tbuckley/cabot-search huggingface dataset:
Characterization of Rearrangements Involving the <i>ALK</i> Gene Reveals a Novel Truncated Form Associated with Tumor Aggressiveness in Neuroblastoma
Authors: Alex Cazes, Caroline Louis-Brennetot, Pierre Mazot, Florent Dingli, Bérangère Lombard, Valentina Boeva, Romain Daveau, Julie Cappo, Valérie Combaret, Gudrun Schleiermacher, Stéphanie Jouannet, Sandrine Ferrand, Gaëlle Pierron, Emmanuel Barillot, Damarys Loew, Marc Vigny, Olivier Delattre, Isabelle Janoueix-Lerosey
Journal: Cancer Research (2012)

Activating mutations of the ALK gene have been identified in sporadic and familial cases of neuroblastoma (NB), a cancer of the peripheral nervous system, and are thought to be the primary mechanism of oncogenic activation of this receptor in this pediatric neoplasm. To address the possibility that ALK activation may occur through genomic rearrangements as detected in other cancers, we first took advantage of high-resolution array-comparative genomic hybridization to search for ALK rearrangements in NB samples. Using complementary experiments by capture/paired-end sequencing and FISH experiments, various types of rearrangements were fully characterized, including partial gains or amplifications, in several NB cell lines and primary tumors. In the CLB-Bar cell line, we described a genomic rearrangement associated with an amplification of the ALK locus, leading to the expression of a 170 kDa protein lacking part of the extracellular domain encoded by exons 4 to 11, named ALK(Δ4-11). Analysis of genomic DNA from the tumor at diagnosis and relapse revealed that the ALK gene was amplified at diagnosis but that the rearranged ALK allele was observed at the relapse stage only, suggesting that it may be implicated in tumor aggressiveness. Consistently, oncogenic and tumorigenic properties of the ALK(Δ4-11) variant were shown after stable expression in NIH3T3 cells. Moreover, we documented an increased constitutive kinase activity of this variant, as well as an impaired maturation and retention into intracellular compartments. These results indicate that genomic rearrangements constitute an alternative mechanism to ALK point mutations resulting in receptor activation.
Different NK cell–activating receptors preferentially recruit Rab27a or Munc13-4 to perforin-containing granules for cytotoxicity
Authors: Stephanie M. Wood, Marie Meeths, Samuel C. C. Chiang, Anne Grete Bechensteen, Jaap J. Boelens, Carsten Heilmann, Hisanori Horiuchi, Steen Rosthøj, Olga Rutynowska, Jacek Winiarski, Jennifer L. Stow, Magnus Nordenskjöld, Jan-Inge Henter, Hans-Gustaf Ljunggren, Yenan T. Bryceson
Journal: Blood (2009)
Validation of 6-Minute Walk Distance as a Surrogate End Point in Pulmonary Arterial Hypertension Trials
Authors: Nicole B. Gabler, Benjamin French, Brian L. Strom, Harold I. Palevsky, Darren B. Taichman, Steven M. Kawut, Scott D. Halpern
Journal: Circulation (2012)

