tbuckley/cabot-search huggingface dataset:
EM011 activates a survivin-dependent apoptotic program in human non-small cell lung cancer cells
Authors: Prasanthi Karna, Starlette M Sharp, Clayton Yates, Satya Prakash, Ritu Aneja
Journal: Molecular Cancer (2009)

Lung cancer remains a leading cause of cancer death among both men and women in the United States. Treatment modalities available for this malignancy are inadequate and thus new drugs with improved pharmacological profiles and superior therapeutic indices are being continually explored. Noscapinoids constitute an emerging class of anticancer agents that bind tubulin but do not significantly alter the monomer/polymer ratio of tubulin. EM011, a rationally-designed member of this class of non-toxic agents, is more potent than the lead molecule, noscapine.Here we report that EM011 inhibited proliferation of a comprehensive panel of lung cancer cells with IC(50)'s ranging from 4-50 microM. In A549 human non-small cell lung cancer cells, the antiproliferative activity was mediated through blockage of cell-cycle progression by induction of a transient but robust mitotic arrest accompanied by activation of the spindle assembly checkpoint. The mitotically-arrested A549 cells then override the activated mitotic checkpoint and aberrantly exit mitosis without cytokinesis resulting in pseudo G1-like multinucleated cells that either succumb directly to apoptosis or continue another round of the cell-cycle. The accumulated enormous DNA perhaps acts as genotoxic stress to trigger cell death. EM011-induced apoptotic cell death in A549 cells was associated with a decrease of the Bcl2/BAX ratio, activation of caspase-3 and cleavage of PARP. Furthermore, EM011 induced downregulation of survivin expression over time of treatment. Abrogation of survivin led to an increase of cell death whereas, overexpression caused decreased apoptosis.These in vitro data suggest that EM011 mediates antiproliferative and proapoptotic activity in non-small cell A549 lung cancer cells by impeding cell-cycle progression and attenuating antiapoptotic signaling circuitries (viz. Bcl2, survivin). The study provides evidence for the potential usefulness of EM011 in chemotherapy of lung cancer.
Covalent and Noncovalent Interactions in Acute Lethal Cell Injury Caused by Chemicals
Authors: S D Nelson, P G Pearson
Journal: The Annual Review of Pharmacology and Toxicology (1990)

Several chemicals, including some drugs, cause cell injury by mechanisms that are poorly characterized. Although a few drugs are toxins that act directly, most require metabolic activation to form the ultimate toxic species. The concept of metabolic activation was first described by the Millers ( 1) in a review of their pioneering work on aminoazo dyes and 2-acetylaminofluorene as procarcinogens. Brodie et al (2) expanded on this concept to include a role for metabolic activation in acute cell injury. Since that time several reviews (3-12) and books ( 13-15) have discussed the role of metabolic activation in the pathogenesis of a variety of toxicities. Although a substantial body of information is available on the metabolic reactions that produce toxic metabolites and on the chemical nature of these metabolites, considerably less is known about how ultimate toxic species interact with cellular constituents and how the interactions cause cell injury. Reactions of toxic metabolites may result in covalent bond formation between the metabolite and a target molecule, or they may alter (usually by oxidation or reduction) the target molecule without formation of a covalent bond. Some of the more likely targets of these interactions are listed in Table 1.
Antithrombotic therapy is associated with better survival in patients with severe heart failure and left ventricular systolic dysfunction (EPICAL study)
Authors: M. Echemann, F. Alla, S. Briançon, Y. Juillière, J.M. Virion, P.M. Mertès, J.P. Villemot, F. Zannad
Journal: European Journal of Heart Failure (2002)
Matrix metalloproteinase 12 is produced by M2 macrophages and plays important roles in the development of contact hypersensitivity
Authors: Daiki Nakagomi, Kotaro Suzuki, Kazuyuki Meguro, Junichi Hosokawa, Tomohiro Tamachi, Hiroaki Takatori, Akira Suto, Hiroyuki Matsue, Osamu Ohara, Toshinori Nakayama, Shinji Shimada, Hiroshi Nakajima
Journal: Journal of Allergy and Clinical Immunology (2014)
Endothelial Progenitor Cells and the Diabetic Paradox
Authors: Gian Paolo Fadini, Saverio Sartore, Ilenia Baesso, Maddalena Lenzi, Carlo Agostini, Antonio Tiengo, Angelo Avogaro
Journal: Diabetes Care (2006)

An unexplained paradox puzzles diabetologists: diabetic patients must face both poor vessel growth in ischemic heart and limbs and increased angiogenesis in retinal complications (1,2).

