tbuckley/cabot-search huggingface dataset:
The p53 Tumor Suppressor Network Is a Key Responder to Microenvironmental Components of Chronic Inflammatory Stress
Authors: Frank Staib, Ana I. Robles, Lyuba Varticovski, Xin W. Wang, Barry R. Zeeberg, Michail Sirotin, Victor B. Zhurkin, Lorne J. Hofseth, S. Perwez Hussain, John N. Weinstein, Peter R. Galle, Curtis C. Harris
Journal: Cancer Research (2005)

Abstract Activation of the p53 network plays a central role in the inflammatory stress response associated with ulcerative colitis and may modulate cancer risk in patients afflicted with this chronic disease. Here, we describe the gene expression profiles associated with four microenvironmental components of the inflammatory response (NO•, H2O2, DNA replication arrest, and hypoxia) that result in p53 stabilization and activation. Isogenic HCT116 and HCT116 TP53−/− colon cancer cells were exposed to the NO• donor Sper/NO, H2O2, hypoxia, or hydroxyurea, and their mRNA was analyzed using oligonucleotide microarrays. Overall, 1,396 genes changed in a p53-dependent manner (P &amp;lt; 0.001), with the majority representing a “unique” profile for each condition. Only 14 genes were common to all four conditions. Included were eight known p53 target genes. Hierarchical sample clustering distinguished early (1 and 4 hours) from late responses (8, 12, and 24 hours), and each treatment was differentiated from the others. Overall, NO• and hypoxia stimulated similar transcriptional responses. Gene ontology analysis revealed cell cycle as a key feature of stress responses and confirmed the similarity between NO• and hypoxia. Cell cycle profiles analyzed by flow cytometry showed that NO• and hypoxia induced quiescent S-phase and G2-M arrest. Using a novel bioinformatic algorithm, we identified several putative p53-responsive elements among the genes induced in a p53-dependent manner, including four [KIAA0247, FLJ12484, p53CSV (HSPC132), and CNK (PLK3)] common to all exposures. In summary, the inflammatory stress response is a complex, integrated biological network in which p53 is a key molecular node regulating gene expression.
A comparison of aortic baroreceptor discharge in normotensive and spontaneously hypertensive rats.
Authors: A M Brown, W R Saum, F H Tuley
Journal: Circulation Research (1976)

Electrophysiological characteristics of individual aortic baroreceptors from normotensive rats (NTR) and spontaneously hypertensive rats (SHR) were compared. Impulse activity of afferent fibers was examined following the application of pressure steps to an in vitro aortic arch-aortic nerve preparation. Thirty-one fibers including seven unmyelinated fibers were studied completely over the range of 0-260 mm Hg, using steps 1-30 seconds in duration. The pressure threshold for peak transient discharge of baroreceptors of SHR's was 88.4 +/- 10.1 (mean +/- SE) mm Hg, whereas for baroreceptors of NTR's it was 77.5 +/- 9.3 mm Hg. The pressure threshold for steady state discharge was 137.3 +/- 5.2 mm Hg for SHR baroreceptors and 103.5 +/- 7.1 for NTR baroreceptors. These values compare favorably to measurements in vivo in the rat. The relationship between peak transient impulse frequency and pressure was linear, whereas the relationship between steady state impulse frequency and pressure was hyperbolic. The curvature of the steady state frequency-pressure curves was significantly reduced for baroreceptors of SHR's. The steady state pressure-volume curves of the aortas of SHR's and NTR's were similar, so that a reduction in distensibility could not account for the larger, significant differences in threshhold and sensitivity. Therefore resetting cannot be attributed simply to reduced vascular compliance.
THE ROLE OF PREFRONTAL LOBE SURGERY AS A MEANS OF ERADICATING INTRACTABLE ANXIETY
Authors: JONATHAN SLOCUM, C. L. BENNETT, J. LAWRENCE POOL
Journal: American Journal of Psychiatry (1959)

