tbuckley/cabot-search huggingface dataset:
What’s hot that the other lot got
Authors: Andrew P Prayle
Journal: Thorax (2019)

The link between poor air quality and paediatric asthma exacerbations is well-established. Surprisingly, this is less clear for ambient air pollutants and asthma incidence. Garcia et al (JAMA 2019;321:1906) undertook a longitudinal epidemiological study and found that as air quality improved, the incidence of childhood asthma reduced. Using data from three cohorts of school children, recruited between 1993 and 2014 from California, USA, they analysed trends in incidence of asthma, exploring the influence of air pollution (estimated using community-level data). Children in the cohort were followed-up annually, and the primary outcome was when the parents/guardians answered yes to the question ‘Has a doctor ever diagnosed this child with asthma?’. Air pollution decreased over time, and in parallel, asthma incidence decreased. In the fully adjusted model, the incidence risk ratio (IRR) for each 4.3ppb drop in nitrogen dioxide was 0.80 (95% CI 0.71 to 0.90), and for a drop of 8.1 µg/m3 in the levels of PM2.5 (particulate matter less than or equal to 2.5 diameter), the IRR was 0.81 (95% CI 0.67 to 0.98). Relationships with PM10 (particulate matter unde 10μm diameteand ozone were not statistically significant. Whether the pollutants are causal, or are markers for other factors, is, of …
Single-Ventricle Palliation in Low- and Middle-Income Countries
Authors: David N. Schidlow, Kimberlee Gauvreau, K.M. Cherian, Xinwei Du, Mahesh Kappanayil, R. Krishna Kumar, Ana Miriam Lenz, William M. Novick, Craig Sable, Kathy J. Jenkins
Journal: Journal of the American College of Cardiology (2019)
Pharmacokinetics and safety of apremilast in pediatric patients with moderate to severe plaque psoriasis: Results from a phase 2 open-label study
Authors: Amy S. Paller, Ying Hong, Emily M. Becker, Raul de Lucas, Maria Paris, Wendy Zhang, Zuoshun Zhang, Claire Barcellona, Peter Maes, Loretta Fiorillo
Journal: Journal of the American Academy of Dermatology (2019)

BackgroundNo oral systemic treatments are approved for pediatric patients with psoriasis.ObjectiveTo evaluate the pharmacokinetics and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in pediatric patients with psoriasis.MethodsThis phase 2, multicenter, open-label study enrolled pediatric patients with moderate to severe plaque psoriasis. Patients received apremilast twice daily without titration for 2 weeks (group 1 [age, 12-17 years; weight, ≥35 kg]: apremilast 20 or 30 mg; group 2 [age, 6-11 years; weight, ≥15 kg]: apremilast 20 mg), followed by a 48-week extension. Primary endpoints were pharmacokinetics and safety. Other endpoints were taste/acceptability and change from baseline in score on the Psoriasis Area and Severity Index.ResultsA total of 42 enrolled patients (21 adolescents [age, 12-17 years] and 21 children [age, 6-11 years]) received apremilast. Pharmacokinetics modeling and noncompartmental analyses showed that weight-based dosing with apremilast 20 mg twice daily in children or apremilast 20 or 30 mg twice daily in adolescents provides exposure (area under the concentration-time curve from time 0 to 12 hours after the dose) that is comparable to that achieved with apremilast 30 mg twice daily in adults. The safety profile was generally similar to that in adults. Most study participants liked the taste of the tablet. Improvements from baseline in mean Psoriasis Area and Severity Index score were 68% for adolescents (overall) and 79% for children.LimitationsNo children weighing less than 20 kg were enrolled.ConclusionsThis first-time-in-children phase 2 study supports weight-based apremilast dosing for future phase 3 studies of pediatric plaque psoriasis.
Abstract #LB-37: Characterization of both allosteric and ATP-Competitive kinase inhibitors with TR-FRET binding assays
Authors: Connie Lebakken, Steve Riddle, Bryan Marks, Upinder Singh, Jack Frazee, Hildegard Eliason, Jill Wolken, Yi Gao, Laurie Reichling, Kurt Vogel
Journal: Cancer Research (2009)

