tbuckley/cabot-search huggingface dataset:
6-Thioguanine Reactivates Epigenetically Silenced Genes in Acute Lymphoblastic Leukemia Cells by Facilitating Proteasome-mediated Degradation of DNMT1
Authors: Bifeng Yuan, Jing Zhang, Hongxia Wang, Lei Xiong, Qian Cai, Tina Wang, Steven Jacobsen, Sriharsa Pradhan, Yinsheng Wang
Journal: Cancer Research (2011)

Thiopurines including 6-thioguanine ((S)G), 6-mercaptopurine, and azathioprine are effective anticancer agents with remarkable success in clinical practice, especially in effective treatment of acute lymphoblastic leukemia (ALL). (S)G is understood to act as a DNA hypomethylating agent in ALL cells, however, the underlying mechanism leading to global cytosine demethylation remains unclear. Here we report that (S)G treatment results in reactivation of epigenetically silenced genes in T leukemia cells. Bisulfite genomic sequencing revealed that (S)G treatment universally elicited demethylation in the promoters and/or first exons of the genes that were reactivated. (S)G treatment also attenuated the expression of histone lysine-specific demethylase 1 (LSD1), thereby stimulating lysine methylation of the DNA methylase DNMT1 and triggering its degradation via the ubiquitin-proteasomal pathway. Taken together, our findings reveal a previously uncharacterized but vital mechanistic link between (S)G treatment and DNA hypomethylation.
Severity of exercise-induced bronchoconstriction is related to airway eosinophilic inflammation in patients with asthma
Authors: T Yoshikawa, S Shoji, T Fujii, H Kanazawa, S Kudoh, K Hirata, J Yoshikawa
Journal: European Respiratory Journal (1998)

Exercise-induced bronchoconstriction (EIB) is widely prevalent in asthmatic patients. Eosinophilic airway inflammation is considered to be a major factor in the pathogenesis of asthma. However, the effects of eosinophilic airway inflammation on EIB have been elucidated insufficiently. To examine the relationship between the severity of EIB and eosinophilic inflammation, sputum induction and exercise challenge were performed in 21 asthmatic patients. Significantly higher percentages of eosinophils and levels of eosinophil cationic protein (ECP) were found in induced sputum in EIB-positive asthmatics (median (range), eosinophils: 23.5 (11.0-61.0)%; ECP: 1,475 (74.8-17,701) ng x mL(-1)) than in EIB-negative asthmatics (eosinophils: 6.0 (1.0-41.5)% (p=0.006); ECP: 270.6 (10.8-7,700) ng x mL(-1) (p=0.049)). There was a significant correlation between the severity of EIB and the sputum eosinophil percentage (r=0.59, p=0.009) and the level of ECP (r=0.47, p=0.037). The area under the curve of the forced expiratory volume in one second for 30 min after exercise correlated with the percentage of eosinophils (r=0.60, p=0.008) and the level of ECP (r=0.45, p=0.04). There was no correlation between airway responsiveness to methacholine on the one hand and EIB, sputum eosinophils or ECP on the other. In conclusion, these results provide evidence that the severity of bronchoconstriction evoked by exercise is more closely related to eosinophilic airway inflammation than airway hyperresponsiveness to methacholine in asthmatic patients.
The 3′ end of the heavy chain constant region locus enhances germline transcription and switch recombination of the four γ genes
Authors: Wesley A. Dunnick, Jian Shi, Kevin A. Graves, John T. Collins
Journal: The Journal of Experimental Medicine (2005)

