tbuckley/cabot-search huggingface dataset:
Small Molecule–Based Approaches to Adult Stem Cell Therapies
Authors: Luke L. Lairson, Costas A. Lyssiotis, Shoutian Zhu, Peter G. Schultz
Journal: The Annual Review of Pharmacology and Toxicology (2013)

There is considerable interest in the development of stem cell–based strategies for the treatment of a broad range of human diseases, including neurodegenerative, autoimmune, cardiovascular, and musculoskeletal diseases. To date, such regenerative approaches have focused largely on the development of cell transplantation therapies using cells derived from pluripotent embryonic stem cells (ESCs). Although there have been exciting preliminary reports describing the efficacy of ESC-derived replacement therapies, approaches involving ex vivo manipulated ESCs are hindered by issues of mutation, immune rejection, and ethical controversy. An alternative approach involves direct in vivo modulation or ex vivo expansion of endogenous adult stem cell populations using drug-like small molecules. Here we describe chemical approaches to the regulation of somatic stem cell biology that are yielding new biological insights and that may ultimately lead to innovative new medicines.
Characteristics of liver injury in drug-induced systemic hypersensitivity reactions
Authors: Taehoon Lee, Yoon Su Lee, Sun-Young Yoon, Sujeong Kim, Yun-Jeong Bae, Hyouk-Soo Kwon, You Sook Cho, Hee-Bom Moon, Tae-Bum Kim
Journal: Journal of the American Academy of Dermatology (2013)
Circulating Mitochondrial Nucleic Acids Have Prognostic Value for Survival in Patients with Advanced Prostate Cancer
Authors: Niven Mehra, Maarten Penning, Jolanda Maas, Nancy van Daal, Rachel H. Giles, Emile E. Voest
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Advanced prostate cancer represents a heterogeneous disease entity with differences in clinical behavior, response to therapy, and survival. We assessed whether we could distinguish poor from good prognosis patients at presentation in our clinic by means of quantifying circulating cell-free mitochondrial and genomic nucleic acids in plasma. Experimental Design: We collected plasma from 75 prostate cancer patients and from 14 subjects with benign disease. Nucleic acids were isolated, and mitochondrial DNA (mtDNA; 16S rRNA), mitochondrial RNA (mtRNA; cytochrome c oxidase subunit 1), and genomic DNA (U1A DNA) transcripts were quantified by real-time amplification. An association between cell-free nucleic acids and metastasis, prostate-specific antigen doubling time, and hemoglobin levels was determined. Multivariate Cox proportional hazard and survival estimation studies were done. Results: We show that elevated mtDNA and mtRNA levels are present in plasma of prostate cancer patients with a poor 2-year survival (P = 0.02 and 0.003, respectively). Cancer patients with high plasma mitochondrial nucleic acids, using a calculated optimal cutoff point, show a decreased survival compared with patients with low levels (35% versus 73% cumulative survival for mtDNA and 21% versus 73% for mtRNA). Multivariate analysis indicates that mtRNA is an independent predictor of 2-year survival. Conclusions: Quantification of plasma mitochondrial nucleic acids may be used to recognize patients with a poor prognosis. In advanced prostate cancer patients, mtRNA seemed the strongest predictor of overall survival and an independent prognostic factor for cancer-related death. Amplification of mitochondrial nucleic acids shows increased sensitivity and specificity over genomic DNA as diagnostic and prognostic marker in prostate cancer patients.
The Ly-49D Receptor Activates Murine Natural Killer Cells
Authors: L.H. Mason, S.K. Anderson, W.M. Yokoyama, H.R.C. Smith, R. Winkler-Pickett, J.R. Ortaldo
Journal: The Journal of Experimental Medicine (1996)

