dataesr/scientific-paragraphs-categorization huggingface dataset:
57Rev1. On the basis of available data on (1R,2S,5R)-isopulegol [FL-no: 02. 067], the Panel concluded that for (1R,2S,5R)-isopulegol [FL-no: 02. 067], (2R,5S)-isopulegone [FL-no: 07. 067] and (1R,2S,5R)isopulegyl acetate [FL-no: 09. 219] there is no concern for genotoxicity and, therefore, they can be evaluated through the Procedure. The Panel agrees with JECFA that these substances should be evaluated via the B-side of the Procedure. From a newly submitted 90-day subchronic oral toxicity study, a NOAEL of 38 mg/kg bw per day can be derived for isopulegol. Based on this, for substances (1R,2S,5R)-isopulegol [FL-no: 02. 067], (2R,5S)-isopulegone [FL-no: 07. 067] and (1R,2S,5R)-isopulegyl acetate [FL-no: 09. 219], adequate margins of safety can be derived and these three substances would not pose a safety concern at the current levels of exposure, based on the MSDI approach.
Despite the big post-communist handicaps of the Romanian health system I decided to dedicate the next few years to developing an HAE comprehensive program in my country. Surrounded by a handful of enthusiastic colleagues, I started to look for sporadic cases in some personal databases of colleagues from immunology labs, and also asked for the addresses of those with low C1 inhibitor results. Since 2005 we have organized workshops related to the annual conferences of the Romanian Society of Allergology and Clinical Immunology and later meetings centered on HAE only. From the beginning the support of HAE experts from Europe and later from Israel and USA was significant. In these past 12 years, we have made presentations at the conferences of the national meetings of paediatrics, dermatology, internal medicine, emergency medicine and published papers in order to increase the awareness about this life-threatening disease.
In the past 10 years, we have participated in 12 multicentre clinical trials. In 2006 we founded the Romanian Network for Hereditary Angioedema, a professional non-profit organization who allowed us to have our own website, to develop a Romanian HAE guideline and to put together a national registry of HAE patients, which currently includes 99 patients. With our support, the Association of the Romanian HAE patients was founded in 2012. Until 2013 no modern treatments were available. Recombinant C1-inhibitor and a C1-inhibitor concentrate were offered in ED in a small amount from 2015 and it was promised that the B2 receptor antagonist (icatibant) will be reimbursed through a national program that will start soon. Hopefully, the quality of life of these patients will improve considerably. There is still a lot to do to raise the awareness and expand the education of both physicians and patients about this disorder; however, our aim is above all to address the challenge of finding an estimated 250 patients that are missing from our database.
Real-time monitoring of F1 + 2 and TAT complex suggest that thrombin contribute to the development of edema formation. We confirmed that D-dimer is a prominent biomarker of an ongoing edematous attack. Elevated levels of fibrinogen before the onset edematous symptoms raise the possibility of using it as a predictive marker. Background: Cinryze, a human plasma-derived C1 inhibitor (C1-INH) is approved for routine prophylaxis against hereditary angioedema (HAE type I and II) attacks in adults, adolescents, and children. We present interim efficacy and safety results as well as the pharmacokinetics and pharmacodynamics of two doses of intravenous (IV) C1-INH in patients 6-11 years of age. Methods: This is an ongoing randomized, phase 3, multi-centre, single-blind, crossover study (NCT02052141).
We present data from 6 patients who completed the study. Following a 12-week baseline observation period (BOP), patients were randomised to receive 500U or 1000U IV C1-INH every 3-4 days for 12 weeks, and then switched to the other dose for 12 weeks. The primary efficacy endpoint was the number of monthly attacks in a treatment period. Secondary efficacy endpoints included attack severity and the number of attacks requiring acute treatment. Clinical and laboratory safety were evaluated. Blood samples were collected before and 1 h after doses 1, 12, and 24 to measure functional C1-INH activity, C1-INH antigen, and C4. Results: Six patients (all female with HAE type I and a median age of 10. 5 years) had a mean (SD) of 2. 26 (1. 62) attacks per month during the BOP. The mean (SD) difference in the number of attacks between the BOP and treatment periods was -1.
There were no SAEs and no severe drug-related AEs. BCX7353-treated subjects had a numerically higher number of mild to moderate gastrointestinal AEs; additionally, BCX7353-related gastrointestinal AEs may have been reported as HAE attacks. Conclusions: Once-daily BCX7353 was associated with a clinically meaningful, statistically significant reduction in attacks in subjects with HAE. BCX7353 was generally safe and well tolerated. These findings support the ongoing evaluation of a range of doses of BCX7353 for prophylaxis of angioedema attacks in HAE patients. Background: Lanadelumab (DX-2930/SHP-643) is a long-acting, highly-specific, potent, human monoclonal antibody targeting plasma kallikrein that received fast track and breakthrough therapy designations. Results from a Phase 1b study (NCT02093923) did not identify safety signals and supported efficacy of lanadelumab in preventing hereditary angioedema (HAE) attacks.
