tbuckley/cabot-search huggingface dataset:
Abstract B42: Modeling MDS in mice through precise molecular lesions in APC and mDia1.
Authors: Julie Davis Turner, Susan Kitchen-Goosen, Andrew M. Howard, Heather Schumacher, Art S. Alberts
Journal: Clinical Cancer Research (2015)

Abstract While the murine equivalent to “5q– syndrome” should map to the distal arms of murine chromosomes 11 and 18, molecular attempts have been unsuccessful in generating a reliable mouse model of myelodysplasia leading to exacerbated myeloid leukemia. Genetic studies suggest interactions between individual proteins in this locus suppress tumor initiation. More specifically, cellular and biochemical studies demonstrated collaboration between two proteins in the commonly deleted regions of 5q– syndrome: mDia1 (mammalian Diaphanous-related Rho GTPase effector formin) and APC (adenomatous polypolis coli). Therefore, we generated mice compounding these two putative disease alleles. Because both mDia1 knockout [Drf1(–/–)] mice and Apcmin (min = multiple intestinal neoplasia; haploinsufficient) mice develop age-dependent myelodysplastic syndrome (MDS), we hypothesized that a mouse strain lacking both proteins will exhibit a more severe MDS phenotype than either mutant allele alone. To define the disease caused by mutation in Drf1 and Apcmin, we monitored erythropoiesis, myelopoiesis, and overall survival. At all ages, mice with both mutant alleles exhibit granulocytosis. Anemia occurs in aged mice (&amp;gt;270 days), exhibiting drastic differences in blood cell morphology that corresponded to differences in long-term survival in comparison to either Drf1–/– or Apcmin animals. Furthermore, immunophenotyping of all subpopulations indicate an accumulation of CD71+/TER-119+ cells in mice with both mutant alleles, however no significant differences in CD11b expression appeared among CD45+ bone marrow subpopulations. Our studies indicate that combined loss of mDia1 and APC expression and function direct disease progression. We are currently defining the hematopoietic precursor cell responsible for anemia and bone marrow failure. This enhanced mouse model also serves as molecular laboratory to study disease progression and to test potential therapeutics under development in our laboratory. Citation Format: Julie Davis Turner, Susan Kitchen-Goosen, Andrew M. Howard, Heather Schumacher, Art S. Alberts. Modeling MDS in mice through precise molecular lesions in APC and mDia1. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B42.
Abstract 17410: A Multiperspective Analysis of the Influence of Medicare Part D on the Cost-effectiveness of Dabigatran versus Warfarin
Authors: Brian M Salata, David W Hutton, Deborah A Levine, James B Froehlich, Geoffrey D Barnes
Journal: Circulation (2014)

Introduction: Dabigatran and warfarin have been shown to be non-inferior for stroke prevention in atrial fibrillation (AF). We aimed to assess the cost perspectives of each payer (Medicare and patient) in relation to administration, monitoring and adverse outcomes for each medication. Hypothesis: We hypothesize that dabigatran 150 mg BID will be more cost-effective when compared to warfarin for both payers (Medicare and patient) regardless of Medicare Part D coverage. Methods: Using a Markov model, we performed a decision analysis comparing two treatment strategies in patients 65 years of age and older with AF: adjusted-dose warfarin and dabigatran 150 mg twice daily in Medicare patients with CHADS2 scores ≥ 1. Results are listed in 2013 US dollars, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER). Patient movement between health states was modeled using 1-month cycles for 35 years or until death. Cost-effectiveness therapies were selected using a willingness to pay threshold of $50,000 per quality-adjusted life year gained. Results: For patients with Medicare Part D coverage, Quality-adjusted life expectancy was 10.74 QALYs with warfarin and 11.22 QALYs with 150 mg dabigatran BID. From Medicare’s perspective, total average costs were $59,684 and $59,284 for warfarin as well as $76,237 and $45,421 for dabigatran, in patients with and without Part D coverage, respectively. From Medicare’s perspective, the ICER comparing dabigatran with warfarin was $34,707 and -$29,065, for patients with and without Part D coverage, respectively. From the patient’s perspective, total costs were $33,466 and $33,866 for warfarin as well as $28,876 and $59,692 for dabigatran, in patients with and without Part D coverage, respectively. From the patient’s perspective, the ICER comparing dabigatran with warfarin was -$9,624 and $54,147, for patients with and without Part D coverage, respectively. Conclusions: In patients ≥ 65 years old with nonvalvular atrial fibrillation (NVAF) and at increased risk of stroke (CHAD2 score = 2), dabigatran 150 mg BID is more cost-effective for both Medicare and the patient, except for individual patients without Medicare Part D coverage.
PWE-170 Management of dysphagia: variations in clinical pracrice: Abstract PWE-170 Table 1
Authors: A Rehman, YC Lim, Y Al-Naeeb, B Javaid
Journal: Gut (2015)