There is a great clinical need to develop selective, high affinity kinase inhibitors. While high throughput kinase activity assays have become readily available, easy to use and cost-effective, activity-based assays have significant limitations in terms of both the extent of target coverage and the type of information they can provide about compounds. We have developed a binding assay platform based on Alexa Fluor® 647 conjugated to kinase inhibitor scaffolds that does not require substrate or an activated kinase preparation. Binding of the conjugate to a kinase is detected by addition of a europium-labeled anti-tag antibody, which binds specifically to the kinase. Binding of the tracer and antibody to a kinase results in a high degree of FRET, whereas displacement of the tracer with a kinase inhibitor results in a loss of FRET. This assay can be utilized to explore activation-state binding selectivity, such as the case of Imatinib binding preferentially to the non-activated form of Abl. Furthermore, this assay can detect binding of allosteric, non-ATP competitive inhibitors, such as the IKK\#946; inhibitor BMS-3455411 and the allosteric MEK inhibitors, PD98059 and PD0325901. In addition, this format can be used to develop robust assays in cases where activity assay development has proven difficult.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-37.
VB1-008: Identification of a fully-human antibody specific for CD44E and CD44-isoform-3
Authors: Jeannick Cizeau, Francina Chahal, Joycelyn Entwistle, Michele Rasamoelisolo, Nick Glover, Glen MacDonald
Journal: Cancer Research (2006)

2903  During the course of their disease, cancer patients often produce antibody responses to their tumors. Humoral tumor immunity has been correlated, in some cases, with a better prognosis and longer survival. Viventia’s product development platforms, Hybridomics™, ImmunoMine™, and UnLock™, have been designed to identify patient tumor-specific antibodies and their cognate tumor-associated antigen. One hybridoma-derived antibody, VB1-008, an IgG MAb, generated from the PBLs of a breast cancer patient, demonstrates preferential binding to the breast cancer tissues/cell lines as tested by immunohistochemistry and flow cytometry with limited normal tissue reactivity. Immunoprecipitation with tumor cell membrane fractions from VB1-008-reactive cell lines showed VB1-008 to react with a ∼110 kDa protein under mild reducing conditions that further resolved over time into one ∼50 kDa band following 1D and two spots varying in pI upon 2D-PAGE analysis. LC-MS/MS analysis of the 1D and 2D spots identified CD44-isoform-3/CD44E and a truncated version of alpha-fetoprotein (AFP). More specifically, with the use of overlapping peptides, VB1-008 reactivity was restricted to the peptide sequence-TNMDSSH, from the unique region constituting the junction of Exon 5 and the variable region, v8 of CD44-isoform-3 and CD44E. CD44E and CD44-isoform-3 differ from each other by only 2 amino acid changes at positions 221 and 230; however, conserving the epitope, TNMDSSH, in both. A synthetic peptide representing the sequence, TNMDSSH, conserved in both isoforms, competes 96% of the original binding by VB1-008. A similar peptide of the same length generated according to the sequence of variable regions v7-v8 of a parent isoform, CD44-isoform 2, MDMDSSH, showed no binding or competition to VB1-008. Extensive analysis by flow cytometry demonstrated that AFP was not present on the cell surface suggesting that this truncated version of AFP was associated with CD44 at the cytosol/membrane interface. The known over-expression of CD44E and CD44-isoform-3 with certain cancers validates the “mining” of the human immune response for the identification of fully-human antibodies specific for drugable cell surface tumor-associated target antigens.
Abstract #LB-65: Test of cytotoxic and targeted anticancer drugs using human primary non-small cell lung cancer xenograft models
Authors: Changnian Liu, Yanli Liu, Dawei Chen, Likun Zhang, Wubin Pan, Zhonghua Tang, Jean-Pierre Wery, Yiyou Chen
Journal: Cancer Research (2009)