Endothelial progenitor cells (EPCs) are marrow-derived cells involved in adult neovascularization and endothelial homeostasis (3,4). It has been postulated that low EPCs in peripheral blood may have a role in cardiovascular disease, and we have demonstrated that EPCs are reduced in macrovascular diabetes complications (5,6). On the other hand, an excess of EPCs may be involved in pathologic neoangiogenesis of cancer and proliferative retinopathy (7,8). Therefore, diabetes complications may be associated with both decreased and increased EPCs. Recently, novel therapeutic approaches have been directed to enrich the EPC pool in ischemic diseases and to block EPC function in proliferative diseases (9,10). These approaches in diabetic subjects require cautious evaluation of the implications carried by the paradox and new studies to unravel its causes (11,12). This study was carried out to investigate the contemporaneous effects of retinal and peripheral vascular complications on circulating progenitor cells.

Ethics committee approval was obtained, and after giving informed consent, 60 type 2 diabetic patients were prospectively included. Patients were characterized in terms of peripheral arterial disease (PAD) and diabetic retinopathy (DR) as the most representative complications at the two extremities of the diabetic paradox. PAD was diagnosed by minimal criteria (including history of claudication or rest pain, pulse examination, ankle-brachial indexes, and ultrasonography) and eventually confirmed by angiography. Diabetic retinopathy (severe nonproliferative or proliferative) was defined by a dilated and comprehensive eye examination and acquisition of high-quality stereoscopic photographs by …
Sodium, Hydrogen exchange type 1 and bile ductular secretory activity in the guinea pig
Authors: Christian Hübner, Wolfgang Stremmel, Christoph Elsing
Journal: Hepatology (2000)

Biliary epithelial cells (BECs) express different Na + , H + exchange (NHE) isoforms. In this study, the potential role of NHE in ductular bile secretion is assessed. Experiments were performed in guinea pig perfused livers and isolated BECs. Inhibition of NHE was achieved by hypotonic stress and by using the unspecific NHE inhibitor, amiloride, or the specific NHE 1 inhibitor, cariporide (HOE 642). Hypotonic stress inhibited basal bile flow by 46% and prevented secretin stimulation of bile flow by reducing biliary bicarbonate output by 50%. Secretin increased bile flow from 3.7 ± 0.8 μL/min/g to 4.78 μL/min/g ( P &lt; .01); subsequent exposure to hypotonic stress decreased secretin-stimulated bile flow by 35% and biliary bicarbonate secretion by ˜50%. Inhibition of NHE by amiloride or cariporide resulted in a similar reduction of secretin-stimulated bile flow and bicarbonate secretion. Basal bile flow was unaffected by the NHE inhibitors. In isolated guinea pig BECs, regulatory volume decrease and inhibition of NHE was demonstrated after hypotonic stress under basal and secretin-stimulated conditions. In contrast, hypotonic exposure inhibited Cl − , HCO 3 − exchange activity in isolated BECs only during basal conditions but incompletely after secretin stimulation. Our study shows that hypotonic stress inhibits basal bile flow in the guinea pig by inhibition of Cl − , HCO 3 − exchange. NHE1 is not involved in basal bile formation. Increased choleresis after ductular stimulation by secretin depends on intact NHE1 activity. These data indicate that BEC volume changes have profound effects on biliary secretory function.
Effects of BMI on task-related VO2 and dyspnea during activities of daily life (ADLs) in COPD
Authors: Anouk W. Vaes, Frits M.E. Franssen, Kenneth Meijer, Martijn W.J. Cuijpers, Emiel F.M. Wouters, Erica P.A. Rutten, Martijn A. Spruit
Journal: European Respiratory Journal (2012)