The switch in immunoglobulin (Ig) heavy chain class is preceded by germline transcription and then mediated by a DNA recombination event. To study germline transcription and class switch recombination we used transgenic mice with a 230-kilobase bacterial artificial chromosome that included a rearranged VDJ gene and the entire heavy chain constant region locus. In addition to several lines with intact transgenes, we identified two lines in which the heavy chain locus transgene lacked Cα and everything 3′ of it, including the regulatory elements HS3a, HS1-2, HS3b, and HS4. B cells from both lines with the truncated transgenes make abundant transgenic (Tg) VDJCμ transcripts and IgM protein. Deletion of the 3′ end of the locus results in dramatically reduced expression of both germline transcripts and switched VDJCH transcripts of the γ3, γ2b, γ2a, and ε genes. In addition, the transgenes lacking the 3′ end of the locus express reduced amounts of γ1 germline transcripts and 2–3% of the amount of Tg IgG1 in tissue culture compared with intact transgenes. Finally, switch recombination to γ1 is undetectable in the transgenes lacking the 3′ elements, as measured by digestion circularization–polymerase chain reaction or by the expression of VDJCγ1 transcripts.
Genetics of amyotrophic lateral sclerosis: an update
Authors: Sheng Chen, Pavani Sayana, Xiaojie Zhang, Weidong Le
Journal: Molecular Neurodegeneration (2013)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both upper motor neurons (UMN) and lower motor neurons (LMN). Enormous research has been done in the past few decades in unveiling the genetics of ALS, successfully identifying at least fifteen candidate genes associated with familial and sporadic ALS. Numerous studies attempting to define the pathogenesis of ALS have identified several plausible determinants and molecular pathways leading to motor neuron degeneration, which include oxidative stress, glutamate excitotoxicity, apoptosis, abnormal neurofilament function, protein misfolding and subsequent aggregation, impairment of RNA processing, defects in axonal transport, changes in endosomal trafficking, increased inflammation, and mitochondrial dysfunction. This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the disease neuropathogenesis.
THE EFFECT OF HETEROLOGOUS ANTI-LYMPHOCYTIC SERUM ON THE SMALL LYMPHOCYTE POPULATION OF RATS
Authors: Hewes D. Agnew
Journal: The Journal of Experimental Medicine (1968)

Treatment of Lewis strain rats with a single subcutaneous dose of rabbit anti-rat thymocyte serum (RARTS) resulted in a marked depletion of small lymphocytes in the blood and thoracic duct lymph for approximately 10 days. While the thoracic duct lymphocytes were declining in numbers, rabbit antibody could be detected on the surfaces of a high percentage of the lymph cells. Furthermore, the thoracic duct lymphocytes were unable to initiate graft vs. host reactions during the period of depletion, even when injected in extremely large doses. Approximately 2 wk after treatment, the numbers and immune competence of the small lymphocytes returned to normal.
COPD and IPF: it's all about regulation and balance
Authors: Argyris Tzouvelekis, Demosthenes Bouros
Journal: Thorax (2014)

The dominant theory of Hippocrates was that of the four humours—that when the four humours were in balance health prevailed. Therefore, the main goal of the medical therapy was to restore humoral equilibrium. We read with great interest the article by Hou et al ,1 where an imbalance between protective and detrimental subgroups of T regulatory (Treg) cells in patients with COPD is showed. On the contrary with previous studies reporting no significant differences in CD4 foxp3+ T cells between patients with COPD and smokers,2 …
AIDS Treatment Center: Is the Concept Premature?
Authors: Jesse Green
Journal: JAMA (1989)

<h3>To the Editor. —</h3> Bennett et al<sup>1</sup>of The RAND Corporation examined hospitalizations for acquired immunodeficiency syndrome (AIDS)—related<i>Pneumocystis carinii</i>pneumonia (PCP) at 15 California hospitals and found lower mortality rates at the hospitals with "high AIDS familiarity." However, because of methodological problems that cast doubt on this finding, policymakers should be cautious about the authors' recommendations, particularly with regard to the regionalization of acute care for AIDS. The sample of hospitals used for this study may not have been suitable for a comparison between high and low levels of AIDS familiarity, because none of the hospitals in California with the highest AIDS familiarity were included. In particular, none of the five most experienced hospitals in San Francisco, which provided 80% of that city's acute AIDS care in 1986, were among the study hospitals.<sup>2</sup>We base this conclusion on the human immunodeficiency virus—related volume statistics presented by the
Toward New Strategies to Select Young Endometrial Cancer Patients for Mismatch Repair Gene Mutation Analysis
Authors: Maran J.W. Berends, Ying Wu, Rolf H. Sijmons, Tineke van der Sluis, Wietske Boersmavan Ek, Marjolijn J.L. Ligtenberg, Neeltje J.W. Arts, Klaske A. ten Hoor, Jan H. Kleibeuker, Elisabeth G.E. de Vries, Marian J.E. Mourits, Harry Hollema, Charles H.C.M. Buys, Robert M.W. Hofstra, Ate G.J. van der Zee
Journal: Journal of Clinical Oncology (2003)