BACKGROUND New oncology drug development has moved from general cytotoxic agents to molecular target-directed therapeutics. Consequently, there is a need to identify tumor types and individual patient tumors that express the target and could benefit from more selective therapies in clinical trials. Therefore, the in vivo models used in preclinical development should be\#8220;disease-oriented\#8221;and target-directed. Recently, we developed non-small cell lung cancer (NSCLC) xenograft models by transplanting human fresh tumor fragments into nude mice (HuPrimeTM), which have been used for test of cytotoxic and targeted anticancer agents. METHODS The fresh NSCLC tumor samples were collected from local hospitals. The tumor fragments of 1-2 mm were subcutaneously implanted in the flanks of the Balb/c nude mice. In the first passage, tumors derived from male patients were implanted into male mice, and tumors from women were inoculated into female mice. All therapeutic efficacy experiments used female mice. The test drugs included paclitaxel, gemcitabine, and the epidermal growth factor receptor (EGFR) inhibitor erlotinib. The EGFR and K-ras mutation status were investigated and compared with their efficacy results. RESULTS A total of 72 NSCLC samples were implanted into nude mice, and 13 HuPrimeTM tumor models were established with a tumor taking rates of 18% for the first passage. The tumor taking rates were higher in the second and third passages ranged from approximately 80-100%. The HuPrime tumor xenografts\#8217; architecture, the cell and histopathological morphology from the three generations mirrored in most of cases the original patient cancers. The mutations for EGFR and K-ras among the tested tumor samples were 56% and 22%, respectively. The two cytotoxic drugs paclitaxel and gemcitatbine produced tumor growth inhibition rates ranged from 50-53% regardless of the EGFR and K-ras mutation status. While erlotinib demonstrated a significant antitumor activity only in the tumors with EGFR mutation and wild-type K-ras, which were consistent with their clinical findings. CONCLUSIONS These results suggest that HuprimeTM tumor xenograft models provide a unique renewable source of tumor material for test of novel anticancer agents. They may predict more relevant clinical response rates and higher correlation with clinical findings than use of traditional xenograft models established from long-term cultured cancer cell lines. Especially, they have advantages for test of target-oriented therapeutics in new drugs development programs.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-65.
DNA methylation status of Smurf2 promoter in patients with multiple myeloma
Authors: E. Hatzimichael, A. Dasoula, J. Stebbing, G. Dranitsaris, T. Crook, K. Bourantas
Journal: Journal of Clinical Oncology (2009)

e19537 Background: Multiple myeloma (MM) is an incurable interleukin (IL)-6 dependent plasma-cell malignancy. Transforming growth factor-β (TGF-β) is the major inducer of IL-6 secretion by bone marrow stromal cells. The signaling responses to TGF-b are mediated by the Smad proteins. The Smurf2 gene (Smad ubiqitiniation regulatory factor 2) encodes a Smad-specific E3 ubiquitin ligase and targets Smad2 and Smad3 for proteasome-dependent degradation. Methods: Bone marrow samples from individuals with MM were obtained at diagnosis and in 5 cases at disease progression as well. Genomic DNA was isolated and bisulphite modification was performed using commercially available kits. The methylation-specific polymerase chain reaction was employed to study the methylation status of the CpG island. Logistic regression analysis was used to measure the association between gene methylation and the development of advanced disease (DS≥ II), extramedullary disease, bone disease, anemia (Hb 10 mg/dl), serum albumin and beta 2 microglobulin levels. Results: We analysed the methylation of Smurf2 in 45 cases of MM (24 male, 21 female, mean age 66.4 years). No sample from the control population was found methylated. The Smurf2 gene promoter was found to be methylated in 11/45 MM patients (24%). Interesting trends were noted where patients with methylated Smurf2 promoter had an increased risk of death (HR = 1.3; p = 0.68), anemia (OR=2.1, p=0.2) and advanced stage (OR=1.3, p=0.6) and a reduced risk of extramedullary disease (OR= 0.2, p=0.2). No association was found between Smurf2 methylation status and bone lytic lesions, serum albumin levels or beta-2 microglobulin levels. Conclusions: Interesting associations between Smurf2 methylation and some relevant clinical parameters in patients with MM were suggested by the data. These findings warrant further evaluation in a larger sample of patients in order to enhance our statistical power and better define the prognostic and clinical value of Smurf2 methylation in MM. No significant financial relationships to disclose.
Prognostic Implications of Left Atrial Enlargement in Degenerative Mitral Regurgitation
Authors: Benjamin Essayagh, Clémence Antoine, Giovanni Benfari, David Messika-Zeitoun, Hector Michelena, Thierry Le Tourneau, Sunil Mankad, Christophe M. Tribouilloy, Prabin Thapa, Maurice Enriquez-Sarano
Journal: Journal of the American College of Cardiology (2019)
Diagnostic Role of Calreticulin Mutation in Patients with Ph/JAK2/MPL Negative Myeloproliferative Neoplasm Not Identified at Disease Presentation
Authors: Tanja Belcic, Sasa Anzej Doma, Irena Zupan, Martina Fink, Natasa Debeljak, Tadej Pajic, Matjaz Sever
Journal: Blood (2017)
The Nlrp6 inflammasome is not required for baseline colonic inner mucus layer formation or function
Authors: Joana K. Volk, Elisabeth E.L. Nyström, Sjoerd van der Post, Beatriz M. Abad, Bjoern O. Schroeder, Åsa Johansson, Frida Svensson, Sofia Jäverfelt, Malin E.V. Johansson, Gunnar C. Hansson, George M.H. Birchenough
Journal: The Journal of Experimental Medicine (2019)

