tbuckley/cabot-search huggingface dataset:
Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease
Authors: Daniel Leffler, Detlef Schuppan, Kumar Pallav, Robert Najarian, Jeffery D Goldsmith, Joshua Hansen, Toufic Kabbani, Melinda Dennis, Ciarán P Kelly
Journal: Gut (2012)

<h3>Objective</h3> Coeliac disease is defined by gluten responsiveness, yet there are few data on gluten challenge (GC) in adults on a gluten-free diet. Lack of data regarding the kinetics of responses to gluten is a limitation in clinical practice and research when GC is performed. <h3>Design</h3> 20 adults with biopsy-proven coeliac disease participated. The study included two run-in visits followed by a 14-day GC at a randomly assigned dose of 3 or 7.5 g of gluten/day. Study visits occurred 3, 7, 14 and 28 days after starting GC. Duodenal biopsy was performed during the run-in and at days 3 and 14 of GC. Villous height to crypt depth ratio (Vh:Cd) and intraepithelial lymphocyte (IEL) count/100 enterocytes were measured by two pathologists. Antibodies to tissue transglutaminase and deamidated gliadin peptides, lactulose to mannitol ratio (LAMA) and symptoms were assessed at each visit. <h3>Results</h3> Significant reduction in Vh:Cd (2.2–1.1, p&lt;0.001) and increase in IELs (32.6–51.8, p&lt;0.001) were seen from baseline to day 14. Antibody titres increased slightly from baseline to day 14 of GC but markedly by day 28. LAMA did not change significantly. Gastrointestinal symptoms increased significantly by day 3 and returned to baseline by day 28. No differences were seen between the two gluten doses. <h3>Conclusions</h3> 14 day GC at ≥3 g of gluten/day induces histological and serological changes in the majority of adults with coeliac disease. These data permit accurate design of clinical trials and indicate that many individuals will meet coeliac diagnostic criteria after a 2-week GC. <h3>Clinical Trials Registration Number</h3> http://clinicaltrials.gov # NCT00931892.
Trafficking regulation of proteins in Alzheimer’s disease
Authors: Shangtong Jiang, Yanfang Li, Xian Zhang, Guojun Bu, Huaxi Xu, Yun Wu Zhang
Journal: Molecular Neurodegeneration (2014)

The β-amyloid (Aβ) peptide has been postulated to be a key determinant in the pathogenesis of Alzheimer's disease (AD). Aβ is produced through sequential cleavage of the β-amyloid precursor protein (APP) by β- and γ-secretases. APP and relevant secretases are transmembrane proteins and traffic through the secretory pathway in a highly regulated fashion. Perturbation of their intracellular trafficking may affect dynamic interactions among these proteins, thus altering Aβ generation and accelerating disease pathogenesis. Herein, we review recent progress elucidating the regulation of intracellular trafficking of these essential protein components in AD.
Fas Gene Mutation in the Progression of Adult T Cell Leukemia
Authors: Takahiro Maeda, Yasuaki Yamada, Ryozou Moriuchi, Kazuyuki Sugahara, Kazuto Tsuruda, Tatsurou Joh, Sunao Atogami, Kunihiro Tsukasaki, Masao Tomonaga, Shimeru Kamihira
Journal: The Journal of Experimental Medicine (1999)

Fas antigen (Apo-1/CD95) is an apoptosis-signaling cell surface receptor belonging to the tumor necrosis factor receptor superfamily. Adult T cell leukemia (ATL) cells express Fas antigen and show apoptosis after treatment with an anti-Fas monoclonal antibody. We established the ATL cell line KOB, which showed resistance to Fas-mediated apoptosis, and found that KOB expressed two forms of Fas mRNA, the normal form and a truncated form. The truncated transcript lacked 20 base pairs at exon 9, resulting in a frame shift and the generation of a premature stop codon at amino acid 239. The same mutation was detected in primary ascitic cells and peripheral blood cells. The mutation was not detected in lymph node cells, however, although all of the primary ATL cells were of the same clonal origin. A retroviral-mediated gene transfer of the truncated Fas to Jurkat cells rendered the cells resistant to Fas-mediated apoptosis, suggesting a dominant negative interference mechanism. These results indicate that an ATL subclone acquires a Fas mutation in the lymph nodes, enabling the subclone to escape from apoptosis mediated by the Fas/Fas ligand system and proliferate in the body. Mutation of the Fas gene may be one of the mechanisms underlying the progression of ATL.
Therapy for chronic hepatitis B with lymphoblastoid interferon-α and levamisole
Authors: Giovanna Fattovich, Giuliano Giustina, Lucio Brollo, Maria Guido, Patrizia Pontisso, Franco Noventa, Alfredo Alberti
Journal: Hepatology (1992)