<h3>Introduction</h3> Dysphagia is a common indication for upper gastrointestinal endoscopy. Dysphagia warrants an urgent referral for Oesophago-gastroduodenoscopy (OGD) under 2 week rule to exclude cancer in the United Kingdom (UK). In cases where no malignancy is identified, subsequent management may differ as there are no national guidelines. This survey evaluates current practice in management of dysphagia across the UK. <h3>Method</h3> An online questionnaire was designed and sent to full and trainee members of British Society of Gastroenterology. The data was collated on an online platform and then downloaded to Microsoft Excel for evaluation. <h3>Results</h3> A total of 906 questionnaires were e-mailed with a 14% (130) response rate. 72% (94) of the respondents were consultants and 28% (36) were trainees. 58% (74) of the these worked in University hospitals, 45% (57) in district general hospitals and 3% (4) in Primary care. Practice varied widely on patient review prior to initiating investigations (See Table 1). Oesophago-duodenoscopy (OGD) was the investigation of choice in 98%(128) response when sent straight for investigation Oesophageal biopsies were always taken by 15%(19), most of the time by 40% (52), sometimes 39% (51), rarely 5% (7), and never 1% (1). If OGD was normal 32% (41) will biopsy all three oesophageal segments, 24% (31) will take mid and lower oesophageal biopsies, 8% (10) will sample upper and lower oesophagus, 21% (27) will biopsy mid oesophagus only, 8% (11) will biopsy lower oesophagus only and 1% (1) will take no biopsies. If OGD was normal 51% (66) would request Barium swallow, 22% (29) would do manometry, 18% (24) would investigate by manometry with impedance studies, 5% (6)would consider other investigations and 4% (5) would not perform any further tests. For patients describing oro-pharyngeal (upper) dysphagia and normal OGD 42% (55) clinicians will review patient in clinic, 27% (35) will arrange further investigations, 17% (22) other strategies and 14% (18) will discharge the patient. <h3>Conclusion</h3> This survey shows that although 98% of clinicians will use OGD as the first line investigation there is wide variation in subsequent management if the OGD was normal. This highlights the need for nationally agreed guidelines across the UK to minimise variations in clinical practice. <h3>Disclosure of interest</h3> None Declared.
Is There Any Basophil Activation in Peripheral Blood in AERD Patients?
Authors: Chihiro Mitsui, Emiko Ono, Keiichi Kajiwara, Hiroaki Hayashi, Yosuke Kamide, Kentaro Watai, Arisa Kinoshita, Yuma Fukutomi, Kiyoshi Sekiya, Takahiro Tsuburai, Akio Mori, Masami Taniguchi
Journal: Journal of Allergy and Clinical Immunology (2016)
Exchange Transfusion in the Treatment of Fulminating Hepatitis
Authors: Robert L. Berger, Rodney M. Liversage, Thomas C. Chalmers, James H. Graham, David M. McGoldrick, Frederick Stohlman
Journal: New England Journal of Medicine (1966)

ACUTE massive hepatic necrosis usually runs a short clinical course.1 The disease may terminate in death before the liver cells have an opportunity to regenerate and resume function. If the patient could be supported during the acute destructive phase until hepatic function returned, the chances for survival might be increased. In the belief that elevated levels of circulating ammonia and other unidentified toxins are critical2 , 3 intestinal nonabsorbable antibiotics have become a part of routine therapy.4 , 5 Massive doses of steroids are almost always employed in patients with fulminating hepatitis, in spite of the absence of any data confirming their efficacy.6 , 7 Recently, . . .
212P: 2nd line chemotherapy in malignant mesothelioma: A center's experience
Authors: D. Vassos, G. Tsironis, A. Kopitopoulou, S. Tsagkouli, S. Tsimpoukis, A. Charpidou, A. Bamias, K. Syrigos
Journal: Journal of Thoracic Oncology (2016)
The Link Between Mental Illness and Firearm Violence: Implications for Social Policy and Clinical Practice
Authors: John S. Rozel, Edward P. Mulvey
Journal: Annual Review of Clinical Psychology (2017)