COPD patients use a higher proportion of their peak VO 2  during the performance of domestic ADLs compared to healthy peers, accompanied by higher task-related dyspnea and fatigue. To date, the influence of BMI on the task-related metabolic demands remains unknown. Therefore, we aimed to study the effects of BMI on metabolic load in 94 COPD patients (61% men, age 60±9 yrs, BMI 25± 5 kg/m 2 , FEV 1  51±19%pred) during the performance of 5 consecutive domestic ADLs: putting on socks, shoes and vest, ADL1; folding 10 towels, ADL2; putting away groceries, ADL3; washing up 4 dishes, cups and saucers, ADL4; sweeping the floor for 4 min, ADL5. Task-related VO 2  was assessed using a mobile oxycon, while Borg scores were used to assess task-related dyspnea and fatigue.  Baseline characteristics were comparable after stratification for BMI. Underweight COPD patients ( 2 , n=24) had the lowest absolute task-related VO 2  after performance of 5 ADLs (629±151mL/min) compared to patients with normal (21-25 kg/m 2 , n=31; VO 2: 818±242 mL/min), overweight (25-30 kg/m 2 , n=26; VO 2:  806±161 mL/min) and obese BMI (>30 kg/m 2 , n=13; VO 2: 1030±259 mL/min; all p 2  expressed as a proportion of peak VO 2  and VO 2  per kilogram fat-free mass (FFM) were comparable between BMI groups (%VO 2 peak: 65±16, 72±19, 65±15 and 73±21%; VO 2 /kgFFM: 16±3, 19±4, 17±3 and 18±4 mL/min/kg in underweight, normal, overweight or obese BMI, respectively). Moreover, Borg symptom scores for dyspnea en fatigue were comparable between BMI groups.  To conclude, patients with different BMI9s perform self-paced domestic ADLs at the same relative metabolic load, accompanied by comparable Borg symptom scores for dyspnea and fatigue.
The requirements for natural Th17 cell development are distinct from those of conventional Th17 cells
Authors: Jiyeon S. Kim, Jennifer E. Smith-Garvin, Gary A. Koretzky, Martha S. Jordan
Journal: The Journal of Experimental Medicine (2011)

CD4+ T helper 17 (Th17) cells play a critical role in the adaptive immune response against extracellular pathogens. Most studies to date have focused on understanding the differentiation of Th17 cells from naive CD4+ T cells in peripheral effector sites. However, Th17 cells are present in the thymus. In this study, we demonstrate that a population of Th17 cells, natural Th17 cells (nTh17 cells), which acquire effector function during development in the thymus before peripheral antigen exposure, shows preferential usage of T cell receptor Vβ3. nTh17 cells are dependent on major histocompatibility complex (MHC) class II for thymic selection, yet unlike conventional CD4+ T cells, MHC class II expression on thymic cortical epithelium is not sufficient for their development, rather expression on medullary epithelium is necessary. Differential signaling requirements for IL-17 priming further distinguish nTh17 from conventional Th17 cells. Collectively, our findings define a Th17 population, poised to rapidly produce cytokines, that is developmentally distinct from conventional Th17 cells and that potentially functions at the interface of innate and adaptive immunity.
Regular inhaled short acting 2 agonists for the management of stable chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis
Authors: F S F Ram
Journal: Thorax (2003)

<b>Background:</b> Despite the lack of reversibility, patients with chronic obstructive pulmonary disease (COPD) often report symptomatic improvement with inhaled short acting β<sub>2</sub> agonist bronchodilators (ISABAs) in the management of both stable and acute exacerbations of COPD. A review of the literature was undertaken to determine the effectiveness of regular treatment with ISABAs compared with placebo in stable COPD. <b>Methods:</b> A search for randomised controlled trials was carried out using the Cochrane Collaboration database of trials up to and including May 2002. <b>Results:</b> Thirteen studies of 7 days to 8 weeks in duration on 237 patients aged 56–70 years with forced expiratory volume in 1 second (FEV<sub>1</sub>) 60–70% predicted were included in the review. All studies used a crossover design with adequate washout periods and were of high methodological quality. ISABA was delivered either through a nebuliser or a pressurised metered dose inhaler. Spirometric tests performed at the end of the study and after the treatment (post-bronchodilator) showed a slight but significant increase in FEV<sub>1</sub> and forced vital capacity (FVC) compared with placebo. In addition, both morning and evening peak expiratory flow rate (PEFR) were significantly better during active treatment than during placebo. An improvement in the daily breathlessness score was observed with ISABA treatment. The risk of treatment failure was reduced by more than 50% with ISABA. Preference for ISABA was nine times higher than for placebo. <b>Conclusions:</b> Use of ISABA on a regular basis for at least 7 days in patients with stable COPD is associated with improvements in post-bronchodilator lung function and decreases in both breathlessness and treatment failure. This review has shown that regular administration of ISABAs is an effective and inexpensive treatment for the management of patients with stable COPD.
Balb/c T cells have the potential to recognize the TEPC 15 prototype antibody and its somatic variants.
Authors: S K Pierce, N A Speck, K Gleason, P J Gearhart, H Köhler
Journal: The Journal of Experimental Medicine (1981)