About one third of patients with chronic hepatitis B show a sustained response when treated with interferon-alpha. Combining interferon-alpha with immunomodulators might be a way to increase response rate. The aim of this study was to compare the efficacy of lymphoblastoid interferon-alpha given alone with its efficacy when combined with levamisole in chronic hepatitis B. Forty-five patients with HBeAg-positive chronic hepatitis were randomly selected (with stratification for ALT levels) to receive a 6-mo course of combination therapy with lymphoblastoid interferon-alpha (5 million units/m2 three times per week) and levamisole (150 mg three times per week) or lymphoblastoid interferon at the same dose regimen and a matching placebo. Final evaluation 18 mo after randomization revealed a loss of both HBeAg and hepatitis B virus DNA with ALT normalization in 38% of patients treated with interferon-alpha alone and in 10% of patients receiving combination therapy. The higher response rate observed in patients treated with interferon-alpha alone was maintained after stratification for basal ALT levels (i.e., higher [45% vs. 10%] or lower [31% vs. 9%] than three times the upper normal value). The length of time to sustained HBeAg clearance was significantly (p < 0.05) shorter in patients receiving monotherapy than in patients receiving combination therapy. Blinded histological assessment revealed improvement in 44% of patients treated with interferon-alpha alone compared with improvement in 6% of patients receiving combination therapy. These results indicate that levamisole has no additive effects when combined with interferon-alpha in the treatment of HBeAg-positive chronic hepatitis.
LOCAL CIRCUITS IN PRIMARY VISUAL CORTEX OF THE MACAQUE MONKEY
Authors: Edward M. Callaway
Journal: Annual Review of Neuroscience (1998)

▪ Abstract The basic laminar organization of excitatory local circuitry in the primary visual cortex of the macaque monkey is similar to that described previously in the cat's visual cortex ( Gilbert 1983 ). This circuitry is described here in the context of a two-level model that distinguishes between feedforward and feedback connections. Embedded within this basic framework is a more complex organization. Within the strictly feedforward pathway, these circuits distribute unique combinations of magno-, parvo-, and koniocellular input from the lateral geniculate nucleus (LGN) to neurons in layers 2–4B. Their input is dependent on the extrastriate cortical areas they target. The local feedback connections from deep layers (5 and 6) arise from a diverse population of pyramidal neurons. Each type forms local connections with a unique relationship to more superficial layers. In the case of layer 6 neurons, these connections are closely related to layer 4 subdivisions receiving input from different functional streams.
Discovery of imatinib-responsive FIP1L1-PDGFRA mutation during refractory acute myeloid leukemia transformation of chronic myelomonocytic leukemia
Authors: Shilpan Shah, Sanam Loghavi, Guillermo Garcia-Manero, Joseph D Khoury
Journal: Journal of Hematology & Oncology (2014)

The FIP1L1-PDGFRA rearrangement results in constitutive activation of the tyrosine kinase PDGFRA. Neoplasms harboring this rearrangement are responsive to imatinib mesylate at doses much lower than those recommended for the treatment of chronic myelogenous leukemia. Only a single report has described the identification of FIP1L1-PDGFRA in chronic myelomonocytic leukemia (CMML). Herein, we present a case report of a patient in whom the FIP1L1-PDGFRA was discovered as he evolved from CMML to acute myeloid leukemia (AML). The presence of a dominant neoplastic clone with FIP1L1-PDGFRA rearrangement was suspected on the basis of sudden onset of peripheral and bone marrow eosinophilia and confirmed by fluorescence in situ hybridization and molecular diagnostic tests. Whereas the patient was initially refractory to chemotherapy before the rearrangement was detected, subsequent therapy with imatinib led to complete remission.
Effects of Ouabain, Atropine, and Ouabain and Atropine, on A-V Nodal Conduction in Man
Authors: RICHARD A. CARLETON, PAUL H. MILLER, JOHN S. GRAETTINGER
Journal: Circulation Research (1967)

