, Miriam R Brezis, Sharon Ben-Hur, Aya Shkedy, Michal Eisenberg-Bord, Ben Levi, Michael Delacher, Yael Goldfarb, Eyal David, Leehee Weinberger, Sergey Viukov, Shifra Ben-Dor, Matthieu Giraud, Jacob H Hanna, Achim Breiling, Frank Lyko, Ido Amit, Markus Feuerer, Jakub Abramson
Journal: Nature Immunology (2016)
Human Platelet Alloantigens (HPA)1, HPA2 and HPA3 SNPs in Tunisian Sickle Cell Disease Patients
Authors: Adel Driss, Karima Kacem, Nana Wilson, Jacqueline Hibbert, Tom Adamkiewicz, Beatrice E Gee, Balkis Meddeb, Jonathan K Stiles
Journal: Blood (2011)
Chronic Lymphocytic Leukemia (CLL) Signaling Profiling Identifies CLL-Specific Signaling Impairment That Discriminates CLL B-Cells From Normal Circulating B Cells
Authors: M. Lia Palomba, Kelly Piersanti, Andrew D Zelenetz, Marcel R.M. van den Brink, Gregoire Altan-Bonnet
Journal: Blood (2010)
Reduced Intensity Conditioning (RIC) Regimen Followed by Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Adult Patients with Acute Lymphoblastic Leukemia (ALL)
Authors: Leandro de Padua Silva, Rima M. Saliba, Sergio Giralt, Marcos De Lima, Chitra Hosing, Issa F Khouri, Uday Popat, Muzaffar Qazilbash, Elizabeth Shpall, Deborah A. Thomas, Hagop Kantarjian, Richard Champlin, Partow Kebriaei
Journal: Blood (2008)
FDG-PET in the Serial Assessment of Patients with Lymphoma in Complete Remission.
Authors: Pier Luigi Zinzani, Vittorio Stefoni, Valentina Ambrosini, Enrico Derenzini, Gerardo Musuraca, Enrica Marchi, Lapo Alinari, Mariapaola Fina, Monica Tani, Cinzia Pellegrini, Stefano Fanti, Michele Baccarani
Journal: Blood (2007)
Pelvic floor muscle training for secondary prevention of pelvic organ prolapse (PREVPROL): a multicentre randomised controlled trial
Authors: Suzanne Hagen, Cathryn Glazener, Doreen McClurg, Christine Macarthur, Andrew Elders, Peter Herbison, Don Wilson, Philip Toozs-Hobson, Christine Hemming, Jean Hay-Smith, Marissa Collins, Sylvia Dickson, Janet Logan
Journal: The Lancet (2016)
Treatment of Relapsed ACUTE Leukemia after ALLO-HSCT By Salvage Chemotherapy with Low-Dose Cytarabine and Aclarubicin Combined with G-CSF Priming: More Effective and LESS Toxic?
Authors: Hua Zhou, Ling Ge, Xiaming Zhu, Huiying Qiu, Zhengming Jin, Miao Miao, Chengcheng Fu, Xiao Ma, Feng Chen, Shengli Xue, Changgeng Ruan, Wu Depei, Xiaowen Tang
Journal: Blood (2014)
The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) and Survival After Extracorporeal Photopheresis, Pentostatin, and Reduced Dose Total Body Irradiation (TUFTs) Conditioning Prior to Allogeneic Stem Cell Transplantation (SCT)
Authors: Shahrukh Hashmi, Jamie L Oliva, Jane L. Liesveld, Gordon L. Phillips, Diane Nichols, Michael Becker
Journal: Blood (2010)
Women with larger social networks have better breast cancer outcomes, study finds
Authors: Jacqui Wise
Journal: BMJ (2016)

Women with breast cancer who have larger social networks have lower rates of recurrence and mortality than more socially isolated patients, a study published in the journal Cancer has found.1

The study included 9267 women with breast cancer from four prospective cohorts in the United States and China. The women were asked about the presence of a spouse or partner, religious ties, community ties, numbers of friends, and living first degree relatives within two years …
Comparison of 2 Commercially Available Next-Generation Sequencing Platforms in Oncology
Authors: Nicole M. Kuderer, Kimberly A. Burton, Sibel Blau, Andrea L. Rose, Stephanie Parker, Gary H. Lyman, C. Anthony Blau
Journal: JAMA Oncology (2016)