The United States has substantially higher levels of firearm violence than most other developed countries. Firearm violence is a significant and preventable public health crisis. Mental illness is a weak risk factor for violence despite popular misconceptions reflected in the media and policy. That said, mental health professionals play a critical role in assessing their patients for violence risk, counseling about firearm safety, and guiding the creation of rational and evidence-based public policy that can be effective in mitigating violence risk without unnecessarily stigmatizing people with mental illness. This article summarizes existing evidence about the interplay among mental illness, violence, and firearms, with particular attention paid to the role of active symptoms, addiction, victimization, and psychosocial risk factors. The social and legal context of firearm ownership is discussed as a preface to exploring practical, evidence-driven, and behaviorally informed policy recommendations for mitigating firearm violence risk.
SP0173 Treatment of Refractory Myositis
Authors: R. Aggarwal
Journal: Annals of the Rheumatic Diseases (2015)

Despite a paucity of controlled clinical trials, glucocorticoids remain the mainstay of initial treatment for inflammatory myopathies. Glucocorticoid-sparing agents, either methotrexate or azathioprine, are often begun concomitantly with glucocorticoid therapy. However, in refractory patients other immunosuppressive or immunomodulatory agents such as mycophenolate mofetil, cyclosporine, tacrolimus, and IVIg are used alone or in various combinations. In a large clinical trial of rituximab in adult and juvenile myositis, the primary outcome was not met but most patients met trial criteria of improvement and rituximab use was associated with a significant glucocorticoid-sparing effect. Some of immunosuppressive agents are more appropriately used when certain disease manifestations predominate such as mycophenolate mofetil (interstitial lung disease and refractory cutaneous disease) and tacrolimus or cyclosporine (interstitial lung disease). Anti-TNF drugs have also been studied but the results are not encouraging. ACTH-gel has an FDA approved indication for polymyositis and dermatomyositis with positive results in a small retrospective case series, however, a more definitive trial is ongoing. Novel therapeutic agents are being studies and have shown favorable outcome in case reports and series, but more definitive trials are ongoing or are needed. The future therapeutic options for myositis will depend on well-designed clinical trials using validated outcomes and improvements in classification schemes based on serologic and histopathologic factors. <h3>Disclosure of Interest</h3> None declared
Simulations of cilengitide PK profiles in pediatric population by means of allometric scaling: Reliability and support to BSA-based dose adjustment strategy.
Authors: M. Zuehlsdorf, M. Campioni, U. Forssmann, A. Munafo, A. Kovar
Journal: Journal of Clinical Oncology (2010)

9548 Background: Cilengitide is a selective αvβ3/αvβ5 integrin inhibitor in clinical development for the treatment of various types of solid tumors. In this study, a population pharmacokinetic (PK) 2-compartment model was developed using data from 3 studies in adult patients (n=136) with advanced solid cancer, NSCLC or advanced unresectable pancreatic cancer. This model was used to simulate the plasma concentration time profiles of cilengitide in pediatric patients of various age/weight. Methods: The population-based PK parameters obtained in adults were allometrically scaled to pediatric populations with average body weight (BW) of 10, 15, 20, 25, 30, 40, 50, and 60 kg (CV 15%). The allometric function used the pediatric BW, a reference adult BW of 70 kg, and a fixed allometric exponent of 0.75 for clearance and of 1 for volume of distribution. Considering that cilengitide clearance is predominantly renal, immature renal function (90% of the mature one) was assumed for children in the 10 kg BW group. Concentration vs. time profiles were simulated for 30 subjects in each group, receiving twice-weekly 1-h infusions of 1800 mg/m2 cilengitide for up to 3 weeks. Results: The dose adjustment based on body surface area (BSA) provided homogeneous predicted cilengitide exposure (AUC0–24h range: 200–1787 μ g·h/mL) and concentration at the end of the 1-h infusion (Cmax range: 100–558 μ g/mL) in a wide range of BW (range: 8–86 kg). For lower BW, BSA-based dose adjustment led to a minimal drift towards higher allometric scaling-predicted concentrations. This was amplified by neglecting renal function immaturity. The simulated profiles compare well with published pediatric profiles (MacDonald et al. 2008), although some slight over-prediction was observed. Conclusions: As corroborated by independent experimental data, cilengitide pediatric PK profiles can reliably be predicted using allometrically-scaled PK parameters derived from adult data. The BSA-based dose adjustment strategy appears justified in children/adolescents, leading to homogenous exposure over a wide range of body weight. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck KGaA, Merck Serono
Driving Along the Zinc Road
Authors: Robert J. Cousins
Journal: Annual Review of Nutrition (2016)

