tbuckley/cabot-search huggingface dataset:
Epitope mapping and reactivity of autoantibodies to the E2 component of 2-oxoglutarate dehydrogenase complex in primary biliary cirrhosis using recombinant 2-oxoglutarate dehydrogenase complex
Authors: S Moteki, P S Leung, E R Dickson, D H Van Thiel, C Galperin, T Buch, D Alarcon-Segovia, D Kershenobich, K Kawano, R L Coppel, S Matuda, M E Gershwin
Journal: Hepatology (1996)

Five different target mitochondrial autoantigens recognized by sera from patients with primary biliary cirrhosis (PBC) have been identified as subunits of the following 2-oxo acid dehydrogenase complexes: the pyruvate dehydrogenase complex (PDC), the branched chain 2-oxo acid dehydrogenase complex (BCOADC), and the 2-oxoglutarate dehydrogenase complex (OGDC). Unlike the E2 subunits of PDC (PDC-E2) and BCOADC (BCOADC-E2), the E2 subunits of OGDC (OGDC-E2) reactivity of PBC sera and the reactive epitope of OGDC-D2 have not hitherto been studied in detail. In this report, we took advantage of a recombinant fusion protein for OGDC-E2 to address these issues. Eighty of 268 (29.9%) PBC patient sera but none of the 45 controls reacted with recombinant OGDC-E2. The recombinant OGDC-E2 was judged to express the immunodominant epitope, because when sera from patients with PBC were preabsorbed with the recombinant fusion protein, such sera were depleted of reactivity against 48 kD OGDC-E2 when probed on beef heart mitochondria (BHM) but retained reactivity toward PDC-E2 and/or BCOADC-E2. Furthermore, affinity-purified PBC sera against recombinant OGDC-E2 reacted only with native OGDC-E2 and not with any other enzyme components of the 2-oxo acid dehydrogenase complex. Antimitochondrial autoantibodies (AMA) against OGDC-E2 included immunoglobulin (Ig)G2, IgG3 and IgM and the relative titers were as follows: IgG2 &gt; IgG3 &gt; IgM. Finally, using overlapping recombinant polypeptides, it was determined that a minimum of 81 amino acids (residues 67-147) corresponding to the lipoyl domain of OGDC-E2 are necessary for reactivity, suggesting that a conformational autoepitope is recognized by AMA. These data suggest that each of the 2-oxo acid dehydrogenase enzymes has distinct antigenicity despite their similarities in structure and function. The availability of recombinant OGDC-E2 autoantigen will allow the design of additional studies to further our understanding of the role of mitochondrial autoantigens in the pathogenesis of PBC.
The quest for liver progenitor cells: A practical point of view
Authors: Laurent Dollé, Jan Best, Jie Mei, Feras Al Battah, Hendrik Reynaert, Leo A. van Grunsven, Albert Geerts
Journal: Journal of Hepatology (2009)

Many chronic liver diseases can lead to hepatic dysfunction with organ failure. At present, orthotopic liver transplantation represents the benchmark therapy of terminal liver disease. However this practice is limited by shortage of donor grafts, the need for lifelong immunosuppression and very demanding state-of-the-art surgery. For this reason, new therapies have been developed to restore liver function, primarily in the form of hepatocyte transplantation and artificial liver support devices. While already offered in very specialized centers, both of these modalities still remain experimental. Recently, liver progenitor cells have shown great promise for cell therapy, and consequently they have attracted a lot of attention as an alternative or supportive tool for liver transplantation. These liver progenitor cells are quiescent in the healthy liver and become activated in certain liver diseases in which the regenerative capacity of mature hepatocytes and/or cholangiocytes is impaired. Although reports describing liver progenitor cells are numerous, they have not led to a consensus on the identity of the liver progenitor cell. In this review, we will discuss some of the characteristics of these cells and the different ways that have been used to obtain these from rodents. We will also highlight the challenges that researchers are facing in their quest to identify and use liver progenitor cells.
Bronchoscopic transparenchymal nodule access (BTPNA): first in human trial of a novel procedure for sampling solitary pulmonary nodules
Authors: F. J. Herth, R. Eberhardt, D. Sterman, G. A. Silvestri, H. Hoffmann, P. L. Shah
Journal: Thorax (2015)