Background— Nearly all available treatments for pulmonary arterial hypertension have been approved based on change in 6-minute walk distance (Δ6MWD) as a clinically important end point, but its validity as a surrogate end point has never been shown. We aimed to validate the difference in Δ6MWD against the probability of a clinical event in pulmonary arterial hypertension trials. Methods and Results— First, to determine whether Δ6MWD between baseline and 12 weeks mediated the relationship between treatment assignment and development of clinical events, we conducted a pooled analysis of patient-level data from the 10 randomized placebo-controlled trials previously submitted to the US Food and Drug Administration (n=2404 patients). Second, to identify a threshold effect for the Δ6MWD that indicated a statistically significant reduction in clinical events, we conducted a meta-regression among 21 drug/dose-level combinations. Δ6MWD accounted for 22.1% (95% confidence interval, 12.1%– 31.1%) of the treatment effect ( P &lt;0.001). The meta-analysis showed an average difference in Δ6MWD of 22.4 m (95% confidence interval, 17.4–27.5 m), favoring active treatment over placebo. Active treatment decreased the probability of a clinical event (summary odds ratio, 0.44; 95% confidence interval, 0.33–0.57). The meta-regression revealed a significant threshold effect of 41.8 m. Conclusions— Our results suggest that Δ6MWD does not explain a large proportion of the treatment effect, has only modest validity as a surrogate end point for clinical events, and may not be a sufficient surrogate end point. Further research is necessary to determine whether the threshold value of 41.8 m is valid for long-term outcomes or whether it differs among trials using background therapy or lacking placebo controls entirely.
Molecular and Cellular Mechanisms of Angiotensin II-Mediated Cardiovascular and Renal Diseases
Authors: Shokei Kim, Hiroshi Iwao
Journal: Pharmacological Reviews (2000)

A growing body of evidence supports the notion that angiotensin II (Ang II), the central product of the renin-angiotensin system, may play a central role not only in the etiology of hypertension but also in the pathophysiology of cardiovascular and renal diseases in humans. In this review, we focus on the role of Ang II in cardiovascular and renal diseases at the molecular and cellular levels and discuss up-to-date evidence concerning the in vitro and in vivo actions of Ang II and the pharmacological effects of angiotensin receptor antagonists in comparison with angiotensin-converting enzyme inhibitors. Ang II, via AT(1) receptor, directly causes cellular phenotypic changes and cell growth, regulates the gene expression of various bioactive substances (vasoactive hormones, growth factors, extracellular matrix components, cytokines, etc.), and activates multiple intracellular signaling cascades (mitogen-activated protein kinase cascades, tyrosine kinases, various transcription factors, etc.) in cardiac myocytes and fibroblasts, vascular endothelial and smooth muscle cells, and renal mesangial cells. These actions are supposed to participate in the pathophysiology of cardiac hypertrophy and remodeling, heart failure, vascular thickening, atherosclerosis, and glomerulosclerosis. Furthermore, in vivo recent evidence suggest that the activation of mitogen-activated protein kinases and activator protein-1 by Ang II may play the key role in cardiovascular and renal diseases. However, there are still unresolved questions and controversies on the mechanism of Ang II-mediated cardiovascular and renal diseases.
Nutritional Supplementation Acutely Increases Albumin Fractional Synthetic Rate in Chronic Hemodialysis Patients
Authors: Lara B. Pupim, Paul J. Flakoll, T. Alp Ikizler
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Uremic malnutrition is associated with increased risk of hospitalization and death in chronic hemodialysis (CHD) patients. Most nutritional intervention studies in CHD patients traditionally have used concentrations of serum albumin as the primary outcome measure and showed slight or no significant improvements. A recent study showed that intradialytic parenteral nutrition (IDPN) improves whole-body protein synthesis in CHD patients. On the basis of this observation, it was hypothesized that the anabolic effects of IDPN are associated with increases in the fractional synthetic rate of albumin, a direct estimate of acute changes in hepatic albumin synthesis. Seven CHD patients were studied during two hemodialysis (HD) sessions, with and without IDPN, using primed-constant infusion of (<sup>13</sup>C) leucine 2 h before, during, and 2 h after HD. Plasma enrichments of (<sup>13</sup>C) leucine and (<sup>13</sup>C) ketoisocaproate were examined to determine the fractional synthetic rate of albumin. The results indicate that administration of IDPN significantly improves the fractional synthetic rate of albumin during HD (16.2 ± 1.5%/d <i>versus</i> 12.8 ± 1.7%/d; <i>P</i> &lt; 0.05) in CHD patients in parallel with significant improvements in whole-body protein synthesis (5.05 ± 1.3 mg/kg fat-free mass/min <i>versus</i> 3.22 ± 0.3 mg/kg fat-free mass/min; <i>P</i> &lt; 0.05). IDPN is protein anabolic in the acute setting in CHD patients, as evidenced by significant concomitant increases in the fractional synthetic rate of albumin and whole-body protein synthesis.
Electronic nicotine delivery systems (ENDS): the beginning of the end or the end of the beginning?
Authors: F. Blasi, B. Ward
Journal: European Respiratory Journal (2014)