A pivotal randomized, doubleblind (DB), placebo-controlled, parallel arm study (NCT02586805) is ongoing, and an open-label extension (OLE; NCT02741596) is currently enrolling patients (pts). Here, we describe the design of a Phase 3 OLE study to evaluate the long-term safety and efficacy of lanadelumab for prevention of angioedema attacks in patients with HAE. Materials and methods: This OLE will include pts (≥12 years old; Type 1/2 HAE) rolling over from the DB study and an additional 50-100 pts who did not participate in the DB study (non-rollover). The non-rollover population will include pts switching to lanadelumab from another prophylactic therapy. Rollover pts will initially receive a single 300 mg subcutaneous dose of lanadelumab and will not receive another dose until after their first HAE attack.
The assay is sensitive to spiked concentrations of CSL312 in the range of 1-10 µg/mL. The assay also discriminates HAE and healthy plasma samples. Less than 10 µg/mL of CSL312 added to HAE plasma restored amidolytic activity to levels seen in normal subjects. The CSL312 concentration needed to treat HAE samples to achieve a target kallikrein activity may be used to predict effective CSL312 doses in HAE patients. Data will also be presented showing characterisation of different HAE patient samples using this assay. Conclusions: CSL312 is a potent inhibitor of FXIIa-mediated kallikrein activity in normal and HAE plasma. This assay shows promise to monitor CSL312 effects and inform clinical dosing regimens. Hereditary angioedema (HAE) is an autosomal dominant inherited disease characterized by painful edema episodes with variable localization and severity.
A next-generation sequencing (NGS) platform (Ampliseq custom panel, Thermo Scientific) was developed by which all coding regions and exon-intron splice junctions of these genes (minimum coverage 90%) were analyzed. Analysis of primary data was conducted with Ion Reporter software v. 5. 2 (Thermo Scientific). Polymorphisms (UCSC Common SNPs) for which no disease associations are reported in the ClinVar database were excluded and pathogenicity of variants was predicted by bioinformatics analysis using SIFT and PolyPhen tools, in comparison to their global (1000 Genomes Global Minor Allele Frequency, ExAC) and European frequency (5000 Exomes European Minor Allele Frequency). Results: In 24/29 patients various heterozygous or homozygous genetic alterations of the analyzed genes were detected, alone (8) or in combination (16).
Seven patients received tranexamic acid for a total of 31 years. During this time period 4 patients were symptom-free. In two patients tranexamic acid was partially effective and in a further patient ineffective. Danazol was effective in 4 patients and ineffective in 2 patients. Two patients were treated with stanozolol for a total of 8 years. Stanozolol   [1]. In this analysis, data from the Icatibant Outcome Survey (IOS) was used to determine which physicians are diagnosing C1-INH-HAE, to help identify where to focus awareness efforts. Methods: The IOS is an international observational study monitoring the safety and effectiveness of icatibant for the treatment of angioedema attacks. All study participants provided written informed consent. Data were collected from 12 countries between July 2009 and January 2017.
O-30 Can routine prophylactic subcutaneous C1-inhibitor [C1-INH(SC)] alleviate psychological and physical disabilities caused by HAE? Findings from the COMPACT study (NCT01912456) William R. Lumry Background: The painful and life-threatening hereditary angioedema (HAE) attacks are associated with oedema leading to disability and impairment in daily activities [1]. This is very stressful for patients and their families and may be associated with anxiety and depression [2]. Here, findings from the subject-reported outcome measures in the Phase 3 COMPACT study are reported. Materials and methods: In this study, 90 subjects with HAE were randomized to 1 of the 4 treatment sequences to receive 40 or 60 IU/ kg C1-INH(SC) twice-weekly for 16 weeks, preceded or followed by placebo for 16 weeks. Analyses were carried out in those subjects who provided at least one subject-reported outcome assessment (Quality-of-Life [QoL] population).
