tbuckley/cabot-search huggingface dataset:
Abstract 134: Reciprocal Cardiac Chromatin Regulation by Ctcf and Hmgb2
Authors: Manuel Rosa-Garrido, Emma Monte, Elaheh Karbassi, Haodong Chen, Christoph Rau, Jessica Wang, Aldons J Lusis, Yibin Wang, Thomas M Vondriska
Journal: Circulation Research (2015)

Chromatin remodeling plays an essential role in cardiac gene reprogramming under pathological conditions. However, we currently lack a detailed understanding of how this process is structurally coordinated across the genome. Previous RNA and proteomic analyses of an in vivo model of heart failure performed by our group identified the chromatin structural proteins CTCF and high mobility group protein B2 (HMGB2) as regulators of heart disease. CTCF is an essential factor in the maintenance of global chromatin organization through the facilitation of long-range interactions and chromatin looping. HMGB2 is a non-nucleosomal structural protein that packages nucleosomes into higher order structures. An unbiased genomic analysis of ~100 strains of mice treated with isoproterenol (ISO) followed by transcriptome and phenotype analyses revealed a general down-regulation of CTCF at the mRNA level across the different strains after ISO treatment, whereas the HMGB2 response was strongly influenced by common genetic variation (i.e. between strains). ChIP-seq data, ChIP-reChIP-PCR experiments (detection of concomitant presence of two proteins at a given locus) and immunofluorescence showed CTCF and HMGB2 bind the same regions of the genome, yet they do not physically co-localize in myocyte nuclei. Loss of HMGB2, which induces hypertrophy in myocytes, causes de-condensation of chromatin, as directly measured by micrococcal nuclease digestion; CTCF knockdown has no effect on global chromatin accessibility by this assay. Examination of other chromatin structural proteins like histone H1 suggests this interaction between CTCF and HMGB2 is specific. Lastly, we showed that CTCF and HMGB2 regulate each other’s expression as well as the transcription of cardiac hypertrophy genes and ribosomal RNA. Our data show that basal HMGB2 (but not CTCF) expression correlates with cardiac mass. The response of HMGB2 levels to heart failure stimuli is highly influenced by genetics, whereas the decrease in CTCF following (ISO) is unaffected by genetic variation. These findings reveal molecular mechanisms of chromatin compaction in cardiac cells, linking them with genetic variability, and revealing a reciprocal relationship between HMGB2 and CTCF in cardiac hypertrophy.
Higher serum 25(OH)D concentrations are associated with improved FEV<sub>1</sub>and FVC in adolescence
Authors: Claudia Flexeder, Elisabeth Thiering, Sibylle Koletzko, Dietrich Berdel, Irina Lehmann, Andrea von Berg, Barbara Hoffmann, Carl-Peter Bauer, Joachim Heinrich, Holger Schulz
Journal: European Respiratory Journal (2017)

Vitamin D plays a role in the development of the immune system and the lung, as well as in airway remodelling. Therefore, this study investigated the association between serum 25-hydroxyvitamin D (25(OH)D) concentrations and spirometric lung function parameters at age 15 years.In the German birth cohorts GINIplus and LISAplus, lung function testing by spirometry and 25(OH)D measurements were performed during the 15-year follow-up examinations. Valid lung function measurements pre- and/or post-bronchodilation and serum 25(OH)D concentrations, which were adjusted for the date of blood sampling to account for seasonal variability, were available for 2607 adolescents. Associations between 25(OH)D concentrations and spirometric parameters were analysed using generalised additive models adjusted for confounding factors.Serum 25(OH)D concentrations were significantly associated with forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC measured before bronchodilation after adjustment for potential confounders: FEV1 increased by 10 mL (95% CI 2-17), FVC by 20 mL (95% CI 12-28) and FEV1/FVC decreased by 0.177% (95% CI -0.286 to -0.067) per 10 nmol·L-1 increase in 25(OH)D concentrations. Flow rates (forced expiratory flow rates at 25, 50 and 75% of exhaled FVC (FEF25, FEF50, FEF75) and mean flow rate between 25 and 75% of FVC (FEF25-75)) were not associated with vitamin D. Similar associations were observed for lung function parameters measured after bronchodilation.Vitamin D concentrations are positively associated with volume-related lung function parameters pre- and post-bronchodilation, suggesting structural changes in peripheral airways.
PNIPAAm-co-Jeffamine® (PNJ) scaffolds as in vitro models for niche enrichment of glioblastoma stem-like cells
Authors: John M. Heffernan, James B. McNamara, Sabine Borwege, Brent L. Vernon, Nader Sanai, Shwetal Mehta, Rachael W. Sirianni
Journal: Biomaterials (2017)
Teprotumumab for Thyroid-Associated Ophthalmopathy
Authors: Terry J. Smith, George J. Kahaly, Daniel G. Ezra, James C. Fleming, Roger A. Dailey, Rosa A. Tang, Gerald J. Harris, Alessandro Antonelli, Mario Salvi, Robert A. Goldberg, James W. Gigantelli, Steven M. Couch, Erin M. Shriver, Brent R. Hayek, Eric M. Hink, Richard M. Woodward, Kathleen Gabriel, Guido Magni, Raymond S. Douglas
Journal: New England Journal of Medicine (2017)