<h3>Introduction</h3> The promise of benefits from lung cancer screening is tempered by the false positive rate and the need to perform diagnostic procedures to determine the aetiology of the solitary pulmonary nodules (SPN) identified. We have developed a novel procedure which allows sampling of SPNs via a transparenchymal approach, and report the results from this as a first in human trial. <h3>Methods</h3> This study was a prospective single-arm interventional study. We recruited patients with a SPN detected on CT imaging, which was suspicious for lung cancer, who were suitable for surgical resection. Using the subject9s CT, an optimal airway wall point of entry (POE), and an avascular path through lung tissue from the POE to the SPN was calculated. A tunnel tract was created from the POE to the nodule using a set of catheter-based tools under fused fluoroscopy guidance. The patients proceeded to surgical resection immediately after the biopsy. The participants were followed-up for 6 months after the procedure. The primary endpoint of the study was to evaluate the feasibility to access and biopsy the nodule. <h3>Results</h3> Twelve patients were recruited, and a tunnel pathway created in 10 patients. There were no adverse events during the procedures. Adequate biopsies were obtained from 10 patients (83%), which correlated with the histological findings from the surgical resection. Inspection of the resected lobes did not raise any safety concerns and indicated appropriately tunnelled pathways to the nodule. <h3>Conclusions</h3> This first in human study demonstrates that bronchoscopic transparenchymal access of SPNs is feasible. <h3>Trial registration number</h3> NCT02130115.
NLCQ-1 (NSC 709257) in combination with radiation against human glioma U251 xenografts
Authors: Maria V. Papadopoulou, William D. Bloomer, Melinda G. Hollingshead
Journal: Cancer Research (2004)

4135   The efficacy of the weak DNA-intercalative hypoxia-selective cytotoxin NLCQ-1 was investigated in combination with single or fractionated doses of radiation against human glioma U251 xenografts. Two “advanced stage” experiments were performed in female athymic nude mice. Animals were allocated in groups of 8-10 (treated groups) and 10-20 (control groups). Tumors (1x10 7  cells) were implanted SC at the base of the tail. At the time of treatment the median tumor weight ranged from 158-196 mg. Mice were irradiated in lead jigs with either single or fractionated radiation doses. Fractionated radiation was administered either qd x 4 or qd x 2, followed by a 9 day rest and repeated dosing. NLCQ-1 (NSC 709257) was administered IP 45 min before each radiation dose. The initial median tumor doubling times were 5.7 and 6.45 days for the two experiments. NLCQ-1 alone did not show antitumor activity or toxicity. Radiation at the highest single dose used (5.0 Gy) showed antitumor activity without weight loss (optimal T/C = -45). Lower single radiation doses (2.0 or 3.0 Gy) were marginally effective (optimal T/C of 34 and 40, respectively). The addition of NLCQ-1 to the treatment with each single radiation dose provided better optimal T/C values (e.g., −64 with 5.0 Gy). When the fractionated radiation protocol was followed, 1.0 Gy qd x 4 showed minimal effectiveness (T/C = 27) but, in combination with NLCQ-1 the T/C value was improved to 19. Radiation alone, given on a 3.0 Gy qd x 2, 9 day rest & repeat schedule was very effective without toxicity and resulted in 5 complete regressions in 10 mice, up to 42 days (Table). The optimal T/C value was −57 (on day 38). When NLCQ-1 was added to the above protocol, 9 out of 10 complete regressions were observed with a follow up of 52 days. The optimal T/C value was −100 from day 38 to day 52. For “advanced stage” tumor tests, complete regression is defined as a decrease in tumor burden below 63 mg but regrowth before the end of the experiment. The above results suggest a significant advantage in combining radiation with NLCQ-1 against glioma tumors.
Cardiac sodium channels: Dysregulation meets myocardial failure
Authors: E SCHULZEBAHR
Journal: Cardiovascular Research (2007)

See article by Hesse et al.  [12]  (pages 498–509) in this issue. 

Within the orchestra of cardiac ion channels, voltage–gated Na+ channels have a key function in the determination of the amplitude and slope of the action potential upstroke. Both are important in the control of impulse conduction velocity and maintenance of appropriate waves of excitation through the working myocardium. The main (α-) subunit of the cardiac sodium channel is encoded by the SCN5A (Nav1.5) gene, and the INa current mediated is responsible for the membrane depolarization. Fast inactivation of sodium channels appears within milliseconds, and the vast majority of sodium channels transit from the open state to a non-conductive state. Gating dysfunction or changes in the number of functional channels of cardiac sodium channels are linked to several cardiac arrhythmias [1–4]. Meanwhile, more than 170 different SCN5A mutations have been reported (currently, 77 for LQT-3, 90 for Brugada syndrome, 10 for conduction disease; see http://www.fsm.it/cardmoc/), and this has enabled evaluation of structure-function relationships of the sodium channel.

