tbuckley/cabot-search huggingface dataset:
Cancer Risk and the ATM Gene: a Continuing Debate
Authors: K K Khanna
Journal: JNCI Journal of the National Cancer Institute (2000)

Deficiencies in the ability of cells to sense and repair damage in individuals with rare genetic instability syndromes increase the risk of developing cancer. Ataxia-telangiectasia (A-T), such a condition, is associated with a high incidence of leukemia and lymphoma that develop in childhood. Although A-T is an autosomal recessive disorder, some penetrance appears in individuals with one mutated ATM gene (A-T carriers), namely, an increased risk of developing breast cancer. The gene mutated in A-T, designated ATM, is homologous to several DNA damage recognition and cell cycle checkpoint control genes from other organisms. Recent studies suggest that ATM is activated primarily in response to double-strand breaks, the major cytotoxic lesion caused by ionizing radiation, and can directly bind to and phosphorylate c-Abl, p53, and replication protein A (RPA). Analysis of ATM mutations in patients with A-T or with sporadic non-A-T cancers has suggested the existence of two classes of ATM mutation: null mutations leading to A-T and dominant negative missense mutations predisposing to cancer in the heterozygous state. Studies with A-T mouse models have helped determine the basis of lymphoid tumorigenesis in A-T and have shown that ATM plays a critical role in maintaining genetic stability by ensuring high-fidelity execution of chromosomal events. Thus, ATM appears to act as a caretaker of the genome.
Lung Recruitment in Patients with the Acute Respiratory Distress Syndrome
Authors: Luciano Gattinoni, Pietro Caironi, Massimo Cressoni, Davide Chiumello, V. Marco Ranieri, Michael Quintel, Sebastiano Russo, Nicolò Patroniti, Rodrigo Cornejo, Guillermo Bugedo
Journal: New England Journal of Medicine (2006)

In the acute respiratory distress syndrome (ARDS), positive end-expiratory pressure (PEEP) may decrease ventilator-induced lung injury by keeping lung regions open that otherwise would be collapsed. Since the effects of PEEP probably depend on the recruitability of lung tissue, we conducted a study to examine the relationship between the percentage of potentially recruitable lung, as indicated by computed tomography (CT), and the clinical and physiological effects of PEEP.Sixty-eight patients with acute lung injury or ARDS underwent whole-lung CT during breath-holding sessions at airway pressures of 5, 15, and 45 cm of water. The percentage of potentially recruitable lung was defined as the proportion of lung tissue in which aeration was restored at airway pressures between 5 and 45 cm of water.The percentage of potentially recruitable lung varied widely in the population, accounting for a mean (+/-SD) of 13+/-11 percent of the lung weight, and was highly correlated with the percentage of lung tissue in which aeration was maintained after the application of PEEP (r2=0.72, P<0.001). On average, 24 percent of the lung could not be recruited. Patients with a higher percentage of potentially recruitable lung (greater than the median value of 9 percent) had greater total lung weights (P<0.001), poorer oxygenation (defined as a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen) (P<0.001) and respiratory-system compliance (P=0.002), higher levels of dead space (P=0.002), and higher rates of death (P=0.02) than patients with a lower percentage of potentially recruitable lung. The combined physiological variables predicted, with a sensitivity of 71 percent and a specificity of 59 percent, whether a patient's proportion of potentially recruitable lung was higher or lower than the median.In ARDS, the percentage of potentially recruitable lung is extremely variable and is strongly associated with the response to PEEP.
Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study
Authors: Lucio Crinò, Eric Dansin, Pilar Garrido, Frank Griesinger, Janessa Laskin, Nick Pavlakis, Daniel Stroiakovski, Nick Thatcher, Chun-Ming Tsai, Yi-long Wu, Caicun Zhou
Journal: The Lancet Oncology (2010)
Separate analysis of asialoglycoprotein receptors in the right and left hepatic lobes using Tc-GSA SPECT
Authors: Kazuhiko Sugahara, Hitoshi Togashi, Kazuei Takahashi, Yuya Onodera, Mai Sanjo, Keiko Misawa, Akihiko Suzuki, Tohru Adachi, Junitsu Ito, Kazuo Okumoto, Etsuko Hattori, Tadashi Takeda, Hisayoshi Watanabe, Koji Saito, Takafumi Saito, Yukio Sugai, Sumio Kawata
Journal: Hepatology (2003)