A series of 18 consecutive patients were selected for frontal lobe surgery over a 10 year period to obtain relief from chronic, intractable anxiety. Of the 13 who were not psychotic, 12 have returned to a well adjusted, independent existence at home without further hospitalization or continuation of therapy. Certain observations based on these case studies have been made, with full realization that generalizations cannot be drawn from 18 cases and that whatever value this study may have is dependent upon intense personal investigation of all relevant factors in a small group of individuals.
Word for word
Authors: J A M. Gray
Journal: BMJ (1979)

and nine hands, with a foot thrown in for good measure.The organs from the mummy Nekht-ankh include lungs, liver, larynx, fingernails, penis, aortic arch, and pericardium.Of the animals, cats are the most frequently represented, followed by six crocodiles.There is no report of these having been radio- graphed, though one of the four imitation crocodiles, made of reeds and covered in cloth, contained a juvenile crocodile and two eggs.Hawk and kestrel were the only birds recorded, apart from two examples of the sacred ibis.The results of examination of these will be given in a further report.To extract as much information as possible about the human mummies with negligible damage seemed to be an ideal job for radiography.Thorough examinations were made at the Man- chester Medical School department of radiology, where it was possible to use not only conventional machines but also, for some examinations, complicated neuroradiological apparatus, the Elema Schonander Mimer 3, and, in a few cases, the Emiscan CT 5005 computerised axial tomograph.Examination of the teeth using an orthopantomograph-which showed maxilla and mandible simultaneously on one film-could be carried out only on the separate heads.Because of the nature of the material of the wrappings, the inclusion of resins and pitch, and the "button" decoration, plain radiography was confusing and tom- ography had to be used.This had the advantages of blurring out all the image except for a thin layer deep within the cartonnage.
Rates of Adult Schizophrenia Following Prenatal Exposure to the Chinese Famine of 1959-1961
Authors: David St Clair, Mingqing Xu, Peng Wang, Yaqin Yu, Yourong Fang, Feng Zhang, Xiaoying Zheng, Niufan Gu, Guoyin Feng, Pak Sham, Lin He
Journal: JAMA (2005)

Schizophrenia is a common major mental disorder. Intrauterine nutritional deficiency may increase the risk of schizophrenia. The main evidence comes from studies of the 1944-1945 Dutch Hunger Winter when a sharp and time-limited decline in food intake occurred. The most exposed cohort conceived during the famine showed a 2-fold increased risk of schizophrenia.To determine whether those who endured a massive 1959-1961 famine in China experienced similar results.The risk of schizophrenia was examined in the Wuhu region of Anhui, one of the most affected provinces. Rates were compared among those born before, during, and after the famine years. Wuhu and its surrounding 6 counties are served by a single psychiatric hospital. All psychiatric case records for the years 1971 through 2001 were examined, and clinical and sociodemographic information on patients with schizophrenia was extracted by researchers who were blinded to the nature of exposure. Data on number of births and deaths in the famine years were available, and cumulative mortality was estimated from later demographic surveys.Evidence of famine was verified, and unadjusted and mortality-adjusted relative risks of schizophrenia were calculated.The birth rates (per 1000) in Anhui decreased approximately 80% during the famine years from 28.28 in 1958 and 20.97 in 1959 to 8.61 in 1960 and 11.06 in 1961. Among births that occurred during the famine years, the adjusted risk of developing schizophrenia in later life increased significantly, from 0.84% in 1959 to 2.15% in 1960 and 1.81% in 1961. The mortality-adjusted relative risk was 2.30 (95% confidence interval, 1.99-2.65) for those born in 1960 and 1.93 (95% confidence interval, 1.68-2.23) for those born in 1961.Our findings replicate the Dutch data for a separate racial group and show that prenatal exposure to famine increases risk of schizophrenia in later life.
Neutrophils, airway hyperresponsiveness and COPD: true, true and related?
Authors: Charles G. Irvin
Journal: European Respiratory Journal (2012)

Once upon a time distinguishing between COPD and asthma in a smoking or ex-smoking patient was easy: a patient who smoked, had a low diffusing capacity of the lung for carbon monoxide or a hyperlucent radiogram, and no bronchodilator response was labelled as COPD; whereas a patient who, whether they smoked or not, had a bronchodilator response and airway hyperresponsiveness (AHR) was an asthmatic. Nothing could be simpler; that is until studies of asthmatics included measurements of inflammation and studies of patients with COPD included performing methacholine challenges. We now know that significant bronchodilator responses can be present in many patients with COPD [1] and, as discussed below, airway responsiveness is also not a stable feature of asthma. As determined by unbiased analysis, such as cluster or factor analysis, asthma [2, 3] and COPD [4] both have been shown to have distinctly different clinical phenotypes. While there is no doubt that these phenotype assignments will prove to be variable, irreproducible and effervescent, at least this clustering of patients’ characteristics provides a conceptual framework to advance the field. The clinical significance is that if a patient with airway disease is assigned a phenotype, then a targeted, effective treatment will be forthcoming, or at least that is the hope.

