tbuckley/cabot-search huggingface dataset:
Evaluation of Infectious Complications after Haploidentical Stem Cell Transplantation in Adult Patients with Hematologic Malignancies
Authors: Razan Mohty, Florent Malard, Annalisa Ruggeri, Eolia Brissot, Remy Duléry, Giorgia Battipaglia, Frederica Giannotti, Mohamad Mohty
Journal: Blood (2017)
Genetic determinants and epigenetic effects of pioneer-factor occupancy
Authors: Julie Donaghey, Sudhir Thakurela, Jocelyn Charlton, Jennifer S. Chen, Zachary D. Smith, Hongcang Gu, Ramona Pop, Kendell Clement, Elena K. Stamenova, Rahul Karnik, David R. Kelley, Casey A. Gifford, Davide Cacchiarelli, John L. Rinn, Andreas Gnirke, Michael J. Ziller, Alexander Meissner
Journal: Nature Genetics (2018)
Abstract 13102: Brain Angiotensin II Type1 Receptor Blockade Ameliorates the Development of Atrial Fibrillation via Sympathoinhibition Independent of Depressor Response in Hypertensive Rats
Authors: Tomomi Nagayama, Yoshitaka Hirooka, Takuya Kishi, Yasushi Mukai, Shujiro Inoue, Akiko Chishaki, Kenji Sunagawa
Journal: Circulation (2014)

Background: Previous studies demonstrated that the pathophysiology of atrial fibrillation (AF) with hypertension is associated with sympathoexcitation or the renin-angiotensin system. Conventional therapies, however, do not sufficiently prevent the development of AF. We reported that sympathoexcitation via brain angiotensin type1 receptors (AT1R) plays an important role in hypertension. Here we examined the hypothesis that brain AT1R-induced sympathoexcitation contributes to the development of AF in hypertension. Methods and Results: Sixteen-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar Kyoto rats (WKY) were divided into 4 groups and administered treatment for 2 weeks, as follows: 1) SHRSP treated with intracerebroventricular infusion (ICV) of vehicle, S-VEH; 2) SHRSP treated with ICV of the AT1R blocker, losartan (1 mg/kg/day), S-LOS; 3) SHRSP treated with oral administration of hydralazine (100 mg/L in drinking water), S-HYD; 4) WKY treated with ICV of vehicle, W-VEH. Systolic blood pressure was significantly lower in both S-LOS and S-HYD than in S-VEH (201.0±1.7 and 172.4±4.0 vs. 233.0±3.5 mmHg, n=7-8/group, respectively, P&lt;0.05). Urinary norepinephrine excretion for 24 hours as an indicator of sympathoexcitation was significantly reduced in S-LOS, but increased in S-HYD despite the larger depressor response. The induction rates of AF by transesophageal burst pacing were higher in S-VEH and S-HYD than in S-LOS and W-VEH (96±2% and 92±4% vs. 74±6% and 71±9%, n=7-8/group, respectively, p&lt;0.05). AF duration was markedly inhibited in S-LOS, but not in S-HYD (Figure). Interstitial atrial fibrosis and echocardiographic parameters did not differ among SHRSP groups. Conclusions: Blockade of brain AT1R lowered the inducibility and sustainability of AF via sympathoinhibition independent of depressor response in hypertensive rats. We conclude that brain AT1R is a potential target of treatment for AF with hypertension.
Gastrointestinal ultrasound in inflammatory bowel disease: an underused resource with potential paradigm-changing application
Authors: Robert Venning Bryant, Antony B Friedman, Emily Kate Wright, Kirstin M Taylor, Jakob Begun, Giovanni Maconi, Christian Maaser, Kerri L Novak, Torsten Kucharzik, Nathan S S Atkinson, Anil Asthana, Peter R Gibson
Journal: Gut (2018)

Evolution of treatment targets in IBD has increased the need for objective monitoring of disease activity to guide therapeutic strategy. Although mucosal healing is the current target of therapy in IBD, endoscopy is invasive, expensive and unappealing to patients. GI ultrasound (GIUS) represents a non-invasive modality to assess disease activity in IBD. It is accurate, cost-effective and reproducible. GIUS can be performed at the point of care without specific patient preparation so as to facilitate clinical decision-making. As compared with ileocolonoscopy and other imaging modalities (CT and MRI), GIUS is accurate in diagnosing IBD, detecting complications of disease including fistulae, strictures and abscesses, monitoring disease activity and detecting postoperative disease recurrence. International groups increasingly recognise GIUS as a valuable tool with paradigm-changing application in the management of IBD; however, uptake outside parts of continental Europe has been slow and GIUS is underused in many countries. The aim of this review is to present a pragmatic guide to the positioning of GIUS in IBD clinical practice, providing evidence for use, algorithms for integration into practice, training pathways and a strategic implementation framework.
New hallmark of hepatocellular carcinoma, early hepatocellular carcinoma and high-grade dysplastic nodules on Gd-EOB-DTPA MRI in patients with cirrhosis: a new diagnostic algorithm
Authors: Matteo Renzulli, Maurizio Biselli, Stefano Brocchi, Alessandro Granito, Francesco Vasuri, Francesco Tovoli, Elisa Sessagesimi, Fabio Piscaglia, Antonietta D’Errico, Luigi Bolondi, Rita Golfieri
Journal: Gut (2018)