The asialoglycoprotein receptor (ASGPR) is abundantly expressed on the sinusoidal surfaces of hepatocytes. We aimed to clarify the clinical significance of the regional distribution of ASGPRs in the human liver, especially in chronic viral hepatitis. Eighteen volunteers, 34 patients with chronic hepatitis, and 33 patients with cirrhosis (11/Child-Pugh A, 11/Child-Pugh B, 11/Child-Pugh C) were studied using a newly developed, conventional technetium-99m-diethylenetriaminepentaacetic acid-galactosyl human serum albumin ((99m)Tc-GSA), single photon emission computed tomography (SPECT) method. Using Cantlie's line as a guide, ASGPR dynamics were analyzed separately in the right and left lobes, as well as in the whole liver, using novel indices (the liver uptake ratio [LUR] and the liver uptake density [LUD], which reflect the amount and density of ASGPRs in the liver, respectively). Mean LUR and LUD values for the whole liver and the right and left lobes decreased with increasing progression of chronic viral hepatitis. The LUR for the whole liver correlated well with parameters measuring the hepatic functional reserve and the platelet count. The right LUR correlated particularly well with conventional liver function tests, and comparison of the right LUD with histologic findings showed that it was a good indicator of periportal and/or bridging necrosis and fibrosis. In conclusion, our (99m)Tc-GSA SPECT method was clinically useful in evaluating regional hepatic function and the progression of chronic viral hepatitis using dynamic changes in ASGPRs.
A New Legionella Species, Legionella feeleii Species Nova, Causes Pontiac Fever in an Automobile Plant
Authors: LOREEN A. HERWALDT
Journal: Annals of Internal Medicine (1984)

From 15 to 21 August 1981, Pontiac fever affected 317 automobile assembly plant workers. Results of serologic tests were negative for Mycoplasma, Chlamydia, respiratory tract viruses, and previously described legionellae. A gram-negative, rod-shaped organism (WO-44C) that did not grow on blood agar, required L-cysteine for growth, and contained large amounts of branched-chain fatty acids was isolated from a water-based coolant. The organism did not react with antisera against other legionellae, and on DNA hybridization the organism was less than 10% related to other Legionella species. Geometric mean titers found by indirect fluorescent antibody testing to WO-44C were significantly higher in ill employees than in controls (p = 0.0001). Attack rates by department decreased linearly with the department's distance from the implicated coolant system. The etiologic agent apparently was a new Legionella species; we propose the name Legionella feeleii species nova (AATC 35072). This is the first outbreak of nonpneumonic legionellosis in which the etiologic agent is not L. pneumophila, serogroup 1.
Usefulness of D-dimer, blood gas, and respiratory rate measurements for excluding pulmonary embolism
Authors: P. Egermayer, G I. Town, J. G Turner, D. C Heaton, A. L Mee, M. E J Beard
Journal: Thorax (1998)

A study was undertaken to assess the usefulness of the SimpliRED D-dimer test, arterial oxygen tension, and respiratory rate measurement for excluding pulmonary embolism (PE) and venous thromboembolism (VTE).Lung scans were performed in 517 consecutive medical inpatients with suspected acute PE over a one year period. Predetermined end points for objectively diagnosed PE in order of precedence were (1) a post mortem diagnosis, (2) a positive pulmonary angiogram, (3) a high probability ventilation perfusion lung scan when the pretest probability was also high, and (4) the unanimous opinion of an adjudication committee. Deep vein thrombosis (DVT) was diagnosed by standard ultrasound and venography.A total of 40 cases of PE and 37 cases of DVT were objectively diagnosed. The predictive value of a negative SimpliRED test for excluding objectively diagnosed PE was 0.99 (error rate 2/249), that of PaO2 of > or = 80 mm Hg (10.7 kPa) was 0.97 (error rate 5/160), and that of a respiratory rate of < or = 20/min was 0.95 (error rate 14/308). The best combination of findings for excluding PE was a negative SimpliRED test and PaO2 > or = 80 mm Hg, which gave a predictive value of 1.0 (error rate 0/93). The predictive value of a negative SimpliRED test for excluding VTE was 0.98 (error rate 5/249).All three of these observations are helpful in excluding PE. When any two parameters were normal, PE was very unlikely. In patients with a negative SimpliRED test and PaO2 of > or = 80 mm Hg a lung scan is usually unnecessary. Application of this approach for triage in the preliminary assessment of suspected PE could lead to a reduced rate of false positive diagnoses and considerable resource savings.
Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomised controlled trial
Authors: Angela M Cheung, Lianne Tile, Savannah Cardew, Sandhya Pruthi, John Robbins, George Tomlinson, Moira K Kapral, Sundeep Khosla, Sharmila Majumdar, Marta Erlandson, Judy Scher, Hanxian Hu, Alice Demaras, Lavina Lickley, Louise Bordeleau, Christine Elser, James Ingle, Harriet Richardson, Paul E Goss
Journal: The Lancet Oncology (2012)
Persistent Regional Downregulation in Mitochondrial Enzymes and Upregulation of Stress Proteins in Swine With Chronic Hibernating Myocardium
Authors: Brian Page, Rebeccah Young, Vijay Iyer, Gen Suzuki, Maciej Lis, Lioubov Korotchkina, Mulchand S. Patel, Kenneth M. Blumenthal, James A. Fallavollita, John M. Canty
Journal: Circulation Research (2007)

