tbuckley/cabot-search huggingface dataset:
Gemtuzumab ozogamicin with fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAG‐GO) as front‐line regimen in patients with core binding factor acute myelogenous leukemia
Authors: Gautam Borthakur, Jorge E. Cortes, Elihu E. Estey, Elias Jabbour, Stefan Faderl, Susan O'Brien, Guillermo Garcia‐Manero, Tapan Mahendra Kadia, Xuemei Wang, Keyur Patel, Rajyalakshmi Luthra, Charles Koller, Mark Brandt, Farhad Ravandi, Hagop Kantarjian
Journal: American Journal of Hematology (2014)

Despite being considered "good-risk" acute myelogenous leukemia (AML), long term outcomes in core binding factor (CBF) AML suggest room for improvement. We report on a regimen consisting of fludarabine, cytarabine, granulocyte colony stimulating factor, and low dose gemtuzumab ozogamicin (FLAG-GO) as front-line therapy of patients with CBF AML. Forty-five patients were enrolled (median age 48 years). Remission rate was 95% with 5% induction deaths. The overall survival (OS) and relapse free survival (RFS) probability at 3 years are 78% and 85%, respectively. FLAG-GO regimen results in high rates of RFS and OS in CBF AML. Our data along with recent data from several large groups strongly argues in favor of incorporation of gemtuzumab ozogamicin in frontline regimens for CBF AML.
Abstract CT208: Absolute bioavailability of dacomitinib (PF-00299804): Comparison of oral and intravenous administration in healthy volunteers
Authors: Nagdeep Giri, Robert R. LaBadie, Yali Liang, Tanya Boutros, Zelanna Goldberg, Carlo L. Bello
Journal: Cancer Research (2014)

Abstract Background: Dacomitinib (D) is a highly selective, irreversible small molecule inhibitor of the human epidermal growth factor receptor family of tyrosine kinases in clinical development for the treatment of non-small cell lung cancer (NSCLC). A 45-mg once daily oral dose is currently being evaluated in Phase 3 for NSCLC therapy in multiple settings. D has not previously been administered clinically as an intravenous dose. The absolute bioavailability (F%) of D in rats, dogs and monkeys was found to range from 56% to 100% at doses between 20 and 50 mg/kg. The current study was conducted to estimate the absolute bioavailability of D after oral administration (Test) relative to intravenous (IV, Reference) administration. Methods: A total of 14 healthy volunteers (HV) were enrolled in this Phase 1, open-label, 2-period, 2-treatment, fixed sequence study. Each HV received 2 treatments of D: Reference (20 mg IV infusion over 1 hour) and Test (45 mg oral), with a washout period of at least 16 days between each. Plasma samples to determine concentrations of D and its metabolite, PF-05199265, were collected at intervals up to 216 hours post-dose after IV or oral dose, and safety was assessed. F% was estimated as the ratio of dose-normalized adjusted geometric means of AUCinf for oral D and IV D using a mixed-effect model with treatment as a fixed effect and subject as a random effect. Corresponding 90% confidence intervals (CIs) were to be obtained from the same model. Results: The mean AUCinf, Cmax and CL/F for D after a single 45-mg oral dose were 1487 ng*hr/mL, 19.84 ng/mL and 30.27 L/hr, respectively. The mean AUCinf, Cmax and CL for D after a single 20-mg IV dose were 847 ng*hr/mL, 52 ng/mL and 23.61 L/hr, respectively. Mean pharmacokinetic parameters following a single oral dose in this study were similar to those observed in other single oral dose studies in HV. Conclusions: Assuming that clearance of D is similar via oral or IV administration at the administered doses, the absolute bioavailability of D was estimated to be 80.01% (90% CI: 74.90%, 85.47%). Single oral doses of D in both treatments were generally safe and well tolerated in the HV evaluated in this study. Citation Format: Nagdeep Giri, Robert R. LaBadie, Yali Liang, Tanya Boutros, Zelanna Goldberg, Carlo L. Bello. Absolute bioavailability of dacomitinib (PF-00299804): Comparison of oral and intravenous administration in healthy volunteers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT208. doi:10.1158/1538-7445.AM2014-CT208
Chronic pseudomonas aeruginosa airway infection induces peribronchial lymphoid neogenesis in mice
Authors: Justine Frija-Masson, Clémence Martin, Guiti Thevenot, Isabelle Fajac, Pierre-Régis Burgel
Journal: European Respiratory Journal (2013)

Background: Lymphoid follicles are absent in normal lungs, but are described in lungs of subjects with severe COPD or bronchiectasis. A role of bacterial infection in the development of lymphoid follicles (lymphoid neogenesis) might be hypothesized.