The inner mucus layer (IML) is a critical barrier that protects the colonic epithelium from luminal threats and inflammatory bowel disease. Innate immune signaling is thought to regulate IML formation via goblet cell Nlrp6 inflammasome activity that controls secretion of the mucus structural component Muc2. We report that isolated colonic goblet cells express components of several inflammasomes; however, analysis of IML properties in multiple inflammasome-deficient mice, including littermate-controlled Nlrp6−/−, detect a functional IML barrier in all strains. Analysis of mice lacking inflammasome substrate cytokines identifies a defective IML in Il18−/− mice, but this phenotype is ultimately traced to a microbiota-driven, Il18-independent effect. Analysis of phenotypic transfer between IML-deficient and IML-intact mice finds that the Bacteroidales family S24-7 (Muribaculaceae) and genus Adlercrutzia consistently positively covary with IML barrier function. Together, our results demonstrate that baseline IML formation and function is independent of inflammasome activity and highlights the role of the microbiota in determining IML barrier function.
Evaluation of proliferation and apoptosis markers in circulating tumor cells (CTCs) of women with early breast cancer who are candidates for tumor dormancy.
Authors: Maria Spiliotaki, Haris Markomanolaki, Galatea Kallergi, Maria A. Papadaki, Vassilis Georgoulias, Dimitrios Mavroudis, Sofia Agelaki
Journal: Journal of Clinical Oncology (2013)

e22101 Background: Clinical dormancy is frequently observed in breast cancer (BC). In the present study, we aimed to characterize CTCs in dormancy candidates (DC) with BC in terms of proliferation and apoptosis. Methods: Cytospins of peripheral blood mononuclear cells (PBMCs) were obtained from DC (n=122) disease-free for ≥5 yrs and from metastatic pts (n=37) on relapse that occurred ≥5 yrs after surgery. Sequential samples (n=27) of 8 DC with late relapse and from 8 relapse-free (n=38), were also analyzed. 10 6 PBMCs were stained with pancytokeratin antibody along with ki-67 and M30 as proliferation and apoptosis markers, respectively. Results: CTCs were identified in 40 (32%) of 122 DC. In 25 (61.5%), all CTCs were ki-67(-)/M30(-), 7 (17.5%) had ki-67(+), 4 (10%) M30(+) CTCs and 4 had both phenotypes. Among 243 CTCs detected, 201 (82.5%) were ki-67(-)/M30(-), 14 (5.7%) ki-67(+) and 29 (11.9%) M30(+). Of 13 (35%) CTC(+) metastatic pts, 6 (46%) had ki-67(+) CTCs (p=0.037) whereas 54 (40%) of total CTCs were ki-67(+) (p&lt;0.001). No M30(+) CTCs were detected. When sequential samples of the 8 DC who relapsed were analyzed, 2 (25%), had only ki-67(-)/M30(-) CTCs, 6 (75%) had ki-67(+) and 4 (50%) M30(+) CTCs. The respective numbers in the non-relapsed group were 4 (50%), 3 (37.5%) and 3 (37.5%). Moreover, ki-67(+) CTCs were more frequently observed in samples of the relapsed pts (29.6% vs 13.1%). Among 382 CTCs detected in all sequential samples from the relapsed group, 337 (88.14%) were ki-67(-)/M30(-), 26 (6.7%) ki-67(+) and 20 (5.1%) M30(+), whereas the respective percentages among 78 CTCs in non-relapsed pts were 77.6%, 6.5% and 15.8% (p=0.001). Conclusions: The great majority of CTCs detected in DC with BC express neither proliferation, nor apoptosis markers. However, the apoptotic index in CTCs is increased during clinical dormancy, whereas the proliferation index is increased on relapse. In addition, apoptotic CTCs are more frequently encountered during follow-up in DC free of relapse. The above observations suggest that monitoring proliferation and apoptosis in CTCs during clinical dormancy could be used to predict subsequent late relapse.
Endoscopic closure using polyglycolic acid sheets for delayed perforation after colonic endoscopic submucosal dissection
Authors: Yasuaki Nagami, Shusei Fukunaga, Atsushi Kanamori, Taishi Sakai, Masaki Ominami, Toshio Watanabe, Yasuhiro Fujiwara
Journal: Endoscopy (2019)