Objective Many improvements have been made in diagnosing hepatocellular carcinoma (HCC), but the radiological hallmarks of HCC have remained the same for many years. We prospectively evaluated the imaging criteria of HCC, early HCC and high-grade dysplastic nodules (HGDNs) in patients under surveillance for chronic liver disease, using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) MRI and diffusion-weighted imaging. Design Our study population included 420 nodules &gt;1 cm in 228 patients. The MRI findings of each nodule were collected in all sequences/phases. The diagnosis of HCC was made according to the American Association for the Study of Liver Diseases (AASLD) criteria; all atypical nodules were diagnosed using histology. Results A classification and regression tree was developed using three MRI findings which were independently significant correlated variables for early HCC/HCC, and the best sequence of their application in a new diagnostic algorithm (hepatobiliary hypointensity, arterial hyperintensity and diffusion restriction) was suggested. This algorithm demonstrated, both in the entire study population and for nodules ≤2 cm, higher sensitivity (96% [95% CI 93.5% to 97.6%] and 96.6% [95% CI 93.9% to 98.5%], P&lt;0.001, respectively) and slightly lower specificity (91.8% [95% CI 88.6% to 94.1%], P=0.063, and 92.7% [95% CI 88.9% to 95.4%], P=0.125, respectively) than those of the AASLD criteria. Our new diagnostic algorithm also showed a very high sensitivity (94.7%; 95% CI 92% to 96.6%) and specificity (99.3%; 95% CI 97.7% to 99.8%) in classifying HGDN. Conclusion Our new diagnostic algorithm demonstrated significantly higher sensitivity and comparable specificity than those of the AASLD imaging criteria for HCC in patients with cirrhosis evaluated using Gd-EOB-DTPA MRI, even for lesions ≤2 cm. Moreover, this diagnostic algorithm allowed evaluating other lesions which could arise in a cirrhotic liver, such as early HCC and HGDN.
MiRNA expression profiling based identification of subclasses in adult acute myeloid leukemia
Authors: Lars Bullinger, Sandrine Sander, Karlheinz Holzmann, Annika Russ, Hans Kestler, Jonathan Pollack, Konstanze Dohner, Richard Schlenk, Hartmut Dohner
Journal: Cancer Research (2007)

2967   Acute myeloid leukemia (AML) encompasses a large number of morphologically similar but at the molecular level quite distinct variants. Recurrent cytogenetic aberrations have been shown to constitute markers of diagnostic and prognostic value. However, despite recent successes in detecting novel molecular markers like FLT3, CEBPA, and NPM1 mutations, and despite recent advances in gene expression profiling treatment stratification is still difficult and the biology underlying distinct AML subclasses is still not fully understood. Recently, deregulated-expression of microRNAs (miRNAs) has been correlated with various cancers including leukemias, and evidence was provided that miRNAs can function both as oncogenes and tumor suppressors. In order to determine a potential role of differential miRNA expression in AML we profiled miRNA expression in a large series of adult AML patients to better characterize AML on the molecular level. Thus, we analyzed 91 samples which encompass the spectrum of cytogenetic and molecular genetic aberrations in AML using DNA microarray technology. We used a miRNA microarray platform validated by quantitative RT-PCR and Northern Blot analyses that contained approximately 250 human miRNAs. By unsupervised hierarchical cluster analysis of our 91 AML samples based on the miRNA expression of 202 filtered miRNAs we were able to identify two large AML subgroups. While these two groups were in part characterized by the differential expression of the miR-17-92 cluster, which recently has been identified to be deregulated in many cancer types, especially Myc-regulated tumors, we also identified several miRNAs not yet known to be differentially expressed in leukemia. Interestingly, correlation of the unsupervised cluster defined groups revealed an association with leukemia morphology as determined by FAB (French-American-British) classification, but there was no significant correlation with cytogenetically or molecular-genetically defined leukemia AML subgroups. On the other hand, by supervised analysis using the significance analysis of microarrays (SAM) methodology we were able to identify miRNA signatures characterizing acute promyelocytic leukemias with a t(15;17) and normal karyotype AML carrying mutations of NPM1. While these findings already support a potential role of differential miRNA expression in AML pathogenesis, future analyses correlating miRNA expression with global gene expression, which are currently underway, are likely to provide additional insights into AML biology, thereby helping to unravel the role of miRNAs in leukemogenesis.
Docetaxel Versus Surveillance After Radical Prostatectomy for High-risk Prostate Cancer: Results from the Prospective Randomised, Open-label Phase 3 Scandinavian Prostate Cancer Group 12 Trial
Authors: Göran M. Ahlgren, Per Flodgren, Teuvo L.J. Tammela, Pirkko Kellokumpu-Lehtinen, Michael Borre, Anders Angelsen, Jon Reidar Iversen, Asgerdur Sverrisdottir, Eirikur Jonsson, Lisa Sengelov
Journal: European Urology (2018)
The Neurotropic Properties of AAV-PHP.B Are Limited to C57BL/6J Mice
Authors: Juliette Hordeaux, Qiang Wang, Nathan Katz, Elizabeth L. Buza, Peter Bell, James M. Wilson
Journal: Molecular Therapy (2018)