Proteins encoded by members of the Ly-49 gene family are predominantly expressed on murine natural killer (NK) cells. Several members of this gene family have been demonstrated to inhibit NK cell lysis upon recognizing their class I ligands on target cells. In this report, we present data supporting that not all Ly-49 proteins inhibit NK cell function. Our laboratory has generated and characterized a monoclonal antibody (mAb) (12A8) that can be used to recognize the Ly-49D subset of murine NK cells. Transfection of Cos-7 cells with known members of the Ly-49 gene family revealed that 12A8 recognizes Ly-49D, but also cross-reacts with the Ly-49A protein on B6 NK cells. In addition, 12A8 demonstrates reactivity by both immuno-precipitation and two-color flow cytometry analysis with an NK cell subset that is distinct from those expressing Ly-49A, C, or G2. An Ly-49D+ subset of NK cells that did not express Ly-49A, C, and G2 was isolated and examined for their functional capabilities. Tumor targets and concanovalin A (ConA) lymphoblasts from a variety of H2 haplotypes were examined for their susceptibility to lysis by Ly-49D+ NK cells. None of the major histocompatibility complex class I-bearing targets inhibited lysis of Ly-49D+ NK cells. More importantly, we demonstrate that the addition of mAb 12A8 to Ly-49D+ NK cells can augment lysis of Fc gamma R+ target cells in a reverse antibody-dependent cellular cytotoxicity-type assay and induces apoptosis in Ly-49D+ NK cells. Furthermore, the cytoplasmic domain of Ly-49D does not contain the V/Ix-YxxL immunoreceptor tyrosine-based inhibitory motif found in Ly-49A, C, or G2 that has been characterized in the human p58 killer inhibitory receptors. Therefore, Ly-49D is the first member of the Ly-49 family characterized as transmitting positive signals to NK cells, rather than inhibiting NK cell function.
Contextual factors in the generation of express and regular saccades
Authors: Martin J&uuml;ttner
Journal: Behavioral and Brain Sciences (1999)

Experiments using a modified gap paradigm, where regular trials are intermingled with catch trials (trials without saccade target), demonstrate that the relative frequency of express versus regular saccades distinctly depends on catch trial frequency. More specifically, it has been shown that the probability of an express saccade depends stochastically on the type of the preceding trial, that is, on the sequence of stimuli. We discuss whether such contextual effects can be accommodated within the framework of Findlay &amp; Walker's model.
Three measures of tumor necrosis factor α activity and insulin resistance in nonobese Japanese type 2 diabetic patients
Authors: Michihiro Ohya, Ataru Taniguchi, Mitsuo Fukushima, Yoshikatsu Nakai, Yukiko Kawasaki, Shoichiro Nagasaka, Akira Kuroe, Yoshiro Taki, Satoru Yoshii, Masaya Hosokawa, Nobuya Inagaki, Yutaka Seino
Journal: Metabolism (2005)
Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector
Authors: H Bobby Gaspar, Kathryn L Parsley, Steven Howe, Doug King, Kimberly C Gilmour, Joanna Sinclair, Gaby Brouns, Manfred Schmidt, Christof Von Kalle, Torben Barington, Marianne A Jakobsen, Hans O Christensen, Abdulaziz Al Ghonaium, Harry N White, John L Smith, Roland J Levinsky, Robin R Ali, Christine Kinnon, Adrian J Thrasher
Journal: The Lancet (2004)
A Natriuretic Hormone–Binding Site on the Sodium Pump
Authors: Jack H. Kaplan
Journal: Journal of the American Society of Nephrology (2008)

The Na+,K+-ATPase, or “sodium pump,” is an integral membrane protein that provides an energetic underpinning to salt and nutrient reabsorption in the nephron, as well as being the central modulator of fluid and electrolyte homeostasis in humans.[1][1],[2][2] The exclusive basolateral
MATURE T LYMPHOCYTE APOPTOSIS—Immune Regulation in a Dynamic and Unpredictable Antigenic Environment
Authors: Michael Lenardo, Francis Ka-Ming Chan, Felicita Hornung, Hugh McFarland, Richard Siegel, Jin Wang, Lixin Zheng
Journal: Annual Review of Immunology (1999)

▪ Abstract Apoptosis of mature T lymphocytes preserves peripheral homeostasis and tolerance by countering the profound changes in the number and types of T cells stimulated by diverse antigens. T cell apoptosis occurs in at least two major forms: antigen-driven and lymphokine withdrawal. These forms of death are controlled in response to local levels of IL-2 and antigen in a feedback mechanism termed propriocidal regulation. Active antigen-driven death is mediated by the expression of death cytokines such as FasL and TNF. These death cytokines engage specific receptors that assemble caspase-activating protein complexes. These signaling complexes tightly regulate cell death but are vulnerable to inherited defects. Passive lymphokine withdrawal death may result from the cytoplasmic activation of caspases that is regulated by mitochondria and the Bcl-2 protein. The human disease, Autoimmune Lymphoproliferative Syndrome (ALPS) is due to dominant-interfering mutations in the Fas/APO-1/CD95 receptor and other components of the death pathway. The study of ALPS patients reveals the necessity of apoptosis for preventing autoimmunity and allows the genetic investigation of apoptosis in humans. Immunological, cellular, and molecular evidence indicates that throughout the life of a T cell, apoptosis may be evoked in excessive, harmful, or useless clonotypes to preserve a healthy and balanced immune system.
Prevalence and Causes of Blindness and Low Vision in Southern Sudan
Authors: Jeremiah Ngondi, Francis Ole-Sempele, Alice Onsarigo, Ibrahim Matende, Samson Baba, Mark Reacher, Fiona Matthews, Carol Brayne, Paul M Emerson
Journal: PLoS Medicine (2006)