Aims: To examine if chronic P. aeruginosa (PA) airway infection could lead to lung lymphoid neogenesis.

Methods: C57BL/6 mice were instilled intratracheally with PAO1 (5.10^5 CFU/mouse)-coated agarose beads, which produces chronic airway infection (Martin et al, Eur. Resp. J. 2011 38:939). Mice with no instillation (Baseline) or instilled with sterile beads (no bacteria) served as Controls. Mice were sacrificed at day (d) 1, d4, d7, d14 and d28 after instillation. Lung sections were immunostained for B (CD20+) and T (CD3+) lymphocytes and for high endothelial venules (PNAd+), and analyzed using quantitative morphometry.

Results: At Baseline, mouse lung contained no lymphoid aggregate. Instillation of PAO1-coated beads induced CD20+ peribronchial lymphocytes recruitment at d1. At d4 and d7, CD20+ positive lymphocytes formed aggregates in bronchi where PAO1-coated beads and surrounding pulmonary infection were present. At d14 and d28, lymphoid aggregates contained areas of CD20+ lymphocytes, separate areas of CD3+ lymphocytes and PNAd+ structures. Lymphoid aggregates were absent in morphologically normal areas in the lung of PAO1-infected mice and in the lung of mice instilled with sterile beads.

Conclusion: Chronic P. aeruginosa airway infection induces peribronchial lymphoid neogenesis in mouse lung. The role of airway epithelium in chemokine-mediated lymphocyte recruitment requires further studies.
Angiotensin II Induces a Region-Specific Hyperplasia of the Ascending Aorta Through Regulation of Inhibitor of Differentiation 3
Authors: A. Phillip Owens, Venkateswaran Subramanian, Jessica J. Moorleghen, Zhenheng Guo, Coleen A. McNamara, Lisa A. Cassis, Alan Daugherty
Journal: Circulation Research (2009)

Angiotensin II (Ang II) has diverse effects on smooth muscle cells (SMCs). The diversity of effects may relate to the regional location of this cell type.The aim of this study was to define whether Ang II exerted divergent effects on smooth muscle cells in the aorta and determine the role of blood pressure and specific oxidant mechanisms.Ang II (1000 ng/kg per minute) infusion for 28 days into mice increased systolic blood pressure and promoted medial expansion of equivalent magnitude throughout the entire aorta. Both effects were ablated by angiotensin II type 1a (AT(1a)) receptor deficiency. Similar increases in systolic blood pressure by administration of norepinephrine promoted no changes in aortic medial thickness. Increased medial thickness was attributable to SMC expansion owing to hypertrophy in most aortic regions, with the exception of hyperplasia of the ascending aorta. Deficiency of the p47(phox) component of NADPH oxidase ablated Ang II-induced medial expansion in all aortic regions. Analysis of mRNA and protein throughout the aorta revealed a much higher abundance of the inhibitor of differentiation 3 (Id3) in the ascending aorta compared to all other regions. A functional role was demonstrated by Id3 deficiency inhibiting Ang II-induced SMC hyperplasia of the ascending aorta.In conclusion, Ang II promotes both aortic medial hypertrophy and hyperplasia in a region-specific manner via an oxidant mechanism. The ascending aortic hyperplasia is dependent on Id3.
Selective Sweep of a cis-Regulatory Sequence in a Non-African Population of Drosophila melanogaster
Authors: S. S. Saminadin-Peter, C. Kemkemer, P. Pavlidis, J. Parsch
Journal: Molecular Biology and Evolution (2011)

Although it is thought that changes in gene expression play an important role in adaptation, the identification of gene-regulatory sequences that have been targets of positive selection has proved difficult. Here, we identify a cis-regulatory element of the Drosophila melanogaster CG9509 gene that is associated with a selective sweep in a derived non-African population of the species. Expression analyses indicate that CG9509 consistently shows greater expression in non-African than in African strains of D. melanogaster. We find that a 1.8 kb region located just upstream of the CG9509 coding region is devoid of DNA sequence polymorphism in a European population sample and that this is best explained by the recent action of positive selection (within the past 4,000–10,000 years). Using a reporter gene construct and phiC31-mediated site-specific integration, we show that the European version of the CG9509 upstream region drives 2–3 times greater expression than the African version in an otherwise identical genetic background. This expression difference corresponds well to that of the native gene and indicates that sequence variation within the CG9509 upstream region can completely account for its high expression in the European population. Selection appears to have favored a quantitative increase in gene expression in the Malphigian tubule, the tissue where CG9509 is predominantly expressed.
The <i>IFNG</i> (IFN-γ) Genotype Predicts Cytogenetic and Molecular Response to Imatinib Therapy in Chronic Myeloid Leukemia
Authors: Dong Hwan (Dennis) Kim, Jee Hyun Kong, Ji Young Byeun, Chul Won Jung, Wei Xu, Xiangdong Liu, Suzanne Kamel-Reid, Yeo-Keyoung Kim, Hyeoung-Joon Kim, Jeffrey H. Lipton
Journal: Clinical Cancer Research (2010)