To determine the frequency of mismatch repair (MMR) gene germline mutations in endometrial cancer patients who were diagnosed at less than 50 years of age; to relate the presence of mutations to family history, histopathologic data, presence of tumor microsatellite instability (MSI), and immunostaining; and to formulate criteria for genetic testing in these patients.Endometrial cancer patients (N = 58), who were diagnosed at less than 50 years of age, were included and questioned about their family history. Mutation analysis of the MLH1, MSH2, and MSH6 genes was performed (denaturing gradient gel electrophoresis and sequence analysis to detect small mutations and multiplex ligation-dependent probe amplification to detect large deletions or duplications). For MSI analysis, five consensus markers were used, and immunostaining of the three MMR proteins was performed.In five of 22 patients with a positive first-degree family history for hereditary nonpolyposis colorectal cancer (HNPCC)-related cancers, pathogenic germline mutations were found (one MLH1, three MSH2, and one MSH6). Four mutation carriers belonged to families fulfilling the revised Amsterdam criteria. No mutations were found in the 35 patients without such family history (P =.006). MSI was detected in 20 of 57 cancers, among which four were from mutation carriers. In 23 of 51 cancers, one or more MMR protein was absent; in all five mutation carriers, immunostaining indicated the involved MMR gene.In 23% of the young endometrial cancer patients with at least one first-degree relative with an HNPCC-related cancer, an MMR gene mutation was detected. Therefore, presence of an HNPCC-related cancer in a first-degree relative seems to be an important selection criterion for mutation analysis. Subsequent immunostaining of MMR proteins will point to the gene(s) that should be analyzed.
Mortality in Patients After a Recent Myocardial Infarction
Authors: A. John Camm, Craig M. Pratt, Peter J. Schwartz, Hussein R. Al-Khalidi, Maria J. Spyt, Michael J. Holroyde, Roger Karam, Edmund H. Sonnenblick, Jose M.G. Brum
Journal: Circulation (2004)

Depressed left ventricular function (LVF) and low heart rate variability (HRV) identify patients at risk of increased mortality after myocardial infarction (MI). Azimilide, a novel class III antiarrhythmic drug, was investigated for its effects on mortality in patients with depressed LVF after recent MI and in a subpopulation of patients with low HRV.A total of 3717 post-MI patients with depressed LVF were enrolled in this randomized, placebo-controlled, double-blind study of azimilide 100 mg on all-cause mortality. Placebo patients with low HRV had a significantly higher 1-year mortality than those with high HRV (>20 U; 15% versus 9.5%, P<0.0005) despite nearly identical ejection fractions. No significant differences were observed between the 100-mg azimilide and placebo groups for all-cause mortality in either the "at-risk" patients identified by depressed LVF (12% versus 12%) or the subpopulation of "high-risk" patients identified by low HRV (14% versus 15%) or for total cardiac or arrhythmic mortality. Significantly fewer patients receiving azimilide developed atrial fibrillation than did patients receiving placebo (0.5% versus 1.2%, P<0.04). The incidences of torsade de pointes and severe neutropenia (absolute neutrophil count < or =500 cells/microL) were slightly higher in the azimilide group than in the placebo group (0.3% versus 0.1% for torsade de pointes and 0.9% versus 0.2% for severe neutropenia).Azimilide did not improve or worsen the mortality of patients after MI. Low HRV independently identified a subpopulation at high risk of mortality.
Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data
Authors: Matthias W Lorenz, Joseph F Polak, Maryam Kavousi, Ellisiv B Mathiesen, Henry Völzke, Tomi-Pekka Tuomainen, Dirk Sander, Matthieu Plichart, Alberico L Catapano, Christine M Robertson, Stefan Kiechl, Tatjana Rundek, Moïse Desvarieux, Lars Lind, Caroline Schmid, Pronabesh DasMahapatra, Lu Gao, Kathrin Ziegelbauer, Michiel L Bots, Simon G Thompson
Journal: The Lancet (2012)
Acute Renal Failure in Endotoxemia is Dependent on Caspase Activation
Authors: Rongqing Guo, Ying Wang, Andrew W. Minto, Richard J. Quigg, Patrick N. Cunningham
Journal: Journal of the American Society of Nephrology (2004)