Improved delivery of adeno-associated virus (AAV) vectors to the CNS will greatly enhance their clinical utility. Selection of AAV9 variants in a mouse model led to the isolation of a capsid called PHP.B, which resulted in remarkable transduction of the CNS following intravenous infusion. However, we now show here that this enhanced CNS tropism is restricted to the model in which it was selected, i.e., a Cre transgenic mouse in a C57BL/6J background, and was not found in nonhuman primates or the other commonly used mouse strain BALB/cJ. We also report the potential for serious acute toxicity in NHP after systemic administration of high dose of AAV.
Concerns about composite reference standards in diagnostic research
Authors: Nandini Dendukuri, Ian Schiller, Joris de Groot, Michael Libman, Karel Moons, Johannes Reitsma, Maarten van Smeden
Journal: BMJ (2018)

Composite reference standards are used to evaluate the accuracy of a new test in the absence of a perfect reference test. A composite reference standard defines a fixed, transparent rule to classify subjects into disease positive and disease negative groups based on existing imperfect tests. The accuracy of the composite reference standard itself has received limited attention. We show that increasing the number of tests used to define a composite reference standard can worsen its accuracy, leading to underestimation or overestimation of the new test's accuracy. Further, estimates based on composite reference standards vary with disease prevalence, indicating that they may not be comparable across studies. These problems can be attributed to the fact that composite reference standards make a simplistic classification and then ignore the uncertainty in this classification. Latent class models that adjust for the accuracy of the different imperfect tests and the dependence between them should be pursued to make better use of data
Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance
Authors: Robert A. Kyle, Dirk R. Larson, Terry M. Therneau, Angela Dispenzieri, Shaji Kumar, James R. Cerhan, S. Vincent Rajkumar
Journal: New England Journal of Medicine (2018)

Monoclonal gammopathy of undetermined significance (MGUS) occurs in approximately 3% of persons 50 years of age or older.We studied 1384 patients who were residing in southeastern Minnesota and in whom MGUS was diagnosed at the Mayo Clinic in the period from 1960 through 1994; the median follow-up was 34.1 years (range, 0.0 to 43.6). The primary end point was progression to multiple myeloma or another plasma-cell or lymphoid disorder.During 14,130 person-years of follow-up, MGUS progressed in 147 patients (11%), a rate that was 6.5 times (95% confidence interval [CI], 5.5 to 7.7) as high as the rate in the control population. The risk of progression without accounting for death due to competing causes was 10% at 10 years, 18% at 20 years, 28% at 30 years, 36% at 35 years, and 36% at 40 years. Among patients with IgM MGUS, the presence of two adverse risk factors - namely, an abnormal serum free light-chain ratio (ratio of kappa to lambda free light chains) and a high serum monoclonal protein (M protein) level (≥1.5 g per deciliter) - was associated with a risk of progression at 20 years of 55%, as compared with 41% among patients who had one adverse risk factor and 19% among patients who had neither risk factor. Among patients with non-IgM MGUS, the risk of progression at 20 years was 30% among those who had the two risk factors, 20% among those who had one risk factor, and 7% among those who had neither risk factor. Patients with MGUS had shorter survival than was expected in the control population of Minnesota residents of matched age and sex (median, 8.1 vs. 12.4 years; P<0.001).Significant differences were noted in the risk of progression between patients with IgM MGUS and those with non-IgM MGUS. Overall survival was shorter among patients with MGUS than was expected in a matched control population. (Funded by the National Cancer Institute.).
Hepatocyte-specific deletion of IL1-RI attenuates liver injury by blocking IL-1 driven autoinflammation
Authors: Nadine Gehrke, Nadine Hövelmeyer, Ari Waisman, Beate K. Straub, Julia Weinmann-Menke, Marcus A. Wörns, Peter R. Galle, Jörn M. Schattenberg
Journal: Journal of Hepatology (2018)
Better than what? Comparisons in low back pain clinical trials
Authors: Mervyn J Travers, Matthew K Bagg, William Gibson, Kieran O’Sullivan, Thorvaldur Skuli Palsson
Journal: British Journal of Sports Medicine (2018)