The growing use of next generation-sequencing to identify cancer-associated alterations as well as the increasing number of targeted drugs holds promise for better matching patients with cancer with effective therapies.The FoundationOne (F1; Foundation Medicine) test sequences clinical tumor samples to characterize the exons of 315 cancer-associated genes and introns from 28 genes involved in rearrangements.The Guardant360 (G360; Guardant Health) test uses cell-free circulating DNA from blood to sequence 70 genes.Both the F1 and G360 tests have high specificities (>99%) and somewhat lower sensitivities. 1,2However, little is known about how different next-generation sequencing tests compare when used in the same patients with cancer.We compared reports from F1 and G360 testing in 9 patients from a community oncology practice to determine the level of concordance between the platforms.Methods | This study was approved by the University of Washington Institutional Review Board.Patients consented to the study, titled "A Tumor Crowd Modeling Platform for Patients with Cancer," via an online patient information statement.Nine patients (mean [SD] age, 61 [19] years; 2 men and 7 women) underwent both F1 and G360 testing from April 14, 2015, to January 30, 2016.Patient reports from results of F1 tumor and G360 circulating tumor DNA testing were examined to generate a list of all genomic alterations detected by either assay and to assess concordance between reports.
Unique Transcriptional Programs Identify Subtypes of AKI
Authors: Katherine Xu, Paul Rosenstiel, Neal Paragas, Christian Hinze, Xiaobo Gao, Tian Huai Shen, Max Werth, Catherine Forster, Rong Deng, Efrat Bruck, Roger W. Boles, Alexandra Tornato, Tejashree Gopal, Madison Jones, Justin Konig, Jacob Stauber, Vivette D’Agati, Hediye Erdjument-Bromage, Subodh Saggi, Gebhard Wagener, Kai M. Schmidt-Ott, Nicholas Tatonetti, Paul Tempst, Juan A. Oliver, Paolo Guarnieri, Jonathan Barasch
Journal: Journal of the American Society of Nephrology (2016)

Two metrics, a rise in serum creatinine concentration and a decrease in urine output, are considered tantamount to the injury of the kidney tubule and the epithelial cells thereof (AKI). Yet neither criterion emphasizes the etiology or the pathogenetic heterogeneity of acute decreases in kidney excretory function. In fact, whether decreased excretory function due to contraction of the extracellular fluid volume (vAKI) or due to intrinsic kidney injury (iAKI) actually share pathogenesis and should be aggregated in the same diagnostic group remains an open question. To examine this possibility, we created mouse models of iAKI and vAKI that induced a similar increase in serum creatinine concentration. Using laser microdissection to isolate specific domains of the kidney, followed by RNA sequencing, we found that thousands of genes responded specifically to iAKI or to vAKI, but very few responded to both stimuli. In fact, the activated gene sets comprised different, functionally unrelated signal transduction pathways and were expressed in different regions of the kidney. Moreover, we identified distinctive gene expression patterns in human urine as potential biomarkers of either iAKI or vAKI, but not both. Hence, iAKI and vAKI are biologically unrelated, suggesting that molecular analysis should clarify our current definitions of acute changes in kidney excretory function.
Towards Phase 2/3 Trials for Epstein - Barr Virus (EBV)-Associated Malignancies,
Authors: Jun Ando, Minhtran Charlotte Ngo, Sravya Ennamuri, Jiali Sun, Helen E. Heslop, Catherine M. Bollard, Carl H. June, Ann M. Leen, Stephen Gottschalk, Cliona M. Rooney
Journal: Blood (2011)
The first‐in‐man randomized trial of a beta3 adrenoceptor agonist in chronic heart failure: the <scp>BEAT‐HF</scp> trial
Authors: Henning Bundgaard, Anna Axelsson, Jakob Hartvig Thomsen, Mathias Sørgaard, Klaus F. Kofoed, Rasmus Hasselbalch, Natasha A.S. Fry, Nana Valeur, Søren Boesgaard, Finn Gustafsson, Lars Køber, Kasper Iversen, Helge H. Rasmussen
Journal: European Journal of Heart Failure (2016)