The exploratory analyses evaluated subject-reported outcome measures at screening and post-treatment. The measure, work productivity and activity impairment (WPAI) was assessed after 5, 8, 11, and 14 weeks of each treatment period while the Hospital Anxiety and Depression Scale (HADS) and Treatment Satisfaction Questionnaire for Medication (TSQM) measures were assessed after 5 and 14 weeks of each treatment period. The absolute mean/median values at each assessment during the active and placebo periods and the within-subject differences for each dose (and both doses combined) of C1-INH(SC) versus placebo were calculated for the individual domains of each measure at week 14. HRQoL was measured by E5QD (range 0-1), HAE-QoL (range 25-135) and AE-QoL (range (0-100). Data were entered into an excel database and statistical analysis was performed using SPSS v.
Then, we analysed 20 C1-INH-HAE patients in remission and during angioedema attack. Concentrations of angiogenic (VEGF-A, Ang1, Ang2) and lymphangiogenic (VEGF-C) factors were evaluated by ELISA. Results: We could not detect differences in the levels of the tested factors between untreated patients and patients undergoing prophylaxis with attenuated androgens. However, these are preliminary data that we plan to expand in a follow-up study. VEGF-A, VEGF-C and Ang2 levels were not modified during attack compared to basal conditions. By contrast, Ang1 levels (a vascular stabilizer) were increased during acute phase and the ratio Ang2/Ang1 (an index of vascular permeability) was decreased.
Ruconest is a recombinant human C1 inhibitor that is approved for treatment of HAE attacks. A treatment registry was established in Europe to review the adverse event profile and efficacy of Ruconest following single and repeated treatment with Ruconest. Methods: Patients with C1-INH-HAE were enrolled following a decision to treat with Ruconest and after providing written informed consent. Medical history and baseline HAE information was collected at a screening visit. Treatment decisions were at the discretion of the health care professionals (HCP) involved in the patients' care according to their standards for the management of C1-INH-HAE and in line with the approved Ruconest summary of product characteristics. Following treatment with Ruconest, the HCP entered data using a web-based questionnaire about the attack, response to therapy, and any adverse events.
Almost all attacks (1349/1351, 99. 8%) were treated with a single dose of Ruconest. Two attacks treated with an initial dose of 2100 U (33 and 28 U/kg) received a second dose of 2100 U. No hypersensitivity or thrombotic/thromboembolic events were reported. No patients had any related serious adverse events. Conclusions: The Ruconest treatment registry provides real-world data on the treatment of 1351 HAE attacks that is consistent with previous reports on the safety and efficacy of Ruconest therapy.
P-28 Hereditary angioedema in Mexican paediatric population Melissa I. Espinosa   1  and 2. Family history of HAE related death was reported in 37 patients (53%). Based on the frequency of attacks patients are grouped in 5 categories (n = 53) (Table  3 ). The location of attacks data is presented in Table  4. Treatment modalities are presented in Table  5. Background: Hereditary angioedema (HAE) is a rare genetic disorder affecting 1:50,000 people. Remarkable progress has been made over the last decade, due to a renewed interest in the disease, better diagnosis and new treatment modalities. The State of Israel (pop. 8,500,000) comprises ethnically heterogeneous society, which undergoes dynamic socioeconomic changes and witnessing constant waves of immigration from Asia, America, Europe and Africa.
1, Timothy Craig 2 , Marco Cicardi 3 , Bruce L. Zuraw4, Hilary Longhurst 5 , Henriette Farkas6, Henrike Feuersenger 7, Douglas J. Watson 7 , Thomas Machnig 7 , on behalf of the Investigators of the COMPACT (NCT01912456) study 1 AARA Research Center, Dallas, TX, 75231, USA; 2 Department of Medicine and Pediatrics, Penn State University Allergy, Immunology and Respiratory Research, Hershey, PA, 17033, USA; 3 Department Biomedical and Clinical Sciences Luigi Sacco University of Milan, ASST Fatebenefratelli Sacco, 20157, Milano, Italy; 4 Department of US HAEA Angioedema Center, UC San Diego, La Jolla, CA, 92193, USA; 5 Department of Immunology, Barts Health NHS Trust, London, E1 1RD, UK; 6 Department of Internal Medicine, Hungarian Angioedema Center, Semmelweis University, Budapest, 1085, Hungary; 7 CSL Behring GmbH, 35002, Marburg, Germany Correspondence: Thomas Machnig (thomas.
Acknowledgements: We thank Priscila A. Nicolicht  for the technical help. Acknowledgements: We thank for their participation:  Dr. S. Amarger ,  Dr. C. Blanchard-Delaunay ,  Dr. A. DuThanh ,  Dr. B. Coppere ,  Dr. B. Floccard ,  Dr. S. Gayet ,  Dr. P. Y. Jeandel ,  Pr L. Martin ,  Dr. F. Pelletier ,  Dr. F. N. Raison Peyron ,  Dr. S. Trouillet  and the  French National Reference Center for Hereditary Angioedema (CREAK).