Blindness and low vision are thought to be common in southern Sudan. However, the magnitude and geographical distribution are largely unknown. We aimed to estimate the prevalence of blindness and low vision, identify the main causes of blindness and low vision, and estimate targets for blindness prevention programs in Mankien payam (district), southern Sudan.A cross-sectional survey of the population aged 5 y and above was conducted in May 2005 using a two-stage cluster random sampling with probability proportional to size. The Snellen E chart was used to test visual acuity, and participants also underwent basic eye examination. Vision status was defined using World Health Organization categories of visual impairment based on presenting visual acuity (VA). A total of 2,954 persons were enumerated and 2,499 (84.6%) examined. Prevalence of blindness (presenting VA of less than 3/60 in the better eye) was 4.1% (95% confidence interval [CI], 3.4-4.8); prevalence of low vision (presenting VA of at least 3/60 but less than 6/18 [corrected] in the better eye) was 7.7% (95% CI, 6.7-8.7); whereas prevalence of monocular visual impairment (presenting VA of at least 6/18 [corrected] in better eye and VA of less than 6/18 [corrected] in other eye) was 4.4% (95% CI, 3.6-5.3). The main causes of blindness were considered to be cataract (41.2%) and trachoma (35.3%), whereas low vision was mainly caused by trachoma (58.1%) and cataract (29.3%). It is estimated that in Mankien payam 1,154 persons aged 5 y and above (lower and upper bounds = 782-1,799) are blind, and 2,291 persons (lower and upper bounds = 1,820-2,898) have low vision.Blindness is a serious public health problem in Mankien, and there is urgent need to implement comprehensive blindness prevention programs. Further surveys are essential to confirm these tragic findings and estimate prevalence of blindness and low vision in the entire region of southern Sudan in order to facilitate planning of VISION 2020 objectives.
Activation of Akt is essential for acetylcholine to trigger generation of oxygen free radicals
Authors: T KRIEG, M LANDSBERGER, M ALEXEYEV, S FELIX, M COHEN, J DOWNEY
Journal: Cardiovascular Research (2003)

Acetylcholine (ACh) receptor activation in the heart causes mitochondrial production of reactive oxygen species (ROS) that is dependent on mitochondrial K(ATP) channel opening. Recent data show that Akt (also known as protein kinase B) is phosphorylated at its activation site following exposure to ACh. However, since no reliable Akt inhibitor is available, it has not been possible to determine whether Akt activation is an actual step in the protective pathway.Cultured rat vascular smooth muscle cells (A7r5) were transiently transfected with a dominant negative Akt (Akt-AAA), thus inhibiting the ability of ACh in these cells to phosphorylate Akt. Transfected cells were identified by co-transfection of enhanced green fluorescent protein (EGFP). ROS production was determined by incubating the cells for 15 min with 1 mM reduced MitoTracker Red which becomes fluorescent only after reacting with ROS. Cells were then triple-washed to remove any voltage-dependent pool of dye and single cell fluorescence was measured.ACh exposure (2 mM) led to a 1.64+/-0.15-fold increase in the average fluorescence over that seen in untreated cells (P=0.002). A similar increase in ROS production occurred after treatment with either the K(ATP) channel opener diazoxide (DIAZ) or the potassium ionophore valinomycin (VAL). Akt-AAA transfection abolished ACh-induced ROS production, but not increased ROS production after treatment with either DIAZ or VAL.Thus, at least in the smooth muscle cell model, Akt phosphorylation is an important step in the signal transduction pathway leading from ACh receptor activation to the generation of ROS. The experiments reveal that Akt is positioned between the receptor and the K(ATP) channel in this model.
Simian Virus 40 Infection Down-Regulates the Expression of Nitric Oxide Synthase in Human Mesothelial Cells
Authors: Elisabetta Aldieri, Sara Orecchia, Dario Ghigo, Loredana Bergandi, Chiara Riganti, Bice Fubini, Pier Giacomo Betta, Amalia Bosia
Journal: Cancer Research (2004)