Thyroid-associated ophthalmopathy, a condition commonly associated with Graves' disease, remains inadequately treated. Current medical therapies, which primarily consist of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin-like growth factor I receptor (IGF-IR) is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy.
Reducing Particulate Air Pollution Exposure Decreases Myocardial Ischemia, Lowers Blood Pressure, and Improves Heart Rate Variability in Patients with Coronary Heart Disease
Authors: Jeremy Langrish, Xi Li, Shengfeng Wang, Matthew Lee, Nicholas Mills, Gareth Barnes, Flemming Cassee, Jing Li, David Newby, Lixin Jiang
Journal: Circulation (2010)
A Novel Dual Monoclonal Sandwich ELISA for Human Erythroferrone
Authors: Huiling Han, Keith Westerman, Vaughn Ostland, Patrick Gutschow, Gordana Olbina, Jacqueline da Silva Guimarães, Juçara Gastaldi Cominal, Ana Maria de Souza, Ana Cristina Silva Pinto, Stefano Rivella, Yelena Ginzburg, Mark D. Fleming, Mark Westerman
Journal: Blood (2016)
Multi-omics approaches to disease
Authors: Yehudit Hasin, Marcus Seldin, Aldons Lusis
Journal: Genome biology (2017)

High-throughput technologies have revolutionized medical research. The advent of genotyping arrays enabled large-scale genome-wide association studies and methods for examining global transcript levels, which gave rise to the field of "integrative genetics". Other omics technologies, such as proteomics and metabolomics, are now often incorporated into the everyday methodology of biological researchers. In this review, we provide an overview of such omics technologies and focus on methods for their integration across multiple omics layers. As compared to studies of a single omics type, multi-omics offers the opportunity to understand the flow of information that underlies disease.
Abstract P282: Increased Nuclear Localization of Fyn May Limit the Cardioprotective Effects of Hydrogen Sulfide by Interfering with Nrf2 Signaling
Authors: Bridgette F Moody, Chad K Nicholson, Rebecca L Hood, John W Calvert
Journal: Circulation Research (2011)

Background: Hydrogen sulfide (H2S) therapy reduces myocardial infarct size by up to 56% in non-diabetic mice. Here, we sought to examine if H2S could provide cardioprotection in the setting of diabetes. Methods and Results: Diabetic mice (db/db) were subjected to 30 min of left coronary artery occlusion (LCA) followed by reperfusion for 24 hours at which time the extent of myocardial infarction was evaluated. Sodium sulfide (Na2S, 100 μ g/kg) administered at the time of reperfusion decreased infarct size relative the area-at-risk by 18% compared to vehicle treated animals (p&lt;0.001). Previously, Na2S has been shown to increase the nuclear localization of Nrf-2 and upregulates its downstream target, heme oxygenase (HO)-1, in non-diabetic mice. To investigate if this cascade contributed to the observed cardioprotection, Na2S was administered (tail vein) to non-diabetic and diabetic mice and heart tissue was excised 1 hr and 24 hrs later. One hr following the administration of Na2S, the nuclear expression of Nrf2 was increased in both groups. In contrast, Na2S only increased the expression of HO-1 (24 hrs) in the non-diabetic heart. Further studies investigating Fyn, a tyrosine kinase known to inhibit Nrf2 signaling, revealed an upregulation of nuclear Fyn expression in the diabetic heart compared to the non-diabetic heart. Conclusion: This data demonstrates the complexity of therapeutic intervention for diabetics following myocardial ischemia, as the robust cardioprotective effects of H2S in the non-diabetic state were found to be diminished in the diabetic state. This data also suggests that interference of Nrf2 signaling by Fyn may be responsible for the loss of protection.
Presence of familial colorectal cancer type X in families fulfilling Amsterdam criteria for Lynch syndrome in southern Brazil.
Authors: Patricia Ashton-Prolla, Naye Balzan Schneider, Cristina Netto, Silvia Liliana Cossio, Patricia Koehler-Santos, Luise Meurer, Joao Carlos Prolla
Journal: Journal of Clinical Oncology (2013)