Low back pain (LBP) has a significant impact on the sufferer and society as a whole. Therefore, we read with great interest the Specific Treatment of Problems of the Spine (STOPS) trial1 suggesting that an individualised physiotherapy approach had a favourable outcome when compared with advice in a cohort of participants with LBP lasting for more than 6 weeks. These findings highlight important issues in the design and subsequent interpretation of randomised controlled trials (RCTs) in this area.

The primary purpose of RCTs is to determine if an intervention meaningfully improves clinical outcomes. This is realised by comparing the intervention with an appropriate control.2 To determine efficacy, the ideal control is a credible placebo, but this is often difficult to design for non-pharmacological treatments. Thus, an alternative intervention is frequently used as the control. This design does not estimate efficacy; rather, it compares whether one approach is superior to another. Therefore, it is possible for an intervention to be deemed effective when compared with a control for which outcomes are suboptimal. This is relevant in LBP clinical trials and in other …
At the Root: Defining and Halting Progression of Early Chronic Obstructive Pulmonary Disease
Authors: Fernando J. Martinez, MeiLan K. Han, James P. Allinson, R. Graham Barr, Richard C. Boucher, Peter M. A. Calverley, Bartolome R. Celli, Stephanie A. Christenson, Ronald G. Crystal, Malin Fagerås, Christine M. Freeman, Lars Groenke, Eric A. Hoffman, Mehmet Kesimer, Kostantinos Kostikas, Robert Paine, Shahin Rafii, Stephen I. Rennard, Leopoldo N. Segal, Renat Shaykhiev, Christopher Stevenson, Ruth Tal-Singer, Jørgen Vestbo, Prescott G. Woodruff, Jeffrey L. Curtis, Jadwiga A. Wedzicha
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Chronic obstructive pulmonary disease is a heterogeneous disorder with varying presentation and progression, but with limited disease-modifying therapies.It is increasingly evident that lung function trajectories in COPD differ significantly and that differences are detectable in young adulthood.It is important to distinguish "early disease" meaning the first signs of disease developing in a young individual from "late mild disease" meaning disease that may be mild in severity in an older individual but may have been present for decades.We propose an operational definition of early COPD as occurring in a person younger than 50; and either: (1) FEV1/FVC less than lower limit of normal; or (2) respiratory symptoms or CT abnormalities (airway abnormality and/or emphysema), (3) evidence of accelerated FEV1 decline; or (4) any combination of categories (1) through (3).The biological underpinnings of early COPD are quite complex.Recent evidence implies that cigarette smoke-exposure induces sequential, stereotypical changes in distal airways, in the absence of inflammatory cell infiltration.Epithelial reprogramming is associated with mucus that is less readily cleared.Focal airway injury has also been associated with polymeric immunoglobulin receptor downregulation.Resulting differences in the lung microbial community structures might prove to be mechanistically important.Global gene analysis suggests that tissue degradation around small airways predominates over repair.Emphysema might also develop in early COPD due to loss of pulmonary endothelial cell-derived factors.To reduce COPD's long-term societal impact, the goal of interventions must change, from a sole focus on reducing symptoms and exacerbations in advanced disease, to halting pathological progression in early disease.This review attempts to stimulate studies focused on younger people to understand the causes, progression, clinical experession and potential therapeutic targets of early COPD.
Short Course of Bortezomib in Anemic Patients with Refractory or Relapsed Cold Agglutinin Disease. a Phase II Prospective Study By the Gimema Group
Authors: Giuseppe Rossi, Francesca Paoloni, Bruno Fattizzo, Francesca Binda, Mariella D'Adda, Mirko Farina, Cecilia Carbone, Francesco Zaja, Elisa Lucchini, Francesca Romana Mauro, Flavia Salvi, Monia Marchetti, Paola Fazi, Wilma Barcellini
Journal: Blood (2017)
High prevalence of latent tuberculosis and bloodborne virus infection in a homeless population
Authors: Robert W Aldridge, Andrew C Hayward, Sara Hemming, Susan K Yates, Gloria Ferenando, Lucia Possas, Elizabeth Garber, John M Watson, Anna Maria Geretti, Timothy Daniel McHugh, Marc Lipman, Alistair Story
Journal: Thorax (2018)