Abstract The cytotoxic effects of asbestos are partly mediated by the production of free radicals, including nitric oxide (NO). SV40 has been suggested to synergize with asbestos in the pathogenesis of malignant mesothelioma. Crocidolite asbestos fibers induced in human mesothelial and malignant mesothelioma cells a significant increase of NO synthase activity and expression, which was absent in SV40-infected cells. Furthermore, SV40 infection prevented the NFκB activation elicited by crocidolite in both mesothelial and mesothelioma cells. These data suggest that SV40, by inhibiting the synthesis of NO, could favor the survival of transformed, potentially neoplastic cells.
Expression and modulation of adipolin/C1qdc2: a novel adipokine in human and murine ATDC-5 chondrocyte cell line
Authors: Javier Conde, Morena Scotece, Verónica López, Rodolfo Gómez, Francisca Lago, Jesús Pino, Juan Jesús Gómez-Reino, Oreste Gualillo
Journal: Annals of the Rheumatic Diseases (2012)

Osteoarthritis (OA) is the most frequent articular disease, characterised by the irreversible loss of articular cartilage and accompanied by changes in the synovium and subchondral bone.1 Chondrocytes are the unique cell type of adult articular cartilage capable of maintaining cartilage components under normal turnover conditions.2

Several factors affect the normal physiology of chondrocytes including mechanical stress, proinflammatory cytokines and obesity.3 The latter is characterised by a dysfunction of adipose tissue and its adipokine secretion pattern, indicating that metabolic changes as a result of obesity may have an additional aetiological influence on OA susceptibility, phenotype and progression. Adipokines such as leptin and adiponectin affect articular cartilage degradation by inducing proinflammatory factors such as interleukin (IL)-6, nitric oxide and IL-8 at the cartilage level.4 ,5 The role of adipokines in joint homeostasis is currently under investigation, but it is a matter of debate since some clinical studies have not been able to identify major involvement of adipokines in OA.

C1qdc2/CTRP12, also called adipolin (adipose-derived insulin-sensitising factor), is a very recently described adipokine which is abundantly expressed in adipose tissue.6 This novel adipokine is decreased in rodent obesity models. Adipolin ameliorates glucose intolerance and insulin resistance in diet-induced obese mice.6 ,7 In addition, …
Controlled Exposure of Healthy Young Volunteers to Ozone Causes Cardiovascular Effects
Authors: Robert B. Devlin, Kelly E. Duncan, Melanie Jardim, Michael T. Schmitt, Ana G. Rappold, David Diaz-Sanchez
Journal: Circulation (2012)

Background— Recent epidemiology studies have reported associations between short-term ozone exposure and mortality. Such studies have previously reported associations between airborne particulate matter pollution and mortality, and support for a causal relationship has come from controlled-exposure studies that describe pathophysiological mechanisms by which particulate matter could induce acute mortality. In contrast, for ozone, almost no controlled-human-exposure studies have tested whether ozone exposure can modulate the cardiovascular system. Methods and Results— Twenty-three young healthy individuals were exposed in a randomized crossover fashion to clean air and to 0.3-ppm ozone for 2 hours while intermittently exercising. Blood was obtained immediately before exposure, immediately afterward, and the next morning. Continuous Holter monitoring began immediately before exposure and continued for 24 hours. Lung function was performed immediately before and immediately after exposure, and bronchoalveolar lavage was performed 24 hours after exposure. Immediately after ozone exposure, we observed a 98.9% increase in interleukin-8, a 21.4% decrease in plasminogen activator inhibitor-1, a 51.3% decrease in the high-frequency component of heart rate variability, and a 1.2% increase in QT duration. Changes in interleukin-1B and plasminogen activator inhibitor-1 were apparent 24 hours after exposure. In agreement with previous studies, we also observed ozone-induced drops in lung function and an increase in pulmonary inflammation. Conclusions— This controlled-human-exposure study shows that ozone can cause an increase in vascular markers of inflammation and changes in markers of fibrinolysis and markers that affect autonomic control of heart rate and repolarization. We believe that these findings provide biological plausibility for the epidemiology studies that associate ozone exposure with mortality. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01492517.
A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group
Authors: G Barosi, C Besses, G Birgegard, J Briere, F Cervantes, G Finazzi, H Gisslinger, M Griesshammer, L Gugliotta, C Harrison, H Hasselbalch, E Lengfelder, J T Reilly, J J Michiels, T Barbui
Journal: Leukemia (2006)
* Azathioprine metabolites in autoimmune hepatitis:relationship with therapeutic efficacy
Authors: R. J. Anderson, H. K. Dhaliwal, S. Schneider, E. McFarlane, D. C. Gleeson, L. Lennard
Journal: Gut (2011)