Analysis of several of these mutations has consistently demonstrated that loss of function is the … 

* Tel.: +49 251 83 529 82; fax: +49 251 83 575 70. Eric.Schulze-Bahr{at}ukmuenster.de
Concentrated Ambient Ultrafine Particle Exposure Induces Cardiac Changes in Young Healthy Volunteers
Authors: James M. Samet, Ana Rappold, Donald Graff, Wayne E. Cascio, Jon H. Berntsen, Yuh-Chin T. Huang, Margaret Herbst, Maryann Bassett, Tracey Montilla, Milan J. Hazucha, Philip A. Bromberg, Robert B. Devlin
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Exposure to ambient ultrafine particles has been associated with cardiopulmonary toxicity and mortality. Adverse effects specifically linked to ultrafine particles include loss of sympathovagal balance and altered hemostasis.To characterize the effects of acute exposure to ambient ultrafine particles in young healthy humans.Nineteen healthy nonsmoking male and female subjects between the ages of 18 and 35 were exposed to filtered air or to an atmosphere in which captured ultrafine (<0.16 microm) particles were concentrated by a factor of up to 20-fold over ambient levels with the use of particle concentrators fitted with size-selective outlets (ultrafine concentrated ambient particles [UFCAPs]). Subjects underwent bronchoalveolar lavage 18 hours after each exposure. Cardiovascular endpoints measured included pulmonary function, clinical chemistry, and hematological parameters, as well as heart rate variability and repolarization indices.Exposure to UFCAPs was statistically associated with an increase in frequency domain markers of heart rate variability, specifically indicative of elevated vagal input to the heart. Consistent with this finding were increases in the variance associated with the duration of the QT interval. In addition, UFCAP exposure resulted in a significant increase in blood levels of the fibrin degradation product D-dimer as well as a modest elevation in the inflammatory chemokine IL-8 recovered in the lavage fluid.These findings show mild inflammatory and prothrombic responses and are suggestive of alterations in cardiac repolarization induced by UFCAP inhalation.
Abstract P2-16-06: Final Overall Survival Results, Including Analysis of Patients with Triple-Negative Disease and Aged ≥70 Years, from the ATHENA Study Evaluating First-Line Bevacizumab-Containing Therapy for Locally Recurrent/Metastatic Breast Cancer
Authors: KI Pritchard, C Thomssen, J-Y Pierga, H Cortes-Funes, L Biganzoli, Z Guan, G Manikhas, D Jendiroba, B Uziely, F Boyle, A Jagiello-Gruszfeld, C Van Arkel, Y Tung, A-A Dunne, IE. Smith
Journal: Cancer Research (2010)

Abstract Background: First-line bevacizumab combined with chemotherapy significantly improves efficacy versus chemotherapy alone in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). ATHENA, a multinational, open-label, single-arm study, further evaluated first-line bevacizumab in combination with standard chemotherapy in patients treated in routine oncology practice. Patients and methods: Eligible patients had HER2-negative LR/mBC, ECOG performance status 0-2, and had received no prior chemotherapy for LR/mBC. They received bevacizumab 10 mg/kg q2w or 15 mg/kg q3w in combination with taxane-based chemotherapy (or other non-anthracycline chemotherapy) until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was safety; secondary endpoints included time to progression (TTP) and overall survival (OS). Results: Between September 2006 and March 2009, 2264 patients began therapy with bevacizumab, combined with single-agent paclitaxel (34%), single-agent docetaxel (33%), taxane-based combination therapy (11%), non-taxane-containing therapy (10%), or sequential chemotherapy (switching chemotherapy regimen before disease progression while continuing on bevacizumab; 12%). After final data cut-off in July 2010, the median duration of follow-up was 20.1 months (range 0.1-43.6 months). Bevacizumab therapy was continued for ≥1 year in 473 patients (21%). The safety profile and median TTP were very similar to those previously reported after median follow-up of 12.7 months and are consistent with findings from randomized phase III trials. Final OS results in the overall population and in clinically important subgroups are reported below for the first time. Conclusion: Median OS in the overall population is consistent with OS results reported from three randomized phase III trials in the first-line setting (25.2-30.2 months). OS results in subsets of patients with TN disease or aged ≥70 years suggest that bevacizumab-containing therapy is an effective option for these patients, who typically have fewer treatment options available. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-16-06.
Drosophila virilis Has Long and Highly Polymorphic Microsatellites
Authors: Christian Schlötterer, Bettina Harr
Journal: Molecular Biology and Evolution (2000)