Materials and methods: The population C1-INH(f ) data in the sub-jects treated with C1-INH were analyzed by nonlinear mixed effects modeling using the package NONMEM (v7. 2) to characterise the pharmacokinetics (PKs) of C1-INH concentrate. PK parameters such as clearance (CL), volume of distribution (Vd), bioavailability (F) and base-line C1-INH(f ) were estimated using the first-order conditional estima-tion method. Results: A total of 124 subjects (108 with HAE and 16 healthy volun-teers) were included in the PK analysis dataset, which comprised of a total of 2103 C1-INH(f ) observations. C1-INH(f ) following adminis-tration of C1-INH was adequately described by a one-compartment model with first-order absorption and elimination, with inter-indi- vidual variability estimated for all the parameters tested.
Only 4% of 818 attacks were severe and first signs manifested most commonly as erythema. Iris Leibovich-Nassi 1 , Karin Andritschke 2 , Christine Symons 3 , John Dempster 4 , Avner Reshef 1 , Henriette Farkas 5 1 Angioedema Research Center, Sheba Medical Center, 5265601, Tel-Hashomer, Israel; 2 Rhein-Main Haemophilia Centre (HZRM), Moer- felden, 64546, Germany; 3 Derriford Hospital, Plymouth, PL6 8DH, UK; O-25 Comorbidities of patients with hereditary angioedema due to C1-inhibitor deficiency in Hungary Kinga V. Kőhalmi, Noémi Andrási, Tamás Szilágyi, Nóra Veszeli, Lilian Varga, Henriette Farkas Hungarian Angioedema Centre, 3rd Department of Internal Medicine, Semmelweis University, Budapest, 1125, Hungary Trial Registration NCT01034969 Reference 1. Zanichelli A, Magerl M, Longhurst H, Fabien V, Maurer M.
13(Suppl 2):O-30 1, Timothy Craig 2 , Marco Cicardi 3 , Bruce L. Zuraw4, Hilary Longhurst 5 , Henriette Farkas6, Henrike Feuersenger 7, Douglas J. Watson 7 , Thomas Machnig 7 , on behalf of the Investigators of the COMPACT (NCT01912456) study 1 AARA Research Center, Dallas, TX, 75231, USA; 2 Department of Medicine and Pediatrics, Penn State University Allergy, Immunology and Respiratory Research, Hershey, PA, 17033, USA; 3 Department Biomedical and Clinical Sciences Luigi Sacco University of Milan, ASST Fatebenefratelli Sacco, 20157, Milano, Italy; 4 Department of US HAEA Angioedema Center, UC San Diego, La Jolla, CA, 92193, USA; 5 Department of Immunology, Barts Health NHS Trust, London, E1 1RD, UK; 6 Department of Internal Medicine, Hungarian Angioedema Center, Semmelweis University, Budapest, 1085, Hungary; 7 CSL Behring GmbH, 35002, Marburg, Germany Correspondence: Thomas Machnig (thomas.
84-138del55, p. Ile274Val, p. Gly429Arg, p. Val454Glu, p. Arg456Glu, p. Arg458Thr(Arg), p. Arg465Val, p. Arg466Ser(His,Leu,Cys), p. Thr467Pro, p. Val473Met, p. Phe477Ser, p. Leu481Phe(Arg), p. Phe489Arg, p. Gly493Arg, p. Phe498Ser (information from https:// www. nextprot. org). Results: • We find 9 splicing, 6 missense, 7 frameshift and 2 nonsense mutations. 10 of them have been found that were not described in the consulted database (http://www. ensembl. org/index. html), but in general only 6 mutations didn't mention in ensemble. org, because we have duplicates of mutations. • 4 small deletions affecting exon 3 (c. 520-524delATCGC, p. Ser173fs254X), exon 8 (c. 1293delA, p. Leu430fs449X), exon 7 (c. 1106delA, p. Glu368fs396X) and exon 5 (c. 744-745delCA, p. 247Serfs255X) have been find. All of them are producing frame-shifts leading to premature stop codons.
We analyzed patient data from the Icatibant Outcome Survey (IOS) to evaluate the relation- Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Luigi Sacco Hospital, Milan, Italy; 2 CEO Cloud-R s. r. l. , Milan, Italy Correspondence: Francesca Perego (francescappe@gmail. com) Allergy, Asthma & Clinical Immunology 2017, 13(Suppl 2):P-32 ship between patient age (birth date) and both age at diagnosis and delay in diagnosis (time between first symptom onset and diagnosis). Methods: The IOS is an international, observational study (NCT01034969). Data were collected from 12 countries between July 2009 and January 2017. Study participants provided written informed consent. Patients with a family history of C1-INH-HAE who were diag-nosed before their first symptoms were excluded from analysis.