The present study analyzed treatment outcomes of imatinib therapy by interindividual genetic variants in candidate biological pathways of chronic myeloid leukemia (CML) such as apoptosis, angiogenesis, IFN-γ signaling pathways, or drug transport/metabolism of imatinib.Peripheral blood DNAs were genotyped for 79 single nucleotide polymorphism markers involved in the pathways of apoptosis, angiogenesis, myeloid cell growth, xenobiotic metabolism, WT1 signaling, IFN signaling, and others in CML patients who were included in discovery (n = 229, Canada) and validation cohorts (n = 187, Korea).We found several genotypes associated with complete cytogenetic response: IFNG (rs1861494, rs2069705), FASL (rs763110), FAS (rs2234767, rs2234978), VEGFR2 (rs1531289), and WT1 (rs2234590); with major molecular response: IFNG (rs1861494, rs2069705), BIRC5 (rs9904341), FAS (rs2234978), and ABCG2 (rs2231142); with loss of response: IFNG (rs2069705), IFNGR2 (rs9808753), BIRC5 (rs9904341), and ORM (rs3182041); and with treatment failure: IFNG (rs2069705), JAK3 (rs3212713), and ORM (rs3182041). External validation for the above significant genotypes confirmed that the IFNG genotype (rs2069705) was predictive of complete cytogenetic response (hazard ratio, 2.17; P < 0.001) and major molecular response (hazard ratio, 1.96; P = 0.0001) in validation cohorts of Korean ethnicity.The IFNG genotype was predictive for response to imatinib therapy, suggesting potential involvement of the IFN-γ signaling pathway in the mechanism of action of imatinib in CML.
The Immunologic and Metabolic Basis of Drug Hypersensitivities
Authors: L R Pohl, H Satoh, D D Christ, J G Kenna
Journal: The Annual Review of Pharmacology and Toxicology (1988)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
Serological association of beta and gamma human papillomaviruses with squamous cell carcinoma of the skin
Authors: T. Waterboer, D. Abeni, F. Sampogna, A. Rother, C. Masini, P. Sehr, K.M. Michael, M. Pawlita
Journal: British Journal of Dermatology (2008)

Cutaneous human papillomaviruses (HPVs) may play a role in the development of squamous cell carcinomas (SCC) of the skin. Objectives Available serological studies on HPV and skin SCC have analysed only few HPV types from the phylogenetic genus beta. The potential association of cutaneous HPV types from the genera alpha, gamma, mu and nu with skin SCC has not been thoroughly analysed so far.Using multiplex serology, a method that allows analysing sera for antibodies to up to 100 different antigens simultaneously, we re-analysed an SCC case-control study in immunocompetent individuals (43 cases, 77 controls) for antibodies to L1 capsid proteins of 29 cutaneous and two mucosal HPV types from five different genera.Significantly increased SCC risks were observed for the beta HPV types 15, 17 and 38, as well as for the gamma HPV type 50, with type-specific odds ratios (ORs) ranging from 2.6 to 3.4. Significant associations were also found in cases of seropositivity for any type of the beta 2 species (OR 3.3, 95% confidence interval [CI] 1.2-8.7) and for any type of the gamma genus (OR 3.1, 95% CI 1.1-8.6). With regression models that included all HPV types and forward stepwise selection, two gamma HPV types (HPV 95, OR 25, 95% CI 1.2-509; HPV 50, OR 3.6, 95% CI 1.4-9.4) were each significantly associated with skin SCC.Our study confirms a possible role of cutaneous HPV in the development of skin SCC. Future studies should include skin HPV types from more than only the beta genus, especially gamma types.
IgG4 levels and plasmablasts as a marker for IgG4-related disease (IgG4-RD)
Authors: Robert I Fox, Carla M Fox
Journal: Annals of the Rheumatic Diseases (2014)

Stone and his coworkers present two elegant papers on IgG4-related disease (IgG4-RD).1

In ‘The Diagnostic Utility of Serum IgG4 Concentrations in IgG4-Related Disease’, Carruthers et al 2 retrospectively analysed charts of 190 patients with elevation of IgG4. They also randomly selected 3360 charts with normal IgG4 levels and reviewed 190 cases for characteristics of IgG4-RD. They found: 

In a closely related study by the same group, Wallace et al describe the ‘Diagnostic Utility of Plasmablasts as a Biomarker for IgG4 Related Disease (IgG4 RD) Independent of Serum IgG4 Levels’. 