After having written hundreds of research articles, reviews, and book chapters, I find it awkward to pen an autobiography. I still do use a pen. As stated by others in the nutrition field who have written of their own experiences in a perspective article for the Annual Review of Nutrition, my course through this field of science has been serendipitous. My interest in nutrition developed during my experiences with horses and then Angus cattle and entry into an animal science degree program. As the age of molecular biology was unfolding, I pursued a PhD in nutritional biochemistry with Hamilton Eaton at the University of Connecticut followed by postdoctoral work with Hector DeLuca at the University of Wisconsin, working on vitamins A and D, respectively. At Rutgers University, one of the two institutions where I have served on the faculty, I started my research program on trace elements with a focus on cadmium toxicity but soon thereafter began my research on zinc metabolism and function. I moved to the University of Florida in 1982 for an endowed position and have been a Florida Gator ever since. At the University of Florida, research expanded to include identification of zinc-responsive genes and physiological outcomes of zinc transport influencing health and disease, particularly as related to inflammation. I had the opportunity to contribute national science policy as president of both the Federation of American Societies for Experimental Biology and the American Society for Nutrition. As the time of this writing, I maintain an active laboratory.
Prospective Comparison of Indirect Methods for Detecting Lactase Deficiency
Authors: Albert D. Newcomer, Douglas B. McGill, Paul J. Thomas, Alan F. Hofmann
Journal: New England Journal of Medicine (1975)

To compare sensitivity, specificity and convenience, four indirect methods of detecting lactase deficiency were tested prospectively in 25 subjects with biopsy-proved lactase deficiency and in 25 with normal lactase activity. After ingestion of 50 g of lactose, containing 1–14C lactose, breath hydrogen was abnormally elevated in all 25 lactase-deficient subjects (>0.30 ml per minute at two hours); breath 14CO2 was below the normal range in 23, and in 19 the plasma glucose increased by less than 20 mg per deciliter. When lactose and ethanol were given together, the rise in plasma galactose remained <5 mg per deciliter in 24 of the lactase-deficient subjects. The specificity of the four tests was excellent, with only one false-positive plasma glucose test. Measurement of breath hydrogen is sensitive and specific, and does not require ethanol or isotopes. It is noninvasive, and is not influenced by gastric emptying or metabolic factors. We believe it to be the most suitable test for population screening for lactase deficiency. (N Engl J Med 293:1232–1235, 1975)
Abstract A1-59: Multiple mechanisms of MYCN dysregulation in Wilms tumor
Authors: Richard D. Williams, Tasnim Chagtai, Marisa Alcaide-German, John Apps, Jenny Wegert, Sergey Popov, Gordan Vujanic, Harm van Tinteren, Marry M. van den Heuvel-Eibrink, Marcel Kool, David Gisselsson, Norbert Graf, Manfred Gessler, Kathy Pritchard-Jones
Journal: Cancer Research (2015)