5 million people in the world die of active smoking and more than 600 000 nonsmokers die from exposure to passive smoke annually [1]. Smoking is recognised as one of the major preventable causes of death. It significantly increases the chances of developing a respiratory disorder and over half of respiratory disease-related deaths are due to smoking [2],[3]. One of the key points in the fight against the tobacco epidemic is to encourage as many smokers as possible to quit [4]. The emergence of electronic nicotine delivery systems (ENDS), or electronic (e)-cigarettes, presents complex considerations in this context. E-cigarettes have been subject to regulatory, legal and evidentiary gaps, and they have been met with contrasting reaction from public health experts, clinicians, scientists and governments [5]–[10]. Some focus strongly on the benefits of these products based on the available evidence while others highlight the risks, also based on the evidence. In certain assessments, they are the beginning of the end for tobacco use, while in others, they herald a new public health threat [11]–[14].

It is argued that e-cigarettes and other novel nicotine devices could provide an effective alternative to conventional cigarettes. The case for the potential benefit is that e-cigarettes could lead to a significant decrease in the prevalence of smoking, prevent many deaths and episodes of serious illness, and help to reduce health inequalities that tobacco smoking currently exacerbates [15]. Moreover, e-cigarettes do not involve the combustion of tobacco, and …
Two distinct allotypic determinants on the antigen-specific suppressor and enhancing T cell factors that are encoded by genes linked to the immunoglobulin heavy chain locus.
Authors: T Tokuhisa, M Taniguchi
Journal: The Journal of Experimental Medicine (1982)

The alloantiserum was raised in BALB/c (H-2d, Igh-1a) mice hyperimmunized with spleen cells of Igh allotype congenic mice, CB-20 (H-2d, Igh-1b). It was found to define the new allotypic determinants (distinct from B cell Igh constant region determinants: Igh allotype) expressed only on a small population of T cells belonging to the Thy-1 dull-stained Lyt-2- or Lyt-2+ population of Igh-1b mice. Genes coding for the determinants were shown to be accommodated somewhere in the right side of the Igh variable region gene (Igh-V) cluster, as the antibody activity was completely absorbed with BAB-14 thymocytes. It was also demonstrated that the products detected by the antiserum represent the allotypic determinants (probably constant region determinants) on the antigen-binding moiety of the antigen-specific augmenting (TaF) and suppressor (TsF) T cell factors. Moreover, determinants on TsF were found to be distinct from those on TaF. Therefore, it can be suggested that the two genes coding for the T cell allodeterminants (distinct from those of the B cell Igh) are located in the right side of the B cell Igh-V on the 12th chromosome, and that both encode the antigen-recognition units of the functionally distinct T cell factors.
Combined anti-microtubule therapy: a phase II study of weekly docetaxel plus estramustine in patients with metastatic breast cancer
Authors: S.E. Soule, K.D. Miller, P. Porcu, R. Ansari, F. Fata, J.W. McClean, R. Zon, G.W. Sledge, L.H. Einhorn
Journal: Annals of Oncology (2002)
ANTIBODY-SUPPRESSIBLE AND NONSUPPRESSIBLE INSULIN-LIKE ACTIVITIES IN HUMAN SERUM AND THEIR PHYSIOLOGIC SIGNIFICANCE. AN INSULIN ASSAY WITH ADIPOSE TISSUE OF INCREASED PRECISION AND SPECIFICITY*
Authors: E. R. Froesch, H. Bürgi, E. B. Ramseier, P. Bally, A. Labhart
Journal: Journal of Clinical Investigation (1963)