Immunization of BALB/c mice with phosphorylcholine-Limulus polyphemus hemocyanin (PC-Hy) induces a population of T cells that recognize the predominant PC-binding antibody, TEPC15 (T15). The splenic fragment culture system was used to examine the specificity of these T cells for a series of PC-binding myeloma and hybridoma antibodies representing the prototype variable region of the heavy chain (VH)T 15 sequence as well as somatic variants of the T15 germ line-encoded sequence. Included in this group of PC-binding proteins were both T15-positive and T15-negative antibodies, as defined by anti-idiotypic antibody. T cell help was identified by the ability to promote TNP-specific B cell responses to trinitrophenylated PC-binding proteins. It was found that T cells generated by immunization with PC-Hy recognize both antibodies with the T15 prototype sequence and the putative somatic variants of this sequence. A population of these T cells appear to recognize common determinants shared by these proteins because immunization with T15 itself also induces the recognition of the somatic variants. This suggests that idiotopes encoded in the T15 germ line gene expressed by the T15 prototype idiotype and the somatic variants can function as targets for T cell recognition and are thus regulatory idiotopes.
Immune and serologic profiles of HIV‐infected and noninfected hemophilic children and adolescents
Authors: Janine Jason, Bruce Evatt, John Murphy, Lynn A. Sleeper, Sharyne M. Donfield, Indira Warrier, Steven Arkin, Edward D. Gomperts
Journal: American Journal of Hematology (1994)

Abstract Objectives: To assess relationships among the effects of HIV on hemophilic children and adolescents' immunologic parameters and vaccine‐related serology. Methods: We analyzed data from extensive baseline immunologic evaluations of 207 HIV antibody‐positive (HIV+) and 126 HIV antibody‐negative (HIV−) hemophilic children and adolescents. Results: HIV+ and HIV‐ participants differed significantly in T‐lymphocyte subpopulation numbers, immunoglobulin levels, and seroprevalence rates for diphtheria toxoid, measles, and mumps antigens. IgG levels, IgM levels, and serologic titers to vaccine antigens showed little correlation with T‐cell parameters. Proportionately more HIV+ participants were nonreactive to each and all of a panel of 7 skin test antigens (71 % vs 28% anerglc, RR 2.6). The odds of anergy increased 1.6 times for every decline of 200 CD4 ± cells/μTl. Conclusions: HIV had significant, largely independent T‐ and B‐lymphocyte effects on this pediatric cohort. © 1994 Wiley‐Liss, Inc.
Withdrawal of disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a systematic review and meta-analysis
Authors: R. O'Mahony, A. Richards, C. Deighton, D. Scott
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Objective</h3> To define the effects of withdrawing disease-modifying antirheumatic drug (DMARD) treatment from patients with established rheumatoid arthritis (RA) receiving stable, effective long-term DMARD treatment. <h3>Methods</h3> A systematic literature search was conducted. Studies were included that were of high quality and enrolled adults with RA over 2 years9 duration. A meta-analysis was performed on the number of disease flares in groups withdrawn from DMARD treatment compared with those who continued to receive DMARD. <h3>Results</h3> The randomised controlled trial data were pooled into a meta-analysis and this showed that patients who withdrew from DMARD had a significantly worse risk of disease flare or deterioration than those who continued DMARD treatment. <h3>Conclusion</h3> In patients who have their disease adequately controlled by DMARD and wish to reduce the dose or withdraw them, this should be done cautiously. Their disease activity should be monitored carefully so that they recommence DMARD therapy in the event of disease flare or deterioration.
Independent Association of Lobular Involution and Mammographic Breast Density With Breast Cancer Risk
Authors: K. Ghosh, C. M. Vachon, V. S. Pankratz, R. A. Vierkant, S. S. Anderson, K. R. Brandt, D. W. Visscher, C. Reynolds, M. H. Frost, L. C. Hartmann
Journal: JNCI Journal of the National Cancer Institute (2010)