AHR was long touted as a “hallmark” of asthma but we now know that hyperresponsiveness is a characteristic of many inflammatory lung diseases [5, 6]. In asthma, hyperresponsiveness is a well-studied end-point relating, in some patients, to inflammation [6], but this is not always the case, as we observed in patients on inhaled corticosteroids (ICS) [7] and …
Cost Effectiveness of <i>EML4-ALK</i> Fusion Testing and First-Line Crizotinib Treatment for Patients With Advanced <i>ALK</i>-Positive Non–Small-Cell Lung Cancer
Authors: Sandjar Djalalov, Jaclyn Beca, Jeffrey S. Hoch, Murray Krahn, Ming-Sound Tsao, Jean-Claude Cutz, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2014)

Purpose ALK-targeted therapy with crizotinib offers significant improvement in clinical outcomes for the treatment of EML4-ALK fusion–positive non–small-cell lung cancer (NSCLC). We estimated the cost effectiveness of EML4-ALK fusion testing in combination with targeted first-line crizotinib treatment in Ontario. Patients and Methods A cost-effectiveness analysis was conducted using a Markov model from the Canadian Public health (Ontario) perspective and a lifetime horizon in patients with stage IV NSCLC with nonsquamous histology. Transition probabilities and mortality rates were calculated from the Ontario Cancer Registry and Cancer Care Ontario New Drug Funding Program (CCO NDFP). Costs were obtained from the Ontario Case Costing Initiative, CCO NDFP, University Health Network, and literature. Results Molecular testing with first-line targeted crizotinib treatment in the population with advanced nonsquamous NSCLC resulted in a gain of 0.011 quality-adjusted life-years (QALYs) compared with standard care. The incremental cost was Canadian $2,725 per patient, and the incremental cost-effectiveness ratio (ICER) was $255,970 per QALY gained. Among patients with known EML4-ALK–positive advanced NSCLC, first-line crizotinib therapy provided 0.379 additional QALYs, cost an additional $95,043 compared with standard care, and produced an ICER of $250,632 per QALY gained. The major driver of cost effectiveness was drug price. Conclusion EML4-ALK fusion testing in stage IV nonsquamous NSCLC with crizotinib treatment for ALK-positive patients is not cost effective in the setting of high drug costs and a low biomarker frequency in the population.
Forefoot alignment prediction in athletes' knee valgus during landing
Authors: L D Mendonça, N F N Bittencourt, L Diniz, G G P Gonçalves, J M Ocarino, A A Silva, S T Fonseca
Journal: British Journal of Sports Medicine (2011)

Background Knee valgus during landing has been identified as a risk factor for anterior cruciate ligament injury. Component motions of knee malalignment are femoral internal rotation and adduction, tibial abduction and ankle eversion. This excessive eversion is frequently attributed to the presence of forefoot varus alignment. Therefore, the proximal and distal segments of the kinetic chain must be assessment to better understanding of high frontal plane knee angle – FPKA (2D valgus analysis). Objective access the potential predictors of FPKA and the interplay between them, through a non-linear statistical model (Classification and Regression Tree-CART). Design observational cross-sectional. Setting all testing took place at Minas Tênis Club and at Sports Injury Prevention and Rehabilitation Laboratory – LAPREV in youth and elite sports. Participants 72 volleyball and basketball athletes (22 female and 50 male) were assessed during national championship preseason. All participants were healthy, with no current complaints of lower limb injury or pain and no history of previous lower extremity surgery. The average+SD age, height and mass of the athletes was 16.7+4.6 years, 179.7+14.7 cm, 68.6+16 Kg. Assessment of risk factors the independent variables were shank-forefoot alignment (SFA), hip abductor torque, hip passive internal rotation and gender. Main outcome measurements frontal plane knee angle during landing from countermovement jump. Results the SFA was the main predictor of High-FPKA. 75% of the athletes with SFA &lt;10.9° and abductor torque &lt;109 Nm/kg and 83% of the athletes with SFA &gt;17° and hip passive IR ROM &gt;47° presented High-FPKA. Conclusion the SFA and interaction between it with reduced abductor torque and great hip passive IR ROM were predictors of knee malalignment in frontal plane. Thus, measuring foot alignment must be simultaneous with hip joint dysfunctions and should be part of athletes' preseason assessment.
Comparative study of IDH1 mutations in gliomas by immunohistochemistry and DNA sequencing
Authors: S. Agarwal, M. C. Sharma, P. Jha, P. Pathak, V. Suri, C. Sarkar, K. Chosdol, A. Suri, S. S. Kale, A. K. Mahapatra, P. Jha
Journal: Neuro-Oncology (2013)