Since we see patients with possible IgG4-RD in a variety of organs (table 1) that are often not easy to biopsy, serum IgG4 levels have incorrectly become a ‘surrogate’ marker for IgG4-RD in clinical practice.3 ,4 These articles will make us take a hard look at our current diagnostic approach to IgG4-RD.

View this table:

Table 1 
IgG4-Related Diseases (IgG4-RD) are a Family Immuno-proliferative Disorders



View this table:

Table 2 
Diagnostic criteria for IgG4-Related Disease



The spectrum of IgG4-RD is remarkably complex (table 1) and it would be nice to simply think of this complex multisystem pathology as a single pathogenetic disorder occurring in a variety of target organs.

Unfortunately, it may not be that simple.

In a critical evaluation of the evolving …
Regionalization of Local Public Health Systems in the Era of Preparedness
Authors: Howard K. Koh, Loris J. Elqura, Christine M. Judge, Michael A. Stoto
Journal: Annual Review of Public Health (2008)

Post-9/11, preparedness planning has catalyzed intrastate regionalization of local public health resources throughout the United States. Investigating this trend unveils several regionalization themes, relevant in other sectors of government, which are applicable to local public health. In this review article, we begin by briefly examining the lessons learned from regionalization for police and fire services, drawing comparisons to public health. Then we provide a brief history of the accelerating regionalization of local public health services sparked by the current attention to emergency preparedness. In particular, we offer case studies from Massachusetts and the National Capital Region to highlight examples of regionalization outcomes related to networking, coordination, standardization, and centralization of public health services. The impact of social capital on preparedness is also explored. Finally, we summarize research needs for the future.
Ticagrelor Versus Clopidogrel in Patients With ST-Elevation Acute Coronary Syndromes Intended for Reperfusion With Primary Percutaneous Coronary Intervention
Authors: Philippe Gabriel Steg, Stefan James, Robert A. Harrington, Diego Ardissino, Richard C. Becker, Christopher P. Cannon, Håkan Emanuelsson, Ariel Finkelstein, Steen Husted, Hugo Katus, Jan Kilhamn, Sylvia Olofsson, Robert F. Storey, W. Douglas Weaver, Lars Wallentin
Journal: Circulation (2010)

Background— Aspirin and clopidogrel are recommended for patients with acute coronary syndromes (ACS) or undergoing coronary stenting. Ticagrelor, a reversible oral P2Y12-receptor antagonist, provides faster, greater, and more consistent platelet inhibition than clopidogrel and may be useful for patients with acute ST-segment elevation (STE) ACS and planned primary percutaneous coronary intervention. Methods and Result— Platelet Inhibition and Patient Outcomes (PLATO), a randomized, double-blind trial, compared ticagrelor with clopidogrel for the prevention of vascular events in 18 624 ACS patients. This report concerns the 7544 ACS patients with STE or left bundle-branch block allocated to either ticagrelor 180-mg loading dose followed by 90 mg twice daily or clopidogrel 300-mg loading dose (with provision for 300 mg clopidogrel at percutaneous coronary intervention) followed by 75 mg daily for 6 to 12 months. The reduction of the primary end point (myocardial infarction, stroke, or cardiovascular death) with ticagrelor versus clopidogrel (10.8% versus 9.4%; hazard ratio [HR], 0.87; 95% confidence interval, 0.75 to 1.01; P =0.07) was consistent with the overall PLATO results. There was no interaction between presentation with STE/left bundle-branch block and randomized treatment (interaction P =0.29). Ticagrelor reduced several secondary end points, including myocardial infarction alone (HR, 0.80; P =0.03), total mortality (HR, 0.82; P =0.05), and definite stent thrombosis (HR, 0.66; P =0.03). The risk of stroke, low in both groups, was higher with ticagrelor (1.7% versus 1.0%; HR,1.63; 95% confidence interval, 1.07 to 2.48; P =0.02). Ticagrelor did not affect major bleeding (HR, 0.98; P =0.76). Conclusion— In patients with STE-ACS and planned primary percutaneous coronary intervention, the effects of ticagrelor were consistent with those observed in the overall PLATO trial. Clinical Trial Registration— URL: http://www.ClinicalTrials.gov . Unique identifier: NCT00391872.
Effectiveness and Cost of Olanzapine and Haloperidol in the Treatment of Schizophrenia&lt;SUBTITLE&gt;A Randomized Controlled Trial&lt;/SUBTITLE&gt;
Authors: Robert Rosenheck
Journal: JAMA (2003)