Hibernating myocardium is accompanied by a downregulation in energy utilization that prevents the immediate development of ischemia during stress at the expense of an attenuated level of regional contractile function. We used a discovery based proteomic approach to identify novel regional molecular adaptations responsible for this phenomenon in subendocardial samples from swine instrumented with a chronic LAD stenosis. After 3 months (n=8), hibernating myocardium was present as reflected by reduced resting LAD flow (0.75±0.14 versus 1.19±0.14 mL · min −1 · g −1 in remote) and wall thickening (1.93±0.46 mm versus 5.46±0.41 mm in remote, P &lt;0.05). Regionally altered proteins were quantified with 2D Differential-in-Gel Electrophoresis (2D-DIGE) using normal myocardium as a reference with identification of candidates using MALDI-TOF mass spectrometry. Hibernating myocardium developed a significant downregulation of many mitochondrial proteins and an upregulation of stress proteins. Of particular note, the major entry points to oxidative metabolism (eg, pyruvate dehydrogenase complex and Acyl-CoA dehydrogenase) and enzymes involved in electron transport (eg, complexes I, III, and V) were reduced ( P &lt;0.05). Multiple subunits within an enzyme complex frequently showed a concordant downregulation in abundance leading to an amplification of their cumulative effects on activity (eg, “total” LAD PDC activity was 21.9±3.1 versus 42.8±1.9 mU, P &lt;0.05). After 5-months (n=10), changes in mitochondrial and stress proteins persisted whereas cytoskeletal proteins (eg, desmin and vimentin) normalized. These data indicate that the proteomic phenotype of hibernating myocardium is dynamic and has similarities to global changes in energy substrate metabolism and function in the advanced failing heart. These proteomic changes may limit oxidative injury and apoptosis and impact functional recovery after revascularization.
Comparison of IL-10 and MCP-1-7ND gene transfer with AAV9 vectors for protection from murine autoimmune myocarditis
Authors: Ziya Kaya, Christoph Leib, Stanislas Werfel, Stefan Göser, Renate Öttl, Barbara Leuchs, Gabriele Pfitzer, Hugo A. Katus, Oliver J. Müller
Journal: Cardiovascular Research (2011)

AimsOverexpression of therapeutic genes with potential disease-limiting effects, specifically at the site of inflammation, remains a major clinical challenge. In this study, we investigate the potential of adeno-associated virus (AAV)-9-mediated cardiac expression of the anti-inflammatory mediators interleukin (IL)-10 and a dominant-negative inhibitor of monocyte chemoattractant protein-1 (MCP1-7ND) on prevention of autoimmune myocarditis.
γ-Adducin Stimulates the Thiazide-sensitive NaCl Cotransporter
Authors: Henrik Dimke, Pedro San-Cristobal, Mark de Graaf, Jacques W. Lenders, Jaap Deinum, Joost G.J. Hoenderop, René J.M. Bindels
Journal: Journal of the American Society of Nephrology (2010)