The prolongation of A-V transmission time that occurs with increasing rates of right atrial pacing has been used to study the effect of ouabain and of ouabain plus atropine on A-V nodal conduction in 14 patients with normal A-V nodes. Drugs were injected into the superior vena cava or pulmonary artery over a 1- to 2-min period. Atropine in a dose of 0.02 mg/kg shortened A-V conduction time by an average of 0.112 sec; ouabain alone in a dose of 0.01 mg/kg lengthened A-V conduction time by 0.053 sec. Ouabain given after large doses of atropine did not prolong A-V conduction at any paced rate. Thus, in these resting patients with normal A-V nodal function, usual digitalizing dosages of ouabain did not have an extravagal or antiadrenergic effect on A-V nodal conduction.
Mechanism of Fas Signaling Regulation by Human Herpesvirus 8 K1 Oncoprotein
Authors: Z. Berkova, S. Wang, J. F. Wise, H. Maeng, Y. Ji, F. Samaniego
Journal: JNCI Journal of the National Cancer Institute (2009)

Human herpesvirus 8 (HHV-8) is involved in the pathogenesis of Kaposi sarcoma ( 1 , 2 ).In addition, HHV-8 is associated with primary effusion lymphoma and some cases of Castleman disease ( 3 ).A key player in these pathologies may be K1, a transmembrane oncoprotein of HHV-8 ( 4 ).HHV-8 -infected cells express K1, and its expression is enhanced during the lytic cycle of the virus and by induction with phorbol esters ( 5 -7 ).The K1 protein immortalizes and transforms epithelial and endothelial cells ( 8 ).K1-expressing transgenic mice exhibit abnormal lymphoproliferation in response to antigens and readily develop splenomegaly and lymphomas with marker expression similar to that of HHV-8 -associated human lymphomas ( 4 , 9 ).The K1 protein contains a cytoplasmic immunoreceptor tyrosine -based activation motif (ITAM), which is proposed to be constitutively active ( 10 -12 ).Through the ITAM domain, K1 activates nuclear factor -kappa B, nuclear factor of activated T cells, and Lyn tyrosine kinase ( 6 , 9 ).Recent evidence indicates that K1 plays a role in regulating Fas-mediated apoptosis by preventing the assembly of the death-inducing signaling complex (DISC) through an unknown mechanism.We previously reported ( 13) that K1-transfected mice survive treatment with a lethal dose of the agonistic Fas antibody Jo2, which induces widespread apoptosis of hepatocytes.The suppression of apoptosis by K1 was Fas specifi c, because it did not affect either the tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL) apoptotic pathway, which also depends on assembly of the DISC, or the radiation (DNA damage)-induced intrinsic apoptotic pathway ( 13 ).Here, we sought to determine how K1 blocks Fas-mediated apoptosis.We studied K1 -Fas interactions in vitro using human embryonic kidney (HEK) 293 and human lymphoma-derived BJAB cells.
Importance of Risk Factors for Febrile Neutropenia Among Patients Receiving Chemotherapy Regimens Not Classified as High-Risk in Guidelines for Myeloid Growth Factor Use
Authors: Derek Weycker, Xiaoyan Li, Rich Barron, Hongsheng Wu, P.K. Morrow, Hairong Xu, Maureen Reiner, Jacob Garcia, Shivani K. Mhatre, Gary H. Lyman
Journal: Journal of the National Comprehensive Cancer Network (2015)

Background: Clinical practice guidelines recommend prophylaxis in patients with cancer receiving a colony-stimulating factor (CSF) when the risk of febrile neutropenia (FN) is high (>20%). For patients receiving chemotherapy regimens not documented as high-risk, the decision regarding CSF prophylaxis use can be challenging, because some patients may be at high risk based on a combination of the regimen and individual risk factors. Methods: A retrospective cohort design and US private health care claims data were used. Study subjects received chemotherapy regimens classified as “low” or “intermediate,” or unclassified, in terms of FN risk, and were stratified by cancer and regimen. For each subject, the first chemotherapy course, and each cycle and FN episode within the course, were identified. FN incidence proportions were estimated by the presence and number of risk factors and chronic comorbidities. Results: Across the 17 tumor/regimen combinations considered (n=160,304 in total), 74% to 98% of patients had 1 or more risk factor for FN and 41% to 89% had 2 or more. Among patients with 1 or more risk factor, FN incidence ranged from 7.2% to 29.0% across regimens, and the relative risk of FN (vs those without risk factors) ranged from 1.1 (95% CI, 0.8–1.3) to 2.2 (95% CI, 1.5–3.0). FN incidence increased in a graded and monotonic fashion with the number of risk factors and comorbidities. Conclusions: In this retrospective evaluation of patients with cancer receiving chemotherapy regimens not classified as high-risk for FN in US clinical practice, most patients had 1 or more FN risk factor and many had 2 or more. FN incidence was found to be elevated in these patients, especially those with multiple risk factors.
Pulmonary arteriole gene expression signature in idiopathic pulmonary fibrosis
Authors: N. M. Patel, S. M. Kawut, S. Jelic, S. M. Arcasoy, D. J. Lederer, A. C. Borczuk
Journal: European Respiratory Journal (2013)