e12546 Background: The clinical diagnosis of Lynch syndrome is usually established when a family fulfills the Amsterdam Criteria, and confirmed by identification of MMR deficiency and/or germline mutations in one of the MMR genes. In a subset of families with Amsterdam criteria, no evidence of DNA mismatch repair deficiency can be identified and this clinical entity has been designated “Familial Colorectal Cancer Type X (FCCTX)”. Methods: The prevalence of MMR deficiency was assessed in a group of 25 individuals with colorectal or endometrial cancer from 20 families fulfilling Amsterdam criteria in Southern Brazil. MMR deficiency was assessed by IHC testing using a panel of antibodies against MSH2, MLH1, MSH6, and PMS2. In cases showing loss of nuclear expression of MLH1, presence of the BRAF p.V600E mutation and microsatellite instability were assessed in the tumor. Results: Fourteen of the 20 families studied fulfilled Amsterdam II criteria. MMR deficiency was identified in the tumor of 11 index cases and in the remaining 9, nuclear expression of all four MMR proteins was normal, suggesting the diagnosis of FCCTX. This FCCTX phenotype was observed in both Amsterdam I and Amsterdam II families. CRC with MMR-deficiency was diagnosed at an earlier age (41.2 years) than CRC showing MMR proficiency (47.2 years), although the difference did not reach significance. Conclusions: FCCTX is a frequent differential diagnosis in hereditary colorectal cancer in patients presenting to high risk cancer genetics clinics in Southern Brazil and further molecular characterization of hereditary colorectal cancer families with these features is warranted.
The incidence of S. aureus bacteraemia in acute hospitals of the Mid-Western Area, Ireland, 2002-2004
Authors: D Whyte, R Monahan, L Boyle, B Slevin, R FitzGerald, D Barron, J De Freitas, K Kelleher
Journal: Eurosurveillance (2005)

Concerns about healthcare-associated infections and the global crisis in antimicrobial resistance has combined to accentuate the fears around so-called "superbugs". In Ireland there is no single agreed indicator regarded as a true measure of the level of methicillin resistant Staphylococcus aureus (MRSA) in hospitals. The objective of this study was to compare two crude measures of MRSA--the percentage of bacteraemia caused by MRSA and the incidence rate (per 1000 bed days used) of MRSA bacteraemia in six acute hospitals. We examined all blood cultures positive for S. aureus (methicillin sensitive and resistant) from 2002 to 2004 in the Health Service Executive (HSE) Mid-Western Area of Ireland. Hospital In-Patient Enquiry (HIPE) data was used to determine monthly in-patient bed days used. Of 245 patient episodes of bacteraemia, 119 were MRSA. The trends in the percentage of isolates that were MRSA and the incidence rate calculated were compared. The incidence rate appears to be a more reliable and robust indicator of MRSA in hospitals than the percentage. Despite many difficulties in interpreting indicators of MRSA they should not preclude the regular publication of data at least at regional level in Ireland.
Can structural priming answer the important questions about language?
Authors: Andrea E. Martin, Falk Huettig, Mante S. Nieuwland
Journal: Behavioral and Brain Sciences (2017)

Abstract Structural priming makes a valuable contribution to psycholinguistics, but it taps into implicit memory representations and processes that may differ from what is deployed during online language processing. As a result, the strength of inductive inference regarding linguistic representation is rather limited. We question whether implicit memory for language can and should be equated with linguistic representation or with language processing.
A phase I study of BPX-201 vaccine plus AP1903 for chemo-naive metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Guru Sonpavde, Thomas E. Hutson, Graeme Bolger, Lawrence Fong, Eric Jay Small, David M. Spencer, Annemarie Moseley, Kevin Mark Slawin
Journal: Journal of Clinical Oncology (2014)