Adipose tissue has been shown to respond to insulin in vitro by several groups of investigators whose work has recently been reviewed by Jean- renaud (1).Martin, Renold, and Dagenais (2) pointed out the extreme sensitivity of adipose tis- sue to insulin.Renold, Sheps, and co-workers (3, 4) used as a metabolic index of serum insu- lin-like activity (ILA) the oxidation of glucose-1- C14 to C140,.Several investigators adopted their method with equally good results (5-7).Hum- bel (8) and others (9, 10) measured the glucose uptake of epididymal adipose tissue as an index of ILA, and Ball and Merrill (11) determined the net gas exchange.When the fat-pad assay is applied to the determination of ILA in human serum, several discrepancies become apparent be- tween its results and those obtained by other biological and immunological assay technics currently in use.The mean value of ILA in undiluted serum of fasting normal subjects approximates 50 /AU per ml by the diaphragm technic (12-14) and about 20 MU per ml by the immunological assay pro- cedure of Yalow and Berson (15).The figures obtained with the adipose tissue method are substantially higher, and vary between 30 and 1,000 MU per ml (4, 16, 17).Randle (18) and Willebrands, Van der Geld, and Groen (19) determined ILA in diluted serum with the dia- phragm and found values in the same high range as those obtained with adipose tissue.Although these discrepancies cannot be fully explained at present, the following points are relevant.1) Adrenaline, noradrenaline, ACTH, growth hor- mone, and glucagon enhance the glucose uptake of adipose tissue in vitro.In contrast to insulin, however, these lipolytic hormones do not increase
Association of Perioperative β-Blockade With Mortality and Cardiovascular Morbidity Following Major Noncardiac Surgery
Authors: Martin J London, Kwan Hur, Gregory G Schwartz, William G Henderson
Journal: JAMA (2013)

<h3>Importance</h3>The effectiveness of perioperative β-blockade in patients undergoing noncardiac surgery remains controversial.<h3>Objective</h3>To determine the associations of early perioperative exposure to β-blockers with 30-day postoperative outcome in patients undergoing noncardiac surgery.<h3>Design, Setting, and Patients</h3>A retrospective cohort analysis evaluating exposure to β-blockers on the day of or following major noncardiac surgery among a population-based sample of 136 745 patients who were 1:1 matched on propensity scores (37 805 matched pairs) treated at 104 VA medical centers from January 2005 through August 2010.<h3>Main Outcomes and Measures</h3>All cause 30-day mortality and cardiac morbidity (cardiac arrest or Q-wave myocardial infarction).<h3>Results</h3>Overall 55 138 patients (40.3%) were exposed to β-blockers. Exposure was higher in the 66.7% of 13 863 patients undergoing vascular surgery (95% CI, 65.9%-67.5%) than in the 37.4% of 122 882 patients undergoing nonvascular surgery (95% CI, 37.1%-37.6%; P &lt; .001). Exposure increased as Revised Cardiac Risk Index factors increased, with 25.3% (95% CI, 24.9%-25.6%) of those with no risk vs 71.3% (95% CI, 69.5%-73.2%) of those with 4 risk factors or more exposed to β-blockers (P &lt; .001). Death occurred among 1.1% (95% CI, 1.1%-1.2%) and cardiac morbidity occurred among 0.9% (95% CI, 0.8%-0.9%) of patients. In the propensity matched cohort, exposure was associated with lower mortality (relative risk [RR], 0.73; 95% CI, 0.65-0.83; P &lt; .001; number need to treat [NNT], 241; 95% CI, 173-397). When stratified by cumulative numbers of Revised Cardiac Risk Index factors, β-blocker exposure was associated with significantly lower mortality among patients with 2 factors (RR, 0.63 [95% CI, 0.50-0.80]; P &lt; .001; NNT, 105 [95% CI, 69-212]), 3 factors (RR, 0.54 [95% CI, 0.39-0.73]; P &lt; .001; NNT, 41 [95% CI, 28-80]), or 4 factors or more (RR, 0.40 [95% CI, 0.25-0.73]; P &lt; .001; NNT, 18 [95% CI, 12-34]). This association was limited to patients undergoing nonvascular surgery. β-Blocker exposure was also associated with a lower rate of nonfatal Q-wave infarction or cardiac arrest (RR, 0.67 [95% CI, 0.57-0.79]; P &lt; .001; NNT, 339 [95% CI, 240-582]), again limited to patients undergoing nonvascular surgery.<h3>Conclusions and Relevance</h3>Among propensity-matched patients undergoing noncardiac, nonvascular surgery, perioperative β-blocker exposure was associated with lower rates of 30-day all-cause mortality in patients with 2 or more Revised Cardiac Risk Index factors. Our findings support use of a cumulative number of Revised Cardiac Risk Index predictors in decision making regarding institution and continuation of perioperative β-blockade. A multicenter randomized trial involving patients at a low to intermediate risk by these factors would be of interest to validate these observational findings.
The Role of Glucagon in the Endogenous Hyperglycemia of Diabetes Mellitus
Authors: R H Unger
Journal: Annual Review of Medicine (1977)