<h3>Introduction</h3> Long term azathioprine (AZA, 2 mg/kg/day) is used to maintain remission in Autoimmune Hepatitis (AIH). However 10–20% of patients are unresponsive to AZA. AZA is a pro-drug and formation of the active metabolite (thioguanine nucleotides-TGNs) varies between individuals. Competing with TGN formation is drug methylation, catalysed by the polymorphic enzyme thiopurine methyltransferase (TPMT), leading to formation of methyl mercaptopurine metabolites (MeMPs). In Inflammatory Bowel Disease (IBD), clinical response is associated with TGN concentrations of above 230–260 pmol/8×10<sup>8</sup> RBCs.1 The study aim was to assess the relationship between TPMT activity, metabolite levels (TGN and MeMPs) and therapeutic response in AIH. <h3>Methods</h3> The authors recruited 68 patients with AIH who had achieved biochemical remission (normalisation of ALT) and were taking maintenance AZA. Erythrocyte TGN, MeMPs and TPMT were measured on serial blood samples (median (range) 3 (1–7) per patient), at a constant AZA dose. Average metabolite concentration for each patient were analysed. Patients were divided into group 1: patients in remission on AZA monotherapy (n=49) and group 2, patients requiring prednisolone also (n=19, dose 5 (2.5–10 mg/day). <h3>Results</h3> TGN concentration was (median (range) 207 (57–839) pmol/8×10<sup>8</sup> RBCs at a median dose 1.83 mg/kg/day. AZA dose (mg/kg/day) correlated positively with MeMPs concentration (r=0.414, p=0.000) but not with TGN (r=0.002, p=0.998). Between the two groups (see table 1), there was no difference in TGN or MeMPs concentrations, or in TPMT activity. Serum ALT was lower in group 1 (median difference 12, 95% CI 4 to 22). Serum ALT was negatively correlated with TGN concentration (r=−0.235, p=0.06) and positively correlated with TPMT activity (r=0.243, p=0.05), both of borderline significance. <h3>Conclusion</h3> TGN concentrations were lower in our patients with AIH, than the therapeutic range for IBD. The authors were unable to identify a threshold associated with an adequate therapeutic response. However, lower TPMT activity and higher TGN concentration, tended to correlate with lower serum ALT. While further studies are needed, these results are consistent with a role for AZA metabolite formation in influencing the efficacy of AZA maintenance therapy in AIH.
Fatal ascaris pancreatitis: an uncommon problem in the west.
Authors: G J Maddern, A R Dennison, L H Blumgart
Journal: Gut (1992)

Gastrointestinal parasites, although an uncommon cause of biliary and pancreatic problems in western medicine, can produce fatal complications. A Swiss patient presented with acute pancreatitis, with no evidence of gall stones or history of alcohol abuse. He died after a short fulminant illness. At necropsy, an Ascaris lumbracoides was found impacted within the ampulla of Vater and serves as a reminder that non-indigenous causes of biliary tract obstruction should not be overlooked.
The British Olympic Association's position statement on athlete confidentiality
Authors: Domnhall Macauley, Roger Bartlett
Journal: British Journal of Sports Medicine (2000)

Warm upSo you're a rocket scientist.That doesn't impress me much.Unless of course you can help me live longer, feel better, and look younger.We do not have all the answers, but we can certainly add a few extra years to some bits.Your bones, for example.You don't need to be a rocket scientist to know the importance of preventing falls and hip fractures in older people nor do you need modern technology to run an exercise programme (p 7).Resistance training helps improve muscular strength and bone density (p 18) and Tai Chi can help balance, flexibility, and fitness (p 29).Looking younger is a little more difficult.So you think you're quite fit.That doesn't impress me much.But if you want to throw further, jump higher, or run faster, the laboratory may be able to help.We can test your fitness by measuring lactate levels (p 35), and assess muscle isokinetic strength and mobility (p 39).But, take care you don't overdo it.Our knowledge of overtraining isincomplete (p 67) and sport can aVect one's perception of mental health (p 4).Measuring your thoughts-that's a diVerent journal.