Mutations involving isocitrate dehydrogenase 1 (IDH 1) occur in a high proportion of diffuse gliomas, with implications on diagnosis and prognosis. About 90% involve exon 4 at codon 132, replacing amino acid arginine with histidine (R132H). Rarer ones include R132C, R132S, R132G, R132L, R132V, and R132P. Most authors have used DNA-based methods to assess IDH1 status. Preliminary studies comparing imunohistochemistry (IHC) with IDH1-R132H mutation-specific antibodies have shown concordance with DNA sequencing and no cross-reactivity with wild-type IDH1 or other mutant proteins. The present study compares results of IHC with DNA sequencing in diffuse gliomas.Fifty diffuse gliomas with frozen tissue samples for DNA sequencing and adequate tissue in paraffin blocks for IHC using IDH1-R132H specific antibody were assessed for IDH1 mutations.Concordance of findings between IHC and DNA sequencing was noted in 88% (44/50) cases. All 6 cases with discrepancy were immunopositive with DIA-H09 antibody. While in 3 of these 6 cases, DNA sequencing failed to reveal any mutations, R132L (arginine replaced by leucine) mutation was found in the rest 3 cases. Interestingly, of the immunopositive cases, 46.6% (14/30) showed immunostaining in only a fraction of tumor cells.IHC is an easy and quick method of detecting IDH1-R132H mutations, but there may be some discrepancies between IHC and DNA sequencing. Although there were no false-negative cases, cross-reactivity with IDH1-R132L was seen in 3, a finding not reported thus far. Because of more universal availability of IHC over genetic testing, cross-reactivity and staining heterogeneity may have bearing over its use in detecting IDH1-R132H mutation in gliomas.
Predictive Performance of Renal Function Equations for Patients with Chronic Kidney Disease and Normal Serum Creatinine Levels
Authors: Andrew G. Bostom, Florian Kronenberg, Eberhard Ritz
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Accurate renal function measurements are important for the diagnosis and treatment of kidney disease, proper medication dosing, interpretation of possible uremic symptoms, and decision-making regarding when to initiate renal replacement therapy. Because the use of highly accurate filtration markers to measure renal function has traditionally been limited by cumbersome and costly techniques and the involvement of radioactivity (among other factors), renal function is typically estimated by using specially derived prediction equations. These formulae usually use serum creatinine levels, i.e., a marker of filtration that is insensitive to mild/moderate decreases in GFR. Although attempts have been made to validate certain renal function prediction equations among patients with chronic kidney disease (CKD) with abnormal serum creatinine levels, this is the first study to specifically evaluate the predictive performance of these equations for patients with CKD and serum creatinine levels in the normal range. The results of eight prediction equations for 109 patients with CKD and serum creatinine levels of ≤1.5 mg/dl were compared with standard iohexol GFR values. The most accurate results were obtained with the Cockroft-Gault and Bjornsson equations. The most precise formulae were the Modification of Diet in Renal Disease Study equations, although they were highly biased. Even the most accurate results exhibited levels of error that made them suboptimal for clinical treatment of these patients. These results suggest that measurement of GFR with endogenous or exogenous filtration markers might be the most prudent strategy for the assessment of renal function in the CKD population with normal serum creatinine levels. Further studies are needed to confirm the generalizability of these findings for this patient subgroup.
Large molecular form of serum HBeAg in chronic hepatitis B virus infection: Relation to liver cell damage
Authors: Kiyohiko Kurai, Shiro Iino, Kiyoshi Kurokawa, Kazumi Shimoda, Kunihiko Hino
Journal: Hepatology (1991)