TPS3132 Background: We have reported promising activity, including one RECIST PR and potential synergy with chemotherapy, in a phase I trial of 18 men with mCRPC administered BPX-101 (Bellicum Pharmaceuticals), an autologous antigen presenting cell (APC)-based vaccine, pulsed with PSMA (prostate specific membrane antigen) and transduced with an adenovirus bearing iCD40, with each dose followed by in vivo activation by dimerizer drug AP1903 infusion (Slawin KM, Sonpavde G, et al, ASCO 2011). This provided a rationale for the study of our second-generation vaccine, BPX-201, manufactured with APCs transduced with an adenoviral vector bearing genes for iMyD88/CD40, which includes signaling elements from the “universal” adjuvant adapter, MyD88 (Narayanan, et al, JCI 2011), and PSMA, and followed by AP1903 activation. Methods: A 3+3 design Phase I dose escalation trial (NCT01823978) evaluating BPX-201 plus AP1903 is ongoing for men with chemo-naive mCRPC in 2 institutions: UAB (University of Alabama, Birmingham, AL) and Baylor Sammons Cancer Center (Dallas, TX). The primary objective is to determine the safety of BPX-201 in doses of 10, 20 and 40 million cells and AP1903 when administered to patients with chemo-naive mCRPC. Six patients will be enrolled per dose cohort (total accrual=18). Secondary objectives are to evaluate efficacy with vaccine and subsequent therapy, pharmacokinetics, and circulating tumor cells for up to 2 years. Extensive immune monitoring is performed during both the vaccination phase and during subsequent therapies. Patients undergo leukapheresis once at baseline followed by therapy with cryopreserved product after 2-3 weeks given intradermally q 2 weeks x 6 doses. AP1903 is administered intravenously 24 hours after each dose of the vaccine. Radiographic evaluation is performed q 3 months or earlier, if required. Post-vaccine systemic therapy is initiated for symptomatic or radiographic progression and not for PSA progression alone. Enrollment on the lowest dose cohort (n=6) is complete without dose limiting toxicities. Cohort 2 started enrolling in January 2014. Clinical trial information: NCT01823978.
The BCR‐ABL1 transcript type influences response and outcome in<scp>P</scp>hiladelphia chromosome‐positive chronic myeloid leukemia patients treated frontline with imatinib
Authors: Fausto Castagnetti, Gabriele Gugliotta, Massimo Breccia, Alessandra Iurlo, Luciano Levato, Francesco Albano, Paolo Vigneri, Elisabetta Abruzzese, Giuseppe Rossi, Serena Rupoli, Francesco Cavazzini, Bruno Martino, Ester Orlandi, Patrizia Pregno, Mario Annunziata, Emilio Usala, Mario Tiribelli, Simona Sica, Massimiliano Bonifacio, Carmen Fava, Filippo Gherlinzoni, Monica Bocchia, Simona Soverini, Maria Teresa Bochicchio, Michele Cavo, Martinelli Giovanni, Giuseppe Saglio, Fabrizio Pane, Michele Baccarani, Gianantonio Rosti
Journal: American Journal of Hematology (2017)

The most frequent BCR‐ABL1 fusion transcripts in chronic myeloid leukemia (CML) are the e13a2 (b2a2) and the e14a2 (b3a2) ones. In the imatinib era few studies addressing the prognostic significance of the BCR‐ABL1 transcript type in early chronic phase CML have been published. Overall, these studies suggest that in e14a2 patients the response to imatinib is faster and deeper. To evaluate if the BCR‐ABL1 transcript type (e13a2 compared to e14a2) affect the response to imatinib and the clinical outcome in newly diagnosed adult CML patients, 559 patients enrolled in 3 prospective studies (NCT00514488, NCT00510926, observational study CML/023) were analyzed. A qualitative PCR was performed at baseline: 52% patients had a e14a2 transcript, 37% a e13a2 transcript, 11% co‐expressed both transcripts and 1% had other rare transcripts. The median follow‐up was 76 months (95% of the patients had at least a 5‐year observation). The complete cytogenetic response rates were comparable in e14a2 and e13a2 patients. The median time to MR 3.0 (6 and 12 months) and MR 4.0 (41 and 61 months) was significantly shorter for e14a2 patients compared to e13a2 patients, with a higher cumulative probability of MR 3.0 (88% and 83%, P &lt; .001) and MR 4.0 (67% and 52%, P = .001). The 7‐year overall survival (90% and 83%, P = .017), progression‐free survival (89% and 81%, P = .005) and failure‐free survival (71% and 54%, P &lt; .001) were significantly better in patients with e14a2 transcript. In conclusion, patients with e13a2 transcript had a slower molecular response with inferior response rates to imatinib and a poorer long‐term outcome.
Abstract 17423: Unique Features of Cortical Bone Stem Cells Associated With Enhanced Cardiac Repair
Authors: Sadia Mohsin, Thomas E Sharp, Shavonn Smith, Hajime Kubo, Remus M Berretta, Joshua M Hare, Steven R Houser
Journal: Circulation (2014)