Recently, polyglycolic acid (PGA) sheets and fibrin glue have been reported to close perforations in several areas of the gastrointestinal tract [1] [2] [3] [4] [5]. However, delayed perforation after colonic endoscopic submucosal dissection (ESD) usually requires emergency surgery. We report on a case of delayed perforation after colonic ESD that was treated with PGA sheets and fibrin glue.
Real-world effectiveness of apremilast in multirefractory mucosal involvement of Behçet’s disease
Authors: Giuseppe Lopalco, Vincenzo Venerito, Pietro Leccese, Giacomo Emmi, Luca Cantarini, Nancy Lascaro, Gerardo Di Scala, Claudia Fabiani, Donato Rigante, Florenzo Iannone
Journal: Annals of the Rheumatic Diseases (2019)

Relapsing oral and genital ulcers (OGUs) represent the stigmata of Behcet’s disease (BD) and may be very painful, affecting both quality of life and relationships. A wide number of topical and immunosuppressive drugs can be used to treat ulcers,1 but failures are commonly reported. The efficacy of the phosphodiesterase-4 inhibitor apremilast has been proven in OGUs of BD in two randomised clinical trials (RCTs),2 3 whereas only two case reports are available until now.4 5 We aimed at evaluating the real-world effectiveness of apremilast in BD patients with OGUs refractory to conventional and/or biological treatments.

We retrospectively evaluated patients classified as BD, according to International Criteria for BD6 and International Study Group7 criteria, who underwent apremilast (30 mg two times per day) for multirefractory OGUs from November 2017 to January 2019. The number of OGUs was assessed at baseline and either at 3 and 6 months. Pain from ulcers and BD activity were …
Preventive therapy compliance in pediatric tuberculosis – A single center experience
Authors: J.C. Santos, J.B. Silva, M.A. Rangel, L. Barbosa, I. Carvalho
Journal: Pulmonology (2019)

Despite its importance, there are some barriers to patient compliance in preventive therapy (PT) of tuberculosis (TB). The purpose of this study was to evaluate the compliance to appointments, PT and follow-up in a pediatric population after TB exposure, followed in a single TB outpatient center, and the subsequent identification of compliance determinants. Retrospective analysis of all pediatric patients who underwent PT in Gaia TB outpatient center from January 2015 to June 2016. Patients were divided into two groups: compliant and non-compliant, according to adherence to screening, visits and medication. The data collection was based on review of medical records. A total of 72 patients were enrolled, 33 (45.8%) on chemoprophylaxis and 39 (54.2%) on latent tuberculosis infection (LTBI) treatment. The majority of patients were compliant (63.9%, n = 46). Non-compliance was found in 36.1% (n = 26): in 12 patients to contact screening, in 11 patients to PT and 22 patients did not attend medical appointments in the first place. In 10 patients, non-compliance was related to social problems/family dysfunction (low socioeconomic status and parent's unemployment). After putting in place several strategies, such as telephone contact, activating social services and direct observation of therapy, a compliance of 98.6% was achieved. Isoniazid was the main drug used (91.7%), during 9 months for LBTI. PT compliance in TB can be challenging, probably related to the lack of risk perception and caregiver's reluctance to undergo a prolonged treatment to an asymptomatic condition. We conclude that implementing interventions can considerably improve treatment compliance and reduce the risk of future tuberculosis development. We emphasize the success in compliance to a 9 month regimen of isoniazid in the vast majority of patients with LTBI.
Methacrylic Acid Copolymer Coating Enhances Constructive Remodeling of Polypropylene Mesh by Increasing the Vascular Response
Authors: Virginie F. Coindre, Miranda M. Carleton, Michael V. Sefton
Journal: Advanced Healthcare Materials (2019)

Abstract This study reports that a methacrylic acid (MAA)‐based copolymer coating generates constructive remodeling of polypropylene (PP) surgical mesh in a subcutaneous model. This coating is non‐bioresorbable and follows the architecture of the mesh without impeding connective tissue integration. Following implantation, the tissue response is biased toward vascularization instead of fibrosis. The vessel density around the MAA mesh is double that of the uncoated mesh two weeks after implantation. This initial vasculature regresses after two weeks while mature vessels remain, suggesting an enhanced healing response. Concurrently, the MAA coating alters the foreign body response to the mesh. Fewer infiltrating cells, macrophages, and foreign body giant cells are found at the tissue–material interface three weeks after implantation. The coating also dampens inflammation, with lower expression levels of pro‐inflammatory and fibrogenic signals (e.g., Tgf‐β1 , Tnf‐α , and Il1‐β ) and similar expression levels of anti‐inflammatory cytokines (e.g., Il10 and Il6 ) compared to the uncoated mesh. Contrary to other coatings that aim to mitigate the foreign body response to PP mesh, a MAA coating does not require the addition of any biological agents to have an effect, making the coated mesh an attractive candidate for soft tissue repair.