Recent advances in our understanding of the glucagon-secreting pancreatic a cell as a vital component of the functional machinery of the primary fuel-regulating organ, the islets of Langerhans, have made possible new insights into its physiology and pathophysiology. It has recently been proposed that glucagon, or closely related polypeptides with biologic actions similar to those of glucagon, plays an essential role in the development of the full diabetic syndrome, specifically, endogenous hyperglycemia ( 1, 2) and hyperketonemia (2, 3). If this is true, a safe and practical means of glucagon suppression might have therapeutic potential in improving the currently unsatisfactory methods of controlling diabetic hyperglycemia. The pur­ pose of this review is to consider briefly the evidence that assigns to glucagon a vital role in the maintenance of euglycemia in nondiabetics and a deleterious role in certain of the metabolic abnormalities of diabetes mellitus.
Cryptogenic fibrosing alveolitis: clinical features and their influence on survival
Authors: M Turner-Warwick, B Burrows, A Johnson
Journal: Thorax (1980)

A retrospective analysis of 220 cases fulfilling criteria for cryptogenic fibrosing alveolitis (CFA) attending the Brompton Hospital between 1955 and 1973 has been carried out and patients have been followed for between four and 21 years. The frequency of various clinical features confirms previous reports. The 2: 1 male preponderance was similar in all age groups. The mean age at presentation was 54 years ± 12 SD; 202 (92%) of the patients presented with dyspnoea, the severity of which was related to the reduction in vital capacity (p&lt;0·003) and to the radiographic profusion score (p&lt;0·01) but not to its duration. Twenty-one per cent of the 220 had joint symptoms, 10% having clinical rheumatoid arthritis. Eleven per cent had other types of connective tissue disorder. In all, 30% had polyarthritis or other immunological disorders and 70% lone CFA. Apart from an increase in rheumatoid factor in those with polyarthritis, there were no other clinical or survival differences between those with and without associated immunological disease. Forty-five per cent of 205 subjects had antinuclear antibody, and this occurred equally in those with and without associated connective tissue disorders. One hundred and forty-seven initial radiographs were available for reclassification using the ILO/UC system and only three were normal. Small rounded opacities were seen in 16% and small irregular opacities in 84%. Pleural changes were uncommon. Histological confirmation had been obtained in 118 patients and material was still available for review using a semiquantitative analysis in 68 (biopsy 42 and necropsy 26). Of the biopsies one could be classified as desquamative interstitial pneumonia (DIP) and 17 as endstage fibrosis; the other 24 showed a mixed cellular and fibrotic pattern. The necropsy material showed much greater fibrosis and less acute inflammatory cellularity in spite of an interval between onset of symptoms and death of less than four years in 21 of 26 patients. One hundred and fifty-six patients have died (mean survival 3·2 years). Eleven (5%) are believed to be alive but have been lost to follow-up. Fifty-five per cent of deaths were attributable directly or indirectly to CFA. There was also an excess of deaths from cardiovascular disease and lung cancer. Using a life-table analysis and a log rank test, longer survival was seen in younger patients (p&lt;0·001) and women (p&lt;0·01). After correction for age and sex, lesser grades of dyspnoea (p&lt;0·03) and lesser radiographic abnormality (p&lt;0·001), absence of right axis deviation (p&lt;0·001), and a higher Pao<sub>2</sub> (p&lt;0·01) also related to longer survival. Subjects with more cellular histology also survived longer (p&lt;0·02). Factors having no influence on survival included duration of dyspnoea before presentation, degree of reduction of FEV<sub>1</sub>, FVC, and TLC, the presence of "connective tissue" disorders, autoantibodies, smoking history, cough, sputum, crackles, clubbing, ESR, or immunoglobulins.
Conventional cytology vs liquid based cytology in preparation of bronchial wash, does the later have potential advantages?
Authors: Bhuvaneswari Kathiresan, Stephen Iles, Leonie Glinski
Journal: European Respiratory Journal (2013)