Rationale: Adoptive transfer of bone marrow and cardiac derived stem cells (CDCs) into failing human hearts has been shown to be safe, yet these cells have induced modest improvements in myocardial function. Recently we have shown in a mouse model that cortical bone derived stem cells (CBSCs) induced a greater enhancement of cardiac function after myocardial infarction than CDCs, possibly through enhanced paracrine signaling and transdifferentiation of the transplanted cells. However, the relative reparative potential of CBSCs relative to other known stem cell types including bone marrow derived mesenchymal stem cells (MSCs) and cardiac derived stem cells (CDCs) is not known. Objective: To characterize surface marker expression, proliferation, survival and differentiation capacity of swine CBSCs relative to MSCs and CDCs. Methods and Results: CBSCs, MSCs and CDCs were isolated from cortical bone, bone marrow and heart (left ventricle) of Gottingen miniswine. CBSCs were morphologically distinct from MSCs and CDCs, with differences in length to width ratio and overall cell surface area. Cell surface marker profiling using RT-PCR analysis revealed that CBSCs express some of the classical MSC markers such as CD106, CD271, CD105, CD90, CD44 and CD29 and are negative for CD45 and CD11-b. CBSCs had an enhanced proliferation capacity versus CPCs and MSCs, measured by CyQuant assay. Concurrently CBSCs had significantly a decreased population doubling time (3.57 and 1.26 fold decrease) as compared to MSC and CDCs respectively. CBSCs were also more hydrogen peroxide stress tolerant than CSCs and MSCs as measured by Annexin-V and propidium iodide (PI) labeling using flow cytometery. A significantly greater % of CBSCs expressed markers of cardiac lineage commitment when exposed to dexamethasone than did CSCs or MSCs. Markers of cardiac lineages including GATA-4, α SMA, Troponin T, Nkx2.5, sm22 were measured with RT-PCR and immunocytochemistry. Conclusion: CBSCs have enhanced proliferative capacity, survival in oxidative stress conditions and cardiac lineage commitment versus CSCs and MSCs. These features make them a promising cell source for cardiac regeneration after myocardial infarction.
DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging
Authors: Sung-Jun Park, Oksana Gavrilova, Alexandra L. Brown, Jamie E. Soto, Shannon Bremner, Jeonghan Kim, Xihui Xu, Shutong Yang, Jee-Hyun Um, Lauren G. Koch, Steven L. Britton, Richard L. Lieber, Andrew Philp, Keith Baar, Steven G. Kohama, E. Dale Abel, Myung K. Kim, Jay H. Chung
Journal: Cell Metabolism (2017)
60 seconds on . . . cancer
Authors: Nigel Hawkes
Journal: BMJ (2017)

Tricky question to answer, which is why it’s led to a long running dispute. It all kicked off when two scientists from Johns Hopkins in Baltimore, Cristian Tomasetti and Bert Vogelstein, published a paper in Science 1 showing that two thirds of cancer causing mutations arise from copying errors when cells divide. Such errors …
Characteristics and Dissemination of Phase 1 Trials Approved by a UK Regional Office in 2012
Authors: Ayodele Odutayo, Bethan Copsey, Susan Dutton, Jonathan Cook, Sally Hopewell, Douglas G. Altman
Journal: JAMA (2017)

This study describes characteristics of phase 1 trials, frequency of harms, and communication between investigators and research ethics committees about adverse events to characterize the safety and improve the regulatory review of UK phase 1 trials.
Hepatitis B virus X protein: TRIMming antiviral defences in hepatocytes
Authors: Emmanuel Thomas
Journal: Gut (2017)

Humans and viruses have coevolved over thousands of years; however, very few viruses are able to manifest as chronic infections with most being cleared after an acute course. Consequently, success of the human species has relied on a functional immune system that is capable of fighting off most viral pathogens. The heptatitis B virus (HBV)  is one of the most successful viruses to establish chronic infection in man with over 300 million individuals currently infected worldwide and over 2 billion humans having been infected by this virus.1 These numbers underscore the tremendous ability of HBV to thwart the human immune system and establish chronic infection. In this issue of Gut , Lim et al 2 have provided evidence for a new mechanism through which HBV is able to establish and maintain chronic infection.

They specifically examine the role of the enigmatic HBx protein3 in the regulation of TRIM22, a protein that has increasingly become associated with innate antiviral responses.4 5 Previous studies have demonstrated that HBx, a virally encoded protein that plays unusual roles in its life cycle, can block the antiviral response in addition …
Financial Conflicts of Interest in Continuing Medical Education
Authors: Barbara Barnes
Journal: JAMA (2017)

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