ContextAlthough olanzapine has been widely adopted as a treatment of choice for schizophrenia, its long-term effectiveness and costs have not been evaluated in a controlled trial in comparison with a standard antipsychotic drug.ObjectiveTo evaluate the effectiveness and cost impact of olanzapine compared with haloperidol in the treatment of schizophrenia.Design and SettingDouble-blind, randomized controlled trial with randomization conducted between June 1998 and June 2000 at 17 US Department of Veterans Affairs medical centers.ParticipantsThree hundred nine patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia or schizoaffective disorder, serious symptoms, and serious dysfunction for the previous 2 years. Fifty-nine percent fully completed and 36% partially completed follow-up assessments.InterventionsPatients were randomly assigned to receive flexibly dosed olanzapine, 5 to 20 mg/d, with prophylactic benztropine, 1 to 4 mg/d (n = 159); or haloperidol, 5 to 20 mg/d (n = 150), for 12 months.Main Outcome MeasuresStandardized measures of symptoms, quality of life, neurocognitive status, and adverse effects of medication. Veterans Affairs administrative data and interviews concerning non-VA service use were used to estimate costs from the perspective of the VA health care system and society as a whole (ie, consumption of all resources on behalf of these patients).ResultsThere were no significant differences between groups in study retention; positive, negative, or total symptoms of schizophrenia; quality of life; or extrapyramidal symptoms. Olanzapine was associated with reduced akathisia in the intention-to-treat analysis (P&lt;.001) and with lower symptoms of tardive dyskinesia in a secondary analysis including only observations during blinded treatment with study drug. Small but significant advantages were also observed on measures of memory and motor function. Olanzapine was also associated with more frequent reports of weight gain and significantly greater VA costs, ranging from $3000 to $9000 annually. Differences in societal costs were somewhat smaller and were not significant.ConclusionOlanzapine does not demonstrate advantages compared with haloperidol (in combination with prophylactic benztropine) in compliance, symptoms, extrapyramidal symptoms, or overall quality of life, and its benefits in reducing akathisia and improving cognition must be balanced with the problems of weight gain and higher cost.
Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with lupus erythematosus: a descriptive study of 17 cases from a national registry and review of the literature
Authors: M. Ziemer, S.H. Kardaun, Y. Liss, M. Mockenhaupt
Journal: British Journal of Dermatology (2011)

Background Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions with high morbidity and mortality. Some expressions of lupus erythematosus (LE) may cause enormous difficulties in differentiating them from SJS and TEN by showing large areas of sheet-like epidermal necrosis. Objective To evaluate clinically and histopathologically probable or definite cases of SJS/TEN with a history of systemic or other LE [(S)LE]. Methods This was a retrospective analysis of validated cases of SJS/TEN with a history of (S)LE, based on a large population-based national registry. Results Among 1366 patients with SJS/TEN, 17 with a sufficiently documented history of (S)LE and representative histological material could be identified, suggesting a considerable over-representation of LE in patients with SJS/TEN. Eight of these showed clinically and/or histopathologically some LE-characteristic features interfering with the diagnosis of SJS/TEN. Differentiation could be elaborated on clinical and histopathological grounds: four patients were classified as SJS/TEN with a preceding (S)LE exacerbation and/or LE-typical histopathological features, and four as 'TEN-like' (S)LE. Conclusion Most patients with SJS/TEN and a history of (S)LE demonstrate clinical and histopathological properties allowing clear differentiation. However, occasionally acute cutaneous manifestations of (S)LE and SJS/TEN can be phenotypically similar, caused by extensive epidermal necrosis. Although no feature by itself is conclusive, a combination of recent (S)LE exacerbation, evident photodistribution, annular lesions and absent or only mild focal erosive mucosal involvement may favour LE over SJS/TEN clinically. Histopathologically, in particular, junctional vacuolar alteration, and the presence of solitary necrotic keratinocytes at lower epidermal levels, combined with moderate to dense periadnexal and perivascular lymphocytic infiltrates with a variable presence of melanophages, and mucin point to a LE-related origin.