We have separated circulating HBeAg into small and large molecular forms by agarose gel electrophoresis and analyzed the relationship between the two forms and other clinical features of chronic hepatitis B, especially in regard to liver cell damage. The large HBeAg accounted for 7.3% +/- 3.4% of serum HBeAg in 9 subjects with normal liver histological findings or nonspecific reactive hepatitis, 38.0% +/- 27.8% in 32 patients with chronic persistent hepatitis and 65.6% +/- 23.3% in 21 patients with chronic active hepatitis (p less than 0.01). A positive correlation was seen between the height of aminotransferase elevations and the percentage of large HBeAg. Three patients who progressed from histologically normal liver or nonspecific reactive hepatitis to chronic active hepatitis had dramatic increases in the percentage of large HBeAg. The finding that the presence of large HBeAg in serum correlated with the severity of hepatitis suggests that HBeAg may play an important role in determining the degree of liver injury in chronic hepatitis B.
Impaired relaxation in transgenic mice overexpressing junctin
Authors: U KIRCHHEFER, J NEUMANN, D BERS, I BUCHWALOW, L FABRITZ, G HANSKE, I JUSTUS, B RIEMANN, W SCHMITZ, L JONES
Journal: Cardiovascular Research (2003)

Objective: Junctin is a major transmembrane protein in cardiac junctional sarcoplasmic reticulum, which forms a quaternary complex with the ryanodine receptor (Ca2+ release channel), triadin, and calsequestrin. Methods: To better understand the role of junctin in excitation–contraction coupling in the heart, we generated transgenic mice with targeted overexpression of junctin to mouse heart, using the α-MHC promoter to drive protein expression. Results: The protein was overexpressed 10-fold in mouse ventricles and overexpression was accompanied by cardiac hypertrophy (19%). The levels of two other junctional SR-proteins, the ryanodine receptor and triadin, were reduced by 32% and 23%, respectively. However, [3H]ryanodine binding and the expression levels of calsequestrin, phospholamban and SERCA2a remained unchanged. Cardiomyocytes from junctin-overexpressing mice exhibited impaired relaxation: Ca2+ transients decayed at a slower rate and cell relengthening was prolonged. Isolated electrically stimulated papillary muscles from junctin-overexpressing hearts exhibited prolonged mechanical relaxation, and echocardiographic parameters of relaxation were prolonged in the living transgenic mice. The amplitude of caffeine-induced Ca2+ transients was lower in cardiomyocytes from junctin-overexpressing mice. The inactivation kinetics of L-type Ca2+ channel were prolonged in junctin-overexpressing cardiomyocytes using Ca2+ or Ba2+ as charge carriers. Conclusion: Our data provide evidence that cardiac-specific overexpression of junctin is accompanied by impaired myocardial relaxation with prolonged Ca2+ transient kinetics on the cardiomyocyte level.
Homocysteine Induces 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Vascular Endothelial Cells
Authors: Hong Li, Avalyn Lewis, Sergey Brodsky, Robert Rieger, Charles Iden, Michael S. Goligorsky
Journal: Circulation (2002)

Background — It has been established that hyperhomocyst(e)inemia (HHCy) is an independent and graded risk factor for atherosclerosis, although the molecular link to the atherosclerotic process remains obscure. Methods and Results — Screening human umbilical vein endothelial cells (HUVECs) with complementary DNA microarray for the gene expression modified by homocysteine (Hcy) revealed that 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) was upregulated. This effect was confirmed using quantitative reverse transcriptase-polymerase chain reaction. Actinomycin D studies revealed that Hcy stabilized HMGCR mRNA (τ 1/2 , 9.5±1.0 versus 5.0±0.2 hours). Expression of immunodetectable HMGCR in both HUVECs and renal microvascular endothelial cells was increased in Hcy-treated cells in association with the increased abundance of caveolin. Application of a cell-permeable superoxide dismutase mimetic, Mn-TBAP, reversed the Hcy-induced expression of HMGCR. Additional biochemical analysis of the abundance of total cellular cholesterol showed that 0, 20, 50, and 100 μmol/L Hcy resulted in 22.2±7.3%, 39.5±1.2%, and 50.4±6.8% increase, respectively. Gas chromatography mass spectrometry analysis of extracted cholesterol from Hcy-treated HUVECs and from the culture medium showed 17.8±5.2% and 24.0±14.5% increases, respectively. Application of simvastatin to Hcy-treated cells reduced cellular cholesterol and prevented Hcy-induced suppression of NO production by HUVECs in a dose-dependent manner. Conclusions — Using a cDNA microarray, the data disclosed an unexpected link between Hcy and cholesterol dysregulation based on the finding of increased abundance of HMGCR mRNA and protein in endothelial cells, demonstrated the possible role of Hcy-induced oxidative stress in this response, and revealed the improvement of endothelial NO production in Hcy-treated HUVECs by statins. Collectively, these findings may provide a solid explanation for the observed proatherogenic effect of HHcy.