The thiazide-sensitive NaCl cotransporter (NCC) plays a key role in renal salt reabsorption and the determination of systemic BP, but the molecular mechanisms governing the regulation of NCC are not completely understood. Here, through pull-down experiments coupled to mass spectrometry, we found that γ-adducin interacts with the NCC transporter. γ-Adducin colocalized with NCC to the distal convoluted tubule. 22Na+ uptake experiments in the Xenopus laevis oocyte showed that γ-adducin stimulated NCC activity in a dose-dependent manner, an effect that occurred upstream from With No Lysine (WNK) 4 kinase. The binding site of γ-adducin mapped to the N terminus of NCC and encompassed three previously reported phosphorylation sites. Supporting this site of interaction, competition with the N-terminal domain of NCC abolished the stimulatory effect of γ-adducin on the transporter. γ-Adducin failed to increase NCC activity when these phosphorylation sites were constitutively inactive or active. In addition, γ-adducin bound only to the dephosphorylated N terminus of NCC. Taken together, our observations suggest that γ-adducin dynamically regulates NCC, likely by amending the phosphorylation state, and consequently the activity, of the transporter. These data suggest that γ-adducin may influence BP homeostasis by modulating renal NaCl transport.
Atenolol use and clinical outcomes after thrombolysis for acute myocardial infarction: the GUSTO-I experience
Authors: Matthias Pfisterer, Jafna L Cox, Christopher B Granger, Sorin J Brener, C.David Naylor, Robert M Califf, Frans van de Werf, Amanda L Stebbins, Kerry L Lee, Eric J Topol, Paul W Armstrong
Journal: Journal of the American College of Cardiology (1998)
A study of the spectrum of skin disease occurring in a black population in south-east London
Authors: None Child, None Fuller, None Higgins, None Du Vivier
Journal: British Journal of Dermatology (1999)

We recorded the diagnosis made in 461 black patients (187 children and 274 adults) attending a dermatology clinic between January and March 1996. In the childhood population, atopic eczema and tinea capitis were the most frequent dermatoses, comprising 63% of diagnoses recorded. In the adult population, acne and acne keloidalis nuchae were seen most frequently. Other conditions observed commonly were eczema, psoriasis, keloid scarring, pityriasis versicolor and postinflammatory changes. Our study demonstrates a wide spectrum of skin disease and includes disorders more common in black skin, disorders unique to black skin, those which present a greater cosmetic disability, and normal findings which have been mistaken for pathological disease.
Evaluation of the reliability of two field hockey specific sprint and dribble tests in young field hockey players
Authors: K A P M Lemmink, M T Elferink-Gemser, C Visscher
Journal: British Journal of Sports Medicine (2004)

Objectives: To determine the reliability of two field hockey specific tests: the shuttle sprint and dribble test (ShuttleSDT) and the slalom sprint and dribble test (SlalomSDT). Methods: The shuttle sprint and dribble performances of 22 young male and 12 young female field hockey players were assessed on two occasions within 4 weeks. Twenty one young female field hockey players took part in the slalom sprint and dribble test twice in a 4 week period. The ShuttleSDT required the players to perform three 30 m shuttle sprints while carrying a hockey stick alternated with short periods of rest and, after a 5 minute rest, three 30 m shuttle sprints alternated with rest while dribbling a hockey ball. The SlalomSDT required the players to run a slalom course and, after a 5 minute rest, to dribble the same slalom with a hockey ball. Results: There were no differences in mean time scores between the two test sessions. The mean differences were small when compared with the means of both test sessions. With the exception of the slalom sprint time, zero lay within the 95% confidence interval of the mean differences indicating that no bias existed between the two measurements. With the exception of delta shuttle time (0.79), all intraclass correlation coefficient values for the ShuttleSDT, met the criterion for reliability of 0.80. Intraclass correlation coefficient values for SlalomSDT were 0.91 for slalom sprint time, 0.78 for slalom dribble time, and 0.80 for delta slalom time. Conclusions: ShuttleSDT and the SlalomSDT are reliable measures of sprint and dribble performances of young field hockey players.
A Controlled Trial Comparing Two Doses of Cyclosporine in Conjunction with Mycophenolate Mofetil and Corticosteroids
Authors: RUUD G. L. DE SÉVAUX, PETER J. H. SMAK GREGOOR, RONALD J. HENÉ, ANDRIES J. HOITSMA, PIETER VOS, WILLEM WEIMAR, TEUN VAN GELDER, LUKAS B. HILBRANDS
Journal: Journal of the American Society of Nephrology (2001)