Introduction Urban homeless populations in the UK have been shown to have high rates of active tuberculosis, but less is known about the prevalence of latent tuberculosis infection (LTBI). This study aimed to estimate the prevalence of LTBI among individuals using homeless hostels in London. Methods We performed a cross-sectional survey with outcome follow-up in homeless hostels in London. Our primary outcome was prevalence of LTBI. Recruitment for the study took place between May 2011 and June 2013. To estimate an LTBI prevalence of 10% with 95% CIs between 8% and 13%, we required 500 participants. Results 491/804 (61.1%) individuals agreed to be screened. The prevalence of LTBI was 16.5% (81/491; 95% CI 13.2 to 19.8). In UK-born individuals, a history of incarceration was associated with increased risk of LTBI (OR 3.49; 95% CI 1.10 to 11.04; P=0.018) after adjusting for age, length of time spent homeless and illicit drug use. Of the three subjects who met English treatment guidelines for LTBI at the time of the study, none engaged with services after referral for treatment. Prevalence of past hepatitis B infection was 10.4% (51/489; 95% CI 7.7 to 13.1), and 59.5% (291/489; 95% CI 55.1 to 63.9) of individuals were non-immune. Prevalence of current hepatitis C infection was 10.4% (51/489; 95% CI 7.8 to 13.1). Conclusions This study demonstrates the high prevalence of LTBI in homeless people in London and the associated poor engagement with care. There is a large unmet need for LTBI and hepatitis C infection treatment, and hepatitis B vaccination, in this group.
E3 Ligase VHL Promotes Group 2 Innate Lymphoid Cell Maturation and Function via Glycolysis Inhibition and Induction of Interleukin-33 Receptor
Authors: Qian Li, Dulei Li, Xian Zhang, Qingqing Wan, Wen Zhang, Mingke Zheng, Le Zou, Chris Elly, Jee H. Lee, Yun-Cai Liu
Journal: Immunity (2018)

Group 2 innate lymphoid cells (ILC2s) are a specialized subset of lymphoid effector cells that are critically involved in allergic responses; however, the mechanisms of their regulation remain unclear. We report that conditional deletion of the E3 ubiquitin ligase VHL in innate lymphoid progenitors minimally affected early-stage bone marrow ILC2s but caused a selective and intrinsic decrease in mature ILC2 numbers in peripheral non-lymphoid tissues, resulting in reduced type 2 immune responses. VHL deficiency caused the accumulation of hypoxia-inducible factor 1α (HIF1α) and attenuated interleukin-33 (IL-33) receptor ST2 expression, which was rectified by HIF1α ablation or inhibition. HIF1α-driven expression of the glycolytic enzyme pyruvate kinase M2 downmodulated ST2 expression via epigenetic modification and inhibited IL-33-induced ILC2 development. Our study indicates that the VHL-HIF-glycolysis axis is essential for the late-stage maturation and function of ILC2s via targeting IL-33-ST2 pathway.
Case 4-2018: A Newborn with Thrombocytopenia, Cataracts, and Hepatosplenomegaly
Authors: Robert S. Baltimore, Katherine Nimkin, Katherine A. Sparger, Virginia M. Pierce, Stanley A. Plotkin
Journal: New England Journal of Medicine (2018)

A newborn boy was transferred to this hospital because of thrombocytopenia and abnormal results on an eye examination for red reflex and on a hearing screening. A diagnostic test was performed.
Clinical implications of cancer gene mutations in patients with chronic lymphocytic leukemia treated with lenalidomide
Authors: Koichi Takahashi, Boyu Hu, Feng Wang, Yuanqing Yan, Ekaterina Kim, Candida Vitale, Keyur P. Patel, Paolo Strati, Curtis Gumbs, Latasha Little, Samantha Tippen, Xingzhi Song, Jianhua Zhang, Nitin Jain, Philip Thompson, Guillermo Garcia-Manero, Hagop Kantarjian, Zeev Estrov, Kim-Anh Do, Michael Keating, Jan A. Burger, William G. Wierda, P. Andrew Futreal, Alessandra Ferrajoli
Journal: Blood (2018)