Comparative genomics is a powerful approach to inference of the dynamics of genome evolution. Most information about the evolution of microsatellites in the genus Drosophila has been obtained from Drosophila melanogaster. For comparison, we collected microsatellite data for the distantly related species Drosophila virilis. Screening about 0.5 Mb of nonredundant genomic sequence from GenBank, we identified 239 dinucleotide microsatellites. On average, D. virilis dinucleotides were significantly longer than D. melanogaster microsatellites (7.69 repeats vs. 6.75 repeats). Similarly, direct cloning of microsatellites resulted in a higher mean repeat number in D. virilis than in D. melanogaster (12.7 repeats vs. 12.2 repeats). Characterization of 11 microsatellite loci mapping to division 40-49 on the fourth chromosome of D. virilis indicated that D. virilis microsatellites are more variable than those of D. melanogaster.
Collaborative Induction of Inflammatory Responses by Dectin-1 and Toll-like Receptor 2
Authors: Benjamin N. Gantner, Randi M. Simmons, Scott J. Canavera, Shizuo Akira, David M. Underhill
Journal: The Journal of Experimental Medicine (2003)

Toll-like receptors (TLRs) mediate recognition of a wide range of microbial products including lipopolysaccharides, lipoproteins, flagellin, and bacterial DNA, and signaling through TLRs leads to the production of inflammatory mediators. In addition to TLRs, many other surface receptors have been proposed to participate in innate immunity and microbial recognition, and signaling through some of these receptors is likely to cooperate with TLR signaling in defining inflammatory responses. In this report we have examined how dectin-1, a lectin family receptor for β-glucans, collaborates with TLRs in recognizing microbes. Dectin-1, which is expressed at low levels on macrophages and high levels on dendritic cells, contains an immunoreceptor tyrosine-based activation motif–like signaling motif that is tyrosine phosphorylated upon activation. The receptor is recruited to phagosomes containing zymosan particles but not to phagosomes containing immunoglobulin G–opsonized particles. Dectin-1 expression enhances TLR-mediated activation of nuclear factor κB by β-glucan–containing particles, and in macrophages and dendritic cells dectin-1 and TLRs are synergistic in mediating production of cytokines such as interleukin 12 and tumor necrosis factor α. Additionally, dectin-1 triggers production of reactive oxygen species, an inflammatory response that is primed by TLR activation. The data demonstrate that collaborative recognition of distinct microbial components by different classes of innate immune receptors is crucial in orchestrating inflammatory responses.
Multiple myeloma–reactive T cells recognize an activation-induced minor histocompatibility antigen encoded by the ATP-dependent interferon-responsive (ADIR) gene
Authors: Cornelis A. M. van Bergen, Michel G. D. Kester, Inge Jedema, Mirjam H. M. Heemskerk, Simone A. P. van Luxemburg-Heijs, Freke M. Kloosterboer, W. A. Erik Marijt, Arnoud H. de Ru, M. Ron Schaafsma, Roel Willemze, Peter A. van Veelen, J. H. Frederik Falkenburg
Journal: Blood (2007)
Prednisolone treatment does affect the performance of the QuantiFERON in-tube test and the tuberculin skin test in patients with autoimmune disorders screened for latent tuberculosis
Authors: Erika Belard, Synne Semb, Morten Ruhwald, Anne Marie Werlinrud, Bolette Søborg, Frank Kriger Jensen, Henrik Thomsen, Annette Brylov, Merete Lund Hetland, Inge Nordgaard-Lasen, Pernille Ravn
Journal: European Respiratory Journal (2011)