To avoid potential bias inherent in the data collected from the youngest generation (time to diagnosis is limited by their age), only patients born before 1990 and diagnosed before 25 years of age were included. Linear regression analyses were performed. Results: Of 685 patients with C1-INH-HAE type I or II in the IOS as of Background: Different forms of angioedema occurring without wheals have been classified (Cicardi et al. Allergy 2014;69:602-16), data on each form are minimal and have never been collected system-atically. Our aim is to gather in a single registry clinical and laboratory data on the various forms of angioedema, providing better characteri-zation to improve diagnostic and therapeutic approaches. Materials and methods: Starting from an Italian database of patients with C1-INH-HAE provided by the Italian network ITACA, a web based multi-center registry was created with the support of the Italian HAE Association.
Systematic review of literature on MC4R variants To assess the functional consequences of all published MC4R mutations, we searched all studies on functional cell-based assays of MC4R variants. We systematically reviewed articles containing the terms "MC4R" or "mc4-r" indexed on MEDLINE from inception to August 31st, 2016 in addition to bibliographies of manually selected articles, mutations published by human genetic databases (1000 Genomes release 16, Exome Variant Server ESP6500SI-V2) and unpublished data from our labs. Because functional consequences of MC4R mutations are assessed and reported in a wide variety of ways, we devised an a priori semi-quantitative scale of the overall residual function. Each non-synonymous mutation could lead to a complete LOF, a partial LOF, or no LOF (wild type like).
In addition, contradictory and unclear published data resulted in ambiguous status for many variants. Functional assay data were collected for each published MC4R variant: cell line, cell surface expression, tested ligands (a-MSH, b-MSH, g1-MSH and artificial agonists such as NDP-a-MSH, melanotan [MT-II]), E max (efficacy, the maximum level of cAMP production in response to increased doses of a given ligand), EC 50 (potency, the concentration of a ligand eliciting half of the maximum response in cAMP production), and in a competitive binding assay B max (the maximal binding capacity to a ligand) and IC 50 (affinity, the concentration of a ligand binding half the receptors). All functional data were normalized to wild type levels, to enable comparison between articles (Figures S1eS2). The assay data were independently abstracted by three authors (T.
Functional characterization of MC4R variants in cell-based assays In order to characterize newly identified MC4R variants or to clarify classification of variants for which the systematic review of published data returned ambiguous results, we performed in vitro assays in transiently transfected HEK293 cells. We assessed relative cell surface expression of the mutant receptors in cell-based ELISA and we employed the cAMP response element-binding protein (CREB) transreporting system (Stratagene) to examine the impact of these variants on the receptor signaling activity via cAMP dependent pathway. MC4R cDNA constructs barring an N-terminal FLAG tag in pCDNA3. 1(þ) vector (Invitrogen) were used throughout the study. Sitedirected mutagenesis was performed using QuikChange kit (Agilent) according to the manufacturer's protocols.
CREB-luciferase reporter assay In order to detect MC4R signaling activity, HEK293 cells were transiently co-transfected with a respective MC4R construct, a transactivator plasmid pFA2-CREB and a reporter plasmid, pFR-Luc at 5, 6 and 25 ng/well, respectively. On the following day, cells were stimulated with increasing concentration of a-MSH for 5 h. The CREB-luciferase activity was determined using Steadylite plus substrate (Perkin Elmer, 6066759). Briefly, cells were washed with Dulbecco's modified PBS (DPBS) supplemented with 0. 9 mM CaCl 2 and 0. 5 mM MgCl 2 (Gibco, 14040). DPBS and ready-to-use luciferase substrate were dispensed in equal volumes, and luminescence was quantified after 20 min using TopCount Microplate Counter (Packard). All results were analyzed using GraphPad Prism 6 (GraphPad Software).
Relative cell surface expression is presented as means AE SEM of three to four independent experiments, each normalized to basal signal for mock transfected cells and MC4R WT expression level in a given assay. CREB-luciferase reporter assays were carried out in triplicates and were independently replicated at least three times. Results of each experiment were normalized to basal signal for mock transfected cells and maximal efficacy of a-MSH for MC4R WT in a given assay. Presented doseeresponse curves were plotted from the merged normalized data analyzed with 4-parameter non-linear regression equation.