In previous work, it was demonstrated that apoptosis occurs in the kidney during LPS-induced acute renal failure (ARF). However, the relative importance of apoptosis in LPS-induced ARF remained unproven. Because the caspase enzyme cascade is responsible for carrying out apoptosis, it was hypothesized that treatment with a caspase inhibitor would protect mice from LPS-induced ARF. C57BL/6 mice received an injection of LPS and were treated with either the broad-spectrum caspase inhibitor z-VAD-fmk or vehicle and compared with unmanipulated mice. LPS induced a significant increase in caspase-3 activity in vehicle-treated mice, which was significantly inhibited by z-VAD. Mice that were treated with z-VAD were protected from ARF and demonstrated significantly less apoptosis as measured by both terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and DNA laddering. Although apoptosis is classically described as a noninflammatory process, z-VAD treatment significantly attenuated multiple markers of inflammation, such as renal neutrophil infiltration and renal expression of the neutrophil chemotactic factor macrophage inflammatory protein-2. Thus, caspase inhibition may protect against LPS-induced ARF not only by preventing apoptotic cell death but also by inhibiting inflammation. These data raise the possibility that apoptotic kidney cells may actually be a source of this local inflammation, contributing to subsequent nonapoptotic renal injury.
Acid pH Increases the Stability of BSC1/NKCC2 mRNA in the Medullary Thick Ascending Limb
Authors: Zoubida Karim, Amel Attmane-Elakeb, Valérie Sibella, Maurice Bichara
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Chronic metabolic acidosis enhances the ability of the medullary thick ascending limb (MTAL) to absorb NH4+ at least in part by stimulating the mRNA and protein expression of BSC1/NKCC2, the MTAL apical Na+-K+(NH4+)-2Cl− co-transporter. For assessing the mechanism by which an acid pH enhances the BSC1 mRNA abundance, MTAL were harvested from adrenalectomized rats and incubated in control (pH 7.35) and acid (pH 7.10) 1:1 mixtures of Ham’s nutrient mixture F-12 and DME. rBSC1 mRNA abundance and gene transcription rate were quantified by quantitative reverse transcription–PCR and run-off assay, respectively. Acid incubation enhanced mRNA abundance within 4 h in whole cell (P < 0.02) but not in nucleus. BSC1 gene transcription rate was not affected by acid incubation. In contrast, under conditions in which gene transcription was blocked, rBSC1 mRNA decreased within 6 h by 38 ± 11% in control but only by 15 ± 15% in acid medium (P < 0.02), which represented an increase in the BSC1 mRNA half-life from approximately 7 to approximately 17 h. Furthermore, in a mouse TAL cell line, acid incubation for 16 h significantly increased (P < 0.02) the amount of BSC1 mRNA in cells transfected with the full-length mBSC1 cDNA but not in cells transfected with a mBSC1 cDNA lacking the 3′-UTR. These results demonstrate that acid pH enhances the stability of BSC1 mRNA probably by activating pathways that act on the AU-rich 3′-UTR of BSC1 mRNA, which contributes to the renal response to metabolic acidosis. E-mail: [email protected]
Transbronchial and transoesophageal (ultrasound-guided) needle aspirations for the analysis of mediastinal lesions
Authors: F. J. F. Herth, K. F. Rabe, S. Gasparini, J. T. Annema
Journal: European Respiratory Journal (2006)

A tissue diagnosis of mediastinal nodes is frequently needed for accurate lung cancer staging as well as the assessment of mediastinal masses. Transbronchial needle aspiration (TBNA) is a safe procedure that is performed during routine bronchoscopy. Provided mediastinal metastases are confirmed, TBNA has a high impact on patient management. Unfortunately, TBNA remains underused in current daily practice, mainly due to the lack of real-time needle visualisation. The introduction of echo-endoscopes has overcome this problem. Endobronchial ultrasound-guided TBNA (EBUS-TBNA) allows real-time controlled tissue sampling of paratracheal, subcarinal and hilar lymph nodes. Mediastinal lymph nodes located adjacent to the oesophagus can be assessed by transoesophageal ultrasound-guided fine needle aspiration (EUS-FNA). Owing to the complementary reach of EBUS-TBNA and EUS-FNA in assessing different regions of the mediastinum, recent studies suggest that complete and accurate mediastinal staging can be achieved by the combination of both procedures. It is expected that implementation of minimally invasive endoscopic methods of endobronchial ultrasound-guided transbronchial needle aspiration and transoesophageal ultrasound-guided fine needle aspiration will reduce the need for surgical staging of lung cancer significantly.
Imaging descriptors improve the predictive power of survival models for glioblastoma patients
Authors: M. A. Mazurowski, A. Desjardins, J. M. Malof
Journal: Neuro-Oncology (2013)