Introduction   Liquid based cytology and Conventional cytology are two techniques used in preparation of bronchial washings and brushings.   Aims   To determine whether Liquid based cytology has better diagnostic rate compared to Conventional cytology when used in preparation of bronchial wash samples in patients with suspected lung cancer.   Methods   Retrospective observational study of bronchial wash samples sent for cytological analysis with radiological diagnosis of lung carcinoma between April 2009 and June 2012 in Royal Cornwall Hospital, United Kingdom.   Results   Conventional cytology was used in preparation of bronchial wash between April 2009 - July 2010 and Liquid based cytology between August 2010 – June 2012. 114 patients had their samples processed using Conventional cytology and 126 using Liquid based cytology during this period.  43 (38%) had positive cytology in Conventional group. 68 (54%) had positive cytology in Liquid based group. The calculated p-value is 0.017 (Two sample t test), suggesting statistically significant difference between two groups.  The volume of sample did not influence diagnostic yield, as the mean volume of sample in Liquid based group is same (7ml) in both positive and negative groups.   Conclusion   Our study demonstrates improved diagnostic rate with Liquid based cytology, which might be due to preserving cells, removing excess red cells and eliminating spread artifact.
Characterization of dimethylguanosine, phenylethylamine, and phenylacetic acid as inhibitors of Ca2+ ATPase in end-stage renal failure.
Authors: J Jankowski, H Luftmann, M Tepel, D Leibfritz, W Zidek, H Schlüter
Journal: Journal of the American Society of Nephrology (1998)

The activity of the plasma membrane Ca2+ ATPase of chronic renal failure patients is decreased by circulating inhibitors yet to be characterized. In this study, inhibitors of Ca2+ ATPase were isolated from ultrafiltrate of patients with end-stage renal failure. They were identified as dimethylguanosine, phenylethylamine, and phenylacetic acid by chromatography and mass spectrometry. Ca2+ ATPase activity was measured spectrophotometrically as the difference in hydrolysis of ATP in the presence and absence of Ca2+ with different concentrations of ATP and the isolated substances. All of the identified compounds are sufficiently lipophilic to penetrate the blood-brain barrier and to accumulate in cerebral tissue. The inhibitory effects of these agents were additive. The apparent K(m) values for ATP and Ca2+ were not altered by these substances, suggesting a noncompetitive mechanism of inhibition. In plasma of healthy subjects, the substances were not detectable. The Ca2+ ATPase inhibitors identified may play a role in the pathophysiology of end-stage renal failure and, potentially, in monitoring toxic effects on cellular Ca2+ metabolism in renal failure.