Background:  During screening for latent tuberculosis infection (LTBI), before anti-TNF-alpha treatment, most patients are already receiving immunosuppressive therapy. Objective was to evaluate the performance of the QuantiFERON In-Tube (QFT-IT) and the Tuberculin Skin Test (TST) in these groups   Methods:  We included 248 patients with Ulcerative Colitis, Crohns disease, rheumatoid arthritis, and spondylo-arthropathy.   Results:  QFT-IT was positive in 7/248 (3%), negative in 229 (92%), and indeterminate in 12 (5%). TST was positive in 54/238 (23%) patients. Chest X-ray was suspect in 5/236 (2%), and 35/167 (21%) had risk-factors.  We found a pronounced negative effect on QFT-IT and TST performance associated with prednisolone treatment; the IFN- response to mitogen stimulation was impaired (median IFN- response 4.9IU/ml (IQR0.8-10.0)) compared to patients a) not receiving corticosteroids (median 10.0 (IQR 5.0-10.0) (p=0.0015) or b) receiving long-acting corticosteroids (median 10.0 (IQR 9.7-10.0) (p=0.0058).  Prednisolone treatment was strongly associated with negative TST, AOR 0.22 (0.1-0.8 (p= 0.018), and with an increased risk of indeterminate QFT-IT results AOR (16.1-69.0) p=0.001). No negative effect was found for long-acting corticosteroids. Prednisolon doses above 10 mgresulted in 27% indeterminate results.   Conclusion:  Oral prednisolone severely suppressed QFT-IT and TST performance whereas long-acting corticosteoroids, Metotrexate, Azathioprin and 5-ASA did not have similar detrimental effect. Patients should be screened for LTBI with QFT-IT or TST prior to initiation of prednisolone.
Are Convergent and Parallel Amino Acid Substitutions in Protein Evolution More Prevalent Than Neutral Expectations?
Authors: Zhengting Zou, Jianzhi Zhang
Journal: Molecular Biology and Evolution (2015)

Convergent and parallel amino acid substitutions in protein evolution, collectively referred to as molecular convergence here, have small probabilities under neutral evolution.For this reason, molecular convergence is commonly viewed as evidence for similar adaptations of different species.The surge in the number of reports of molecular convergence in the last decade raises the intriguing question of whether molecular convergence occurs substantially more frequently than expected under neutral evolution.We here address this question using all one-to-one orthologous proteins encoded by the genomes of 12 fruit fly species and those encoded by 17 mammals.We found that the expected amount of molecular convergence varies greatly depending on the specific neutral substitution model assumed at each amino acid site and that the observed amount of molecular convergence is explainable by neutral models incorporating site-specific information of acceptable amino acids.Interestingly, the total number of convergent and parallel substitutions between two lineages, relative to the neutral expectation, decreases with the genetic distance between the two lineages, regardless of the model used in computing the neutral expectation.We hypothesize that this trend results from differences in the amino acids acceptable at a given site among different clades of a phylogeny, due to prevalent epistasis, and provide simulation as well as empirical evidence for this hypothesis.Together, our study finds no genomic evidence for higherthan-neutral levels of molecular convergence, but suggests the presence of abundant epistasis that decreases the likelihood of molecular convergence between distantly related lineages.
Sunlight exposure behaviour and vitamin D status in photosensitive patients: longitudinal comparative study with healthy individuals at U.K. latitude
Authors: L.E. Rhodes, A.R. Webb, J.L. Berry, S.J. Felton, E.J. Marjanovic, J.D. Wilkinson, A. Vail, R. Kift
Journal: British Journal of Dermatology (2014)

Low vitamin D status is prevalent in wintertime in populations at northerly latitudes. Photosensitive patients are advised to practise sun avoidance, but their sunlight exposure levels, photoprotective measures and resulting vitamin D status are unknown. To examine seasonal vitamin D status in photosensitive patients relative to healthy individuals and to assess quantitatively behavioural and demographic contributors. This was a longitudinal prospective cohort study (53·5°N) examining year‐round 25‐hydroxyvitamin D [25(OH)D] levels, sun‐exposure behaviour and oral vitamin D intake in photosensitive patients diagnosed at a photoinvestigation unit (n =53), compared with concurrently assessed healthy adults (n =109). Photosensitive patients achieved seasonal 25(OH)D variation, but insufficient (< 20 ng mL−1; 50 nmol L−1) and even deficient (< 10 ng mL−1; 25 nmol L−1) levels occurred at the summer peak in 47% and 9% of patients, respectively, rising to 73% and 32% at the winter trough. Adjusting for demographic factors, the mean values were lower than for healthy volunteers by 18% [95% confidence interval (CI) 4–29] in summer (P = 0·02) and 25% (95% CI 7–39) in winter (P =0·01). Behavioural factors explained 25(OH)D differences between cohorts. Patients demonstrated lower weekend ultraviolet B doses (P <0·001), smaller skin surface area exposure (P = 0·004) and greater sunscreen use (P <0·001), while average oral vitamin D intake was low in both groups (photosensitive: 2·94 μg per day). Supplementation and summer surface area exposure predicted summer peak and winter trough 25(OH)D levels. A 1 μg per day increment in supplementary vitamin D raised summer and winter 25(OH)D by 5% (95% CI 3–7) and 9% (95% CI 5–12), respectively (both P <0·001). Photosensitive patients are, through their photoprotective measures, at high risk of year‐round low vitamin D status. Guidance on oral measures should target this patient group and their physicians.