Abstract. It is unknown whether the addition of mycophenolate mofetil (MMF) to cyclosporine (CsA) and prednisone after renal transplantation (RTx) allows for a reduced dose of CsA, to minimize the incidence of CsA-related side effects and to reduce costs. Therefore, 313 renal allograft recipients were randomized for treatment with MMF (1000 mg twice a day), prednisone, and either conventional- or low-dose CsA during the first 3 mo after RTx. The target trough levels were 300 and 150 ng/ml, respectively, during the first 3 mo and 150 ng/ml in both groups thereafter. A total of 313 patients were included: 161 patients received a conventional dose and 152 received a low dose of CsA. During the first 6 mo after RTx, graft failure or patient death occurred in 19 of 161 patients (12%) in the conventional-dose group and in 11 of 152 patients (7%) in the low-dose group (not significant). Biopsy-proven acute rejection occurred in 36 of 161 patients (22%) in the conventional-dose group and in 29 of 152 patients (19%) in the low-dose group (not significant). The incidence of delayed graft function was similar in both groups (31 of 161 [19%] versus 28 of 152 [18%]; not significant). Serum creatinine did not differ between the conventional- and the low-dose groups: 151 ± 56 μmol/L versus 142 ± 49 μmol/L at 3 mo and 141 ± 60 μmol/L versus 136 ± 49 μmol/L at 6 mo. There were no differences between the groups regarding BP, lipid metabolism, and infectious complications. In the low-dose group, an estimated $500 per patient was saved on the costs of CsA. In conclusion, the addition of MMF to CsA and prednisone after RTx allows the use of a lower-than-conventional dose of CsA, without increasing the risk of rejection.
European survey to predict survival on renal replacement therapy - Comparison of a simple scoring system with a regression model
Authors: J.G. Fox, C.C. Geddes, K. Simpson, W. Metcalfe, K.J. Jager, A.H. Zwinderman, Dijk, P.C.W., van, J.D. Briggs
Journal: Journal of the American Society of Nephrology (2003)
Evidence for Compensatory Evolution of Ribosomal Proteins in Response to Rapid Divergence of Mitochondrial rRNA
Authors: Felipe S. Barreto, Ronald S. Burton
Journal: Molecular Biology and Evolution (2012)

Abstract Rapid evolution of mitochondrial DNA (mtDNA) places intrinsic selective pressures on many nuclear genes involved in mitochondrial functions. Mitochondrial ribosomes, for example, are composed of mtDNA-encoded ribosomal RNAs (rRNAs) and a set of more than 60 nuclear-encoded ribosomal proteins (mRP) distinct from the cytosolic RPs (cRP). We hypothesized that the rapid divergence of mt-rRNA would result in rapid evolution of mRPs relative to cRPs, which respond to slowly evolving nuclear-encoded rRNA. In comparisons of rates of nonsynonymous and synonymous substitutions between a pair of divergent populations of the copepod Tigriopus californicus, we found that mRPs showed elevated levels of amino acid changes relative to cRPs. This pattern was equally strong at the interspecific level, between three pairs of sister species (Nasonia vitripennis vs. N. longicornis, Drosophila melanogaster vs. D. simulans, and Saccharomyces cerevisae vs. S. paradoxus). This high rate of mRP evolution may result in intergenomic incompatibilities between taxonomic lineages, and such incompatibilities could lead to dysfunction of mitochondrial ribosomes and the loss of fitness observed among interpopulation hybrids in T. californicus and interspecific hybrids in other species.
Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions
Authors: Jie Du, Xiaonan Wang, Christiane Miereles, James L. Bailey, Richard Debigare, Bin Zheng, S. Russ Price, William E. Mitch
Journal: Journal of Clinical Investigation (2004)

With trauma, sepsis, cancer, or uremia, animals or patients experience accelerated degradation of muscle protein in the ATP-ubiquitin-proteasome (Ub-P’some) system. The initial step in myofibrillar proteolysis is unknown because this proteolytic system does not break down actomyosin complexes or myofibrils, even though it degrades monomeric actin or myosin. Since cytokines or insulin resistance are common in catabolic states and will activate caspases, we examined whether caspase-3 would break down actomyosin. We found that recombinant caspase-3 cleaves actomyosin, producing a characteristic, approximately 14-kDa actin fragment and other proteins that are degraded by the Ub-P’some. In fact, limited actomyosin cleavage by caspase-3 yields a 125% increase in protein degradation by the Ub-P’some system. Serum deprivation of L6 muscle cells stimulates actin cleavage and proteolysis; insulin blocks these responses by a mechanism requiring PI3K. Cleaved actin fragments are present in muscles of rats with muscle atrophy from diabetes or chronic uremia. Accumulation of actin fragments and the rate of proteolysis in muscle stimulated by diabetes are suppressed by a caspase-3 inhibitor. Thus, in catabolic conditions, an initial step resulting in loss of muscle protein is activation of caspase-3, yielding proteins that are degraded by the Ub-P’some system. Therapeutic strategies could be designed to prevent these events.