A third of patients with idiopathic pulmonary fibrosis (IPF) develop pulmonary hypertension (PH-IPF), which is associated with increased mortality. Whether an altered gene expression profile in the pulmonary vasculature precedes the clinical onset of PH-IPF is unknown. We compared gene expression in the pulmonary vasculature of IPF patients with and without PH with controls. Pulmonary arterioles were isolated using laser capture microdissection from 16 IPF patients: eight with PH (PH-IPF) and eight with no PH (NPH-IPF), and seven controls. Probe was prepared from extracted RNA, and hybridised to Affymetrix Hu133 2.0 Plus genechips. Biometric Research Branch array tools and Ingenuity Pathway Analysis software were used for analysis of the microarray data. Univariate analysis revealed 255 genes that distinguished IPF arterioles from controls (p&lt;0.001). Mediators of vascular smooth muscle and endothelial cell proliferation, Wnt signalling and apoptosis were differentially expressed in IPF arterioles. Unsupervised and supervised clustering analyses revealed similar gene expression in PH-IPF and NPH-IPF arterioles. The pulmonary arteriolar gene expression profile is similar in IPF patients with and without coexistent PH. Pathways involved in vascular proliferation and aberrant apoptosis, which may contribute to pulmonary vascular remodelling, are activated in IPF patients.
Behavior Therapy of Anorexia Nervosa: Effectiveness of Activity as a Reinforcer of Weight Gain
Authors: BARTON J. BLINDER, DANIEL M.A. FREEMAN, ALBERT J. STUNKARD
Journal: American Journal of Psychiatry (1970)

The authors present a technique for weight restoration in a condition that is often highly refractory to therapy, with mortality rates of up to 15 percent. Operant reinforcement was applied to three consecutive patients by making access to physical activity contingent upon weight gain. Treatment of from four to six weeks resulted in rapid weight restoration. Modifications of the technique, illustrating variations in operant reinforcement, are also reported.
Ethanol stimulates endothelial cell angiogenic activity via a Notch- and angiopoietin-1-dependent pathway
Authors: D. Morrow, J. P. Cullen, P. A. Cahill, E. M. Redmond
Journal: Cardiovascular Research (2008)

Our aims were to determine the effect of alcohol (EtOH) on endothelial angiogenic activity and to delineate the cell signalling mechanisms involved. Treatment of human umbilical vein endothelial cells (HUVECs) with EtOH (1–100 mM, 24 h) dose-dependently increased their network formation on Matrigel (an index of angiogenesis) with a maximum response (2.5- to 3-fold increase) at 25 mM. Ethanol also stimulated the proliferation (by cell count and proliferating cell nuclear antigen expression) and migration (by scratch wound assay) of HUVECs. In parallel cultures, EtOH stimulated Notch receptor (1 and 4) and Notch target gene (hrt-1, -2, and -3) mRNA and protein expression and enhanced CBF-1/RBP-Jk promoter activity. EtOH also stimulated, at the mRNA and protein level, the expression of angiopoietin-1 (Ang1) and its Tie2 receptor in these cells. Knockdown of Notch 1 or 4 by siRNA or inhibition of Notch-mediated, CBF-1/RBP-Jk-regulated gene expression by the Epstein–Barr virus-encoded protein RPMS-1 inhibited both ethanol-induced Ang1/Tie2 expression in HUVECs and their network formation on Matrigel. Moreover, knockdown of Ang1 or Tie2 by siRNA inhibited ethanol-induced endothelial network formation. These data demonstrate that ethanol, at levels consistent with moderate consumption, enhances endothelial angiogenic activity in vitro by stimulating a novel Notch/CBF-1/RBP-JK–Ang1/Tie2-dependent pathway. These actions of ethanol may be relevant to the cardiovascular effects of alcohol consumption purported by epidemiological studies.
Identification of Serum Biomarker Signatures Associated with Pancreatic Cancer
Authors: Christer Wingren, Anna Sandström, Ralf Segersvärd, Anders Carlsson, Roland Andersson, Matthias Löhr, Carl A. K. Borrebaeck
Journal: Cancer Research (2012)