BackgroundLobular involution, or age-related atrophy of breast lobules, is inversely associated with breast cancer risk, and mammographic breast density (MBD) is positively associated with breast cancer risk.
Transmission of Response to Trauma? Second-Generation Holocaust Survivors’ Reaction to Cancer
Authors: L Baider, T Peretz, P E Hadani, S Perry, R Avramov, A K De-Nour
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Opinions differ about the effects of the Holocaust on the adult offspring of survivors. The authors studied cancer patients who were second-generation Holocaust survivors in an attempt to determine whether they react to their illness with the high distress found to be a characteristic of Holocaust survivors.METHOD: In a study population of women with breast cancer, 106 second-generation Holocaust survivors were compared to 102 women whose parents were not in the Holocaust. Background information was obtained by interviews. In addition, all patients completed three self-reports: the Mental Attitude to Cancer Scale, the Brief Symptom Inventory, and the Impact of Event Scale.RESULTS: The two groups had identical mean scores on the Mental Attitude to Cancer Scale. The offspring of Holocaust survivors had scores on the Brief Symptom Inventory and the Impact of Event Scale that were substantially and significantly higher and in the range of psychopathology. Within the group, married women and women whose mothers were still alive were even more distressed. Other independent variables shed little light on why the second-generation Holocaust survivors suffered from extreme distress.CONCLUSIONS: Second-generation Holocaust survivors are particularly vulnerable to psychological distress and, when faced with a trauma such as breast cancer, react with extreme psychological distress.
The Relationship of Reduced Peripheral Nerve Function and Diabetes With Physical Performance in Older White and Black Adults
Authors: Elsa S. Strotmeyer, Nathalie de Rekeneire, Ann V. Schwartz, Kimberly A. Faulkner, Helaine E. Resnick, Bret H. Goodpaster, Ronald I. Shorr, Aaron I. Vinik, Tamara B. Harris, Anne B. Newman
Journal: Diabetes Care (2008)

OBJECTIVE—Poor peripheral nerve function is prevalent in diabetes and older populations, and it has great potential to contribute to poor physical performance. RESEARCH DESIGN AND METHODS—Cross-sectional analyses were done for the Health, Aging, and Body Composition (Health ABC) Study participants (n = 2,364; 48% men; 38% black; aged 73–82 years). Sensory and motor peripheral nerve function in legs/feet was assessed by 10- and 1.4-g monofilament perception, vibration detection, and peroneal motor nerve conduction amplitude and velocity. The Health ABC lower-extremity performance battery was a supplemented version of the Established Populations for the Epidemiologic Studies of the Elderly battery (chair stands, standing balance, and 6-m walk), adding increased stand duration, single foot stand, and narrow walk. RESULTS—Diabetic participants had fewer chair stands (0.34 vs. 0.36 stands/s), shorter standing balance time (0.69 vs. 0.75 ratio), slower usual walking speed (1.11 vs. 1.14 m/s), slower narrow walking speed (0.80 vs. 0.90 m/s), and lower performance battery score (6.43 vs. 6.93) (all P &amp;lt; 0.05). Peripheral nerve function was associated with each physical performance measure independently. After addition of peripheral nerve function in fully adjusted models, diabetes remained significantly related to a lower performance battery score and slower narrow walking speed but not to chair stands, standing balance, or usual walking speed. CONCLUSIONS—Poor peripheral nerve function accounts for a portion of worse physical performance in diabetes and may be directly associated with physical performance in older diabetic and nondiabetic adults. The impact of peripheral nerve function on incident disability should be evaluated in older adults.
Evolution of the trnF(GAA) Gene in Arabidopsis Relatives and the Brassicaceae Family: Monophyletic Origin and Subsequent Diversification of a Plastidic Pseudogene
Authors: Marcus A. Koch, Christoph Dobeš, Michaela Matschinger, Walter Bleeker, Johannes Vogel, Markus Kiefer, Thomas Mitchell-Olds
Journal: Molecular Biology and Evolution (2005)

Recently, we used the 5′-trnL(UAA)–trnF(GAA) region of the chloroplast DNA for phylogeographic reconstructions and phylogenetic analysis among the genera Arabidopsis, Boechera, Rorippa, Nasturtium, and Cardamine. Despite the fact that extensive gene duplications are rare among the chloroplast genome of higher plants, within these taxa the anticodon domain of the trnF(GAA) gene exhibit extensive gene duplications with one to eight tandemly repeated copies in close 5′ proximity of the functional gene. Interestingly, even in Arabidopsis thaliana we found six putative pseudogenic copies of the functional trnF gene within the 5′-intergenic trnL-trnF spacer. A reexamination of trnL(UAA)-trnF(GAA) regions from numerous published phylogenetic studies among halimolobine, cardaminoid, and other cruciferous taxa revealed not only extensive trnF gene duplications but also favor the hypothesis about a single origin of trnF pseudogene formation during evolution of the Brassicaceae family 16–21 MYA. Conserved sequence motifs from this tandemly repeated region are codistributed nonrandomly throughout the plastome, and we found some similarities with a DNA sequence duplication in the rps7 gene and its adjacent spacer. Our results demonstrate the potential evolutionary dynamics of a plastidic region generally regarded as highly conserved and probably cotranscribed and, as shown here for several genera among cruciferous plants, greatly characterized by parallel gains and losses of duplicated trnF copies.