Abstract Background and Purpose: Wilms tumor (WT) is the commonest pediatric renal malignancy. A significant minority of cases have mutations in known genes or recurrent copy number aberrations, but few of these have prognostic value. We have previously observed MYCN copy number gain in WT, an aberration associated with poor outcome in several other childhood cancers. We therefore set out to assess the prognostic significance of MYCN gain in a large WT series, and to explore other mechanisms by which the function of this gene may be dysregulated. Methods: MYCN copy number was measured in 293 tumours by Multiplex ligation-dependent probe amplification. Whole exome sequencing (Agilent SureSelect V4+UTR/Illumina HiSeq) was carried out on 51 WT tumour/germline pairs. Sanger sequencing was used to confirm variants of interest and to assess an independent panel of 168 WTs. 65 WTs were profiled on Affymetrix SNP arrays (250K Nsp or SNP 6.0), Illumina HumanMethylation450 arrays, and Illumina HumanHT-12 expression arrays, and additional selected tumors on Illumina HumanCytoSNP-12 arrays. Results: MYCN gain is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. A somatic p.P44L (c.131C&amp;gt;t) mutation was detected in 3/45 exomes that gave informative data at this position, and in 5/168 additional tumors screened for this variant, an overall frequency of 3.8%. MYCN overexpression in high risk tumors was associated with hypomethylation at specific loci. We observed parallel evolution of genomic copy number gain and point mutation of MYCN in the contralateral tumors of a remarkable bilateral case in which independent contralateral mutations of TP53 also evolved over time. In a second bilateral case, we detected MYCN gain as a germline aberration. Conclusions: MYCN gain is associated with poor outcome and anaplastic histology in WT. MYCN also appears to be disrupted by other mechanisms in WT, including DNA hypomethylation and a recurrent potential gain of function mutation, P44L. The discovery of a germline aberration suggests that MYCN dysregulation may contribute to tumor predisposition. Citation Format: Richard D. Williams, Tasnim Chagtai, Marisa Alcaide-German, John Apps, Jenny Wegert, Sergey Popov, Gordan Vujanic, Harm van Tinteren, Marry M. van den Heuvel-Eibrink, Marcel Kool, David Gisselsson, Norbert Graf, Manfred Gessler, Kathy Pritchard-Jones. Multiple mechanisms of MYCN dysregulation in Wilms tumor. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-59.
Hormones and Hemodynamics in Heart Failure
Authors: Robert W. Schrier, William T. Abraham
Journal: New England Journal of Medicine (1999)

Heart failure is a major cause of cardiovascular mortality and morbidity, resulting in more than 1 million hospitalizations per year, and is the most common hospital-discharge diagnosis among patients older than 65 years.1 In recent years, much has been learned about the pathophysiology of heart failure, particularly in the area of fluid and electrolyte metabolism, and this will be the focus of the present review.Regulation of Body-Fluid VolumeThere is considerable evidence in support of a unifying hypothesis of the regulation of body-fluid volume that is applicable to patients with edematous disorders such as cardiac failure, to patients with . . .
Early Reduction of Pulmonary Vascular Resistance after Mitral-Valve Replacement
Authors: James E. Dalen, Jack M. Matloff, Gerald L. Evans, Frederic G. Hoppin, Prem Bhardwaj, Dwight E. Harken, Lewis Dexter
Journal: New England Journal of Medicine (1967)

PULMONARY-artery pressure rises out of proportion to the left atrial, pulmonary venous and pulmonary capillary pressure in some patients with elevated left atrial pressure secondary to mitral stenosis.1 This rise results in severe pulmonary hypertension and pulmonary vascular disease as manifested by marked elevation of calculated pulmonary vascular resistance. Wood2 found that 12 per cent of 500 patients with mitral stenosis had severe pulmonary vascular disease defined as pulmonary vascular resistance greater than 10 units (greater than 800 dyne sec. cm.-5). The mechanism of the inordinate increase in pulmonary-artery pressure is not clear.The presence of pulmonary vascular disease . . .
Chlamydia Pneumonia and Meningoencephalitis
Authors: Maja Socan, Bojana Beovic, Darja Kese
Journal: New England Journal of Medicine (1994)

To the Editor: Chlamydia pneumoniae causes respiratory1 and nonrespiratory2,3 clinical syndromes. We describe a case of pneumonia caused by C. pneumoniae and associated with meningoencephalitis. An...
Clinical Outcomes and Costs of Transcatheter as Compared with Surgical Closure of Patent Ductus Arteriosus
Authors: Darryl T. Gray, Donald C. Fyler, Alexander M. Walker, Milton C. Weinstein, Thomas C. Chalmers
Journal: New England Journal of Medicine (1993)

Transcatheter implantation of the Rashkind PDA occluder is an alternative to conventional surgical closure of isolated patent ductus arteriosus. Neither the clinical outcomes nor the costs of these procedures have been formally compared.