Abstract Pancreatic cancer is an aggressive disease with poor prognosis, due, in part, to the lack of disease-specific biomarkers that could afford early and accurate diagnosis. With a recombinant antibody microarray platform, targeting mainly immunoregulatory proteins, we screened sera from 148 patients with pancreatic cancer, chronic pancreatitis, autoimmune pancreatitis (AIP), and healthy controls (N). Serum biomarker signatures were derived from training cohorts and the predictive power was evaluated using independent test cohorts. The results identified serum portraits distinguishing pancreatic cancer from N [receiver operating characteristics area under the curve (AUC) of 0.95], chronic pancreatitis (0.86), and AIP (0.99). Importantly, a 25-serum biomarker signature discriminating pancreatic cancer from the combined group of N, chronic pancreatitis, and AIP was determined. This signature exhibited a high diagnostic potential (AUC of 0.88). In summary, we present the first prevalidated, multiplexed serum biomarker signature for diagnosis of pancreatic cancer that may improve diagnosis and prevention in premalignant diseases and in screening of high-risk individuals. Cancer Res; 72(10); 2481–90. ©2012 AACR.
An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy
Authors: Michael N Weedon, Sian Ellard, Marc J Prindle, Richard Caswell, Hana Lango Allen, Richard Oram, Koumudi Godbole, Chittaranjan S Yajnik, Paolo Sbraccia, Giuseppe Novelli, Peter Turnpenny, Emma McCann, Kim Jee Goh, Yukai Wang, Jonathan Fulford, Laura J McCulloch, David B Savage, Stephen O'Rahilly, Katarina Kos, Lawrence A Loeb, Robert K Semple, Andrew T Hattersley
Journal: Nature Genetics (2013)
Recurrent Exacerbations in Severe Asthma Are Associated with Enhanced Airway Closure During Stable Episodes
Authors: JOHANNES C. C. M.in‘t VEEN, ANNELIES J. BEEKMAN, ELISABETH H. BEL, PETER J. STERK
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Excessive airway narrowing is a cardinal feature of asthma, and results in closure of airways. Therefore, asthmatic patients in whom airway closure occurs relatively early during expiration might be prone to severe asthma attacks. To test this hypothesis, we compared closing volume (CV) and closing capacity (CC) in a group of asthmatic patients with recurrent exacerbations (more than two exacerbations in the previous year; difficult-to-control asthma), consisting of 11 males and two females, aged 20 to 51 yr, with those in a group of equally severely asthmatic controls without recurrent exacerbations (stable asthma) consisting of 13 males and two females aged 18 to 52 yr. Both groups used equivalent doses of inhaled corticosteroids and were matched for sex, age, atopy, postbronchodilator FEV1, and provocative concentration of methacholine causing a 20% decrease in FEV1. They were studied during a clinically stable period of their disease. The patients inhaled 400 μ g salbutamol via a spacer device, after which TLC and RV were measured by multibreath helium equilibration, together with the slope of Phase 3 (dN2), CV, and CC, by single-breath nitrogen washout. CV and CC were expressed as ratios of VC and TLC, respectively, and all data are presented as % predicted (mean ± SEM). There was no difference in TLC in patients with difficult-to-control asthma and those with stable asthma (106.7 ± 4.0% predicted versus 101.7 ± 4.3% predicted, p = 0.40), RV (113.1 ± 7.8% predicted versus 100.9 ± 7.1% predicted, p = 0.26), or dN2 (142.7 ± 16.3% predicted versus 116.0 ± 20.2% predicted, p = 0.23). In contrast, CV and CC were increased in the patients with difficult-to-control asthma as compared with the group with stable asthma (CV: 159.5 ± 26.8% predicted versus 98.8 ± 12.5% predicted, p = 0.024; CC: 114.0 ± 6.4% predicted versus 99.9 ± 3.6% predicted, p = 0.030). These findings show that asthmatic individuals with recurrent exacerbations have increased CV and CC as compared with equally severely asthmatic but stable controls, even after bronchodilation during well-controlled episodes. The findings imply that airway closure at relatively high lung volumes under clinically stable conditions might be a risk factor for severe exacerbations in asthmatic patients.