Because effective prediction of survival time can be highly beneficial for the treatment of glioblastoma patients, the relationship between survival time and multiple patient characteristics has been investigated. In this paper, we investigate whether the predictive power of a survival model based on clinical patient features improves when MRI features are also included in the model.The subjects in this study were 82 glioblastoma patients for whom clinical features as well as MR imaging exams were made available by The Cancer Genome Atlas (TCGA) and The Cancer Imaging Archive (TCIA). Twenty-six imaging features in the available MR scans were assessed by radiologists from the TCGA Glioma Phenotype Research Group. We used multivariate Cox proportional hazards regression to construct 2 survival models: one that used 3 clinical features (age, gender, and KPS) as the covariates and 1 that used both the imaging features and the clinical features as the covariates. Then, we used 2 measures to compare the predictive performance of these 2 models: area under the receiver operating characteristic curve for the 1-year survival threshold and overall concordance index. To eliminate any positive performance estimation bias, we used leave-one-out cross-validation.The performance of the model based on both clinical and imaging features was higher than the performance of the model based on only the clinical features, in terms of both area under the receiver operating characteristic curve (P < .01) and the overall concordance index (P < .01).Imaging features assessed using a controlled lexicon have additional predictive value compared with clinical features when predicting survival time in glioblastoma patients.
Colonic Secretion of Water and Electrolytes Induced by Bile Acids: Perfusion Studies in Man
Authors: Hagop S. Mekhjian, Sidney F. Phillips, Alan F. Hofmann
Journal: Journal of Clinical Investigation (1971)

Each of the three major bile acids of man was tested for its influence on electrolyte and water absorption in the human colon. Transport from isotonic solutions, with or without added bile acids, was compared in 35 studies on 20 healthy volunteers by colonic perfusions under steady-state conditions. Electrolytes and water were always absorbed from control solutions, but dihydroxy bile acid solutions induced continuous secretion or inhibition of sodium, potassium, and water absorption, which was reversible. Deoxycholic acid caused consistent secretion at 3 mm concentrations, whereas chenodeoxycholic acid did not induce secretion until the concentration was 5 mm. The trihydroxy bile acid (cholic acid) produced no significant change in absorption at 10 mm. Inhibition of absorption was also induced by mixtures of the glycine or taurine conjugated bile acids. Secretion of sodium and chloride, induced by bile acid perfusion, was linearly correlated with secretion of water; potassium secretion was relatively constant regardless of the volume of secretion. These results establish a striking influence of bile acids on colonic absorptive activity, provide an explanation in part for the diarrhea that frequently accompanies ileal disease or resection, and imply that diarrhea should occur in other disease states that produce elevated concentrations of dihydroxy bile acids in the colonic lumen.
Mass Transport in Arteries and the Localization of Atherosclerosis
Authors: John M. Tarbell
Journal: Annual Review of Biomedical Engineering (2003)

Atherosclerosis is a disease of the large arteries that involves a characteristic accumulation of high-molecular-weight lipoprotein in the arterial wall. This review focuses on the mass transport processes that mediate the focal accumulation of lipid in arteries and places particular emphasis on the role of fluid mechanical forces in modulating mass transport phenomena. In the final analysis, four mass transport mechanisms emerge that may be important in the localization of atherosclerosis: blood phase controlled hypoxia, leaky endothelial junctions, transient intercellular junction remodeling, and convective clearance of the subendothelial intima and media. Further study of these mechanisms may contribute to the development of therapeutic strategies for atherosclerotic diseases.
Diagnosis and Management of Depressant Drug Dependence
Authors: JOHN A. EWING, WILLIAM E. BAKEWELL
Journal: American Journal of Psychiatry (1967)

Patients who are dependent on a depressant drug, or combinations of them, are being seen quite regularly in hospital psychiatric practice. After discussing epidemiology, etiology, and diagnosis, the authors emphasize the importance of differentiating between the toxic effects of overdosage and the abstinence syndrome. The latter is best treated in the hospital, with drug requirements being determined by a test dose of pentobarbital. Thereafter a withdrawal regime over a ten-day period avoids serious complications.