tbuckley/cabot-search huggingface dataset:
Prevention Strategies with Aromatase Inhibitors
Authors: Paul E. Goss, Kathrin Strasser-Weippl
Journal: Clinical Cancer Research (2004)

Abstract Aromatase (estrogen synthetase) inhibitors are superior to tamoxifen in terms of both efficacy and toxicity in the treatment of advanced breast cancer and also in the neoadjuvant setting. Recent results from the Arimidex, Tamoxifen, Alone or in Combination adjuvant trial showed a marked reduction in contralateral primary breast cancer with anastrozole, an apparent prevention effect. A similar effect was seen in the MA.17 adjuvant trial comparing letrozole with placebo after 5 years of adjuvant tamoxifen. This has accelerated interest in aromatase inhibitors as primary preventive therapy. Two studies being conducted by the National Cancer Institute of Canada’s Clinical Trials Group select women by virtue of mammographic breast density. The International Breast Cancer Intervention Study 2 trial randomizes women at elevated risk to anastrozole or placebo. Because of its steroidal structure, exemestane may be more effective than the nonsteroidal aromatase inhibitors and may protect bone and lipid metabolism from the effects of estrogen ablation. Elevated prostaglandin E2 levels from cyclooxygenase-2 induction by preinvasive and invasive breast lesions increase a number of tumor-promoting pathways, including aromatase, as well as angiogenetic, antiapoptotic, and others. Additive or synergistic effects between celecoxib, a cyclooxygenase-2 inhibitor, and exemestane have been demonstrated and have led to the National Cancer Institute of Canada’s Clinical Trials Group MAP.3 trial, which will randomize women at elevated risk to placebo or to exemestane with or without celecoxib. The efficacy and long-term toxicity data from the aromatase inhibitor prevention trials, and the identification of risk profiles from trial results, are awaited with interest.
Small-Molecule MDM2 Antagonists as a New Therapy Concept for Neuroblastoma
Authors: Tom Van Maerken, Frank Speleman, Joëlle Vermeulen, Irina Lambertz, Sarah De Clercq, Els De Smet, Nurten Yigit, Vicky Coppens, Jan Philippé, Anne De Paepe, Jean-Christophe Marine, Jo Vandesompele
Journal: Cancer Research (2006)

Circumvention of the p53 tumor suppressor barrier in neuroblastoma is rarely caused by TP53 mutation but might arise from inappropriately increased activity of its principal negative regulator MDM2. We show here that targeted disruption of the p53-MDM2 interaction by the small-molecule MDM2 antagonist nutlin-3 stabilizes p53 and selectively activates the p53 pathway in neuroblastoma cells with wild-type p53, resulting in a pronounced antiproliferative and cytotoxic effect through induction of G(1) cell cycle arrest and apoptosis. A nutlin-3 response was observed regardless of MYCN amplification status. Remarkably, surviving SK-N-SH cells adopted a senescence-like phenotype, whereas CLB-GA and NGP cells underwent neuronal differentiation. p53 dependence of these alternative outcomes of nutlin-3 treatment was evidenced by abrogation of the effects when p53 was knocked down by lentiviral-mediated short hairpin RNA interference. The diversity of cellular responses reveals pleiotropic mechanisms of nutlins to disable neuroblastoma cells and exemplifies the feasibility of exploiting, by a single targeted intervention, the multiplicity of anticancer activities exerted by a key tumor suppressor as p53. The observed treatment effects without the need of imposing a genotoxic burden suggest that selective MDM2 antagonists might be beneficial for treatment of neuroblastoma patients with and without MYCN amplification.
A reverse genetic screen in Drosophila using a deletion-inducing mutagen.
Authors: Knud Nairz, Peder Zipperlen, Charles Dearolf, Konrad Basler, Ernst Hafen
Journal: Genome biology (2004)

We report the use of the cross-linking drug hexamethylphosphoramide (HMPA), which introduces small deletions, as a mutagen suitable for reverse genetics in the model organism Drosophila melanogaster. A compatible mutation-detection method based on resolution of PCR fragment-length polymorphisms on standard DNA sequencers is implemented. As the spectrum of HMPA-induced mutations is similar in a variety of organisms, it should be possible to transfer this mutagenesis and detection procedure to other model systems.
Smooth Muscle α-Actin CArG Elements Coordinate Formation of a Smooth Muscle Cell–Selective, Serum Response Factor–Containing Activation Complex
Authors: Christopher P. Mack, Maria M. Thompson, Susan Lawrenz-Smith, Gary K. Owens
Journal: Circulation Research (2000)

Abstract —Previous studies have shown that multiple serum response factor (SRF)-binding CArG elements were required for smooth muscle cell (SMC)-specific regulation of smooth muscle (SM) α-actin expression. However, a critical question remains as to the mechanisms whereby a ubiquitously expressed transcription factor such as SRF might contribute to SMC-specific expression. The goal of the present study was to investigate the hypothesis that SMC-selective expression of SM α-actin is due at least in part to (1) unique CArG flanking sequences that distinguish the SM α-actin CArGs from other ubiquitously expressed CArG-dependent genes such as c- fos , (2) cooperative interactions between CArG elements, and (3) SRF-dependent binding of SMC-selective proteins to the CArG-containing regions of the promoter. Results demonstrated that specific sequences flanking CArG B were important for promoter activity in SMCs but not in bovine aortic endothelial cells. We also provided evidence indicating that the structural orientation between CArGs A and B was an important determinant of promoter function. Electrophoretic mobility shift assays and methylation interference footprinting demonstrated that a unique SRF-containing complex formed that was selective for SMCs and, furthermore, that this complex was probably stabilized by protein-protein interactions and not by specific interactions with CArG flanking sequences. Taken together, the results of these studies provide evidence that SM α-actin expression in SMCs is complex and may involve the formation of a unique multiprotein initiation complex that is coordinated by SRF complexes bound to multiple CArG elements.
Gene-specific increase in the energetic cost of contraction in hypertrophic cardiomyopathy caused by thick filament mutations
Authors: E. Rosalie Witjas-Paalberends, Ahmet Güçlü, Tjeerd Germans, Paul Knaapen, Hendrik J Harms, Alexa M.C. Vermeer, Imke Christiaans, Arthur A.M. Wilde, Cris Dos Remedios, Adriaan A. Lammertsma, Albert C. van Rossum, Ger J.M. Stienen, Marjon van Slegtenhorst, Arend F. Schinkel, Michelle Michels, Carolyn Y. Ho, Corrado Poggesi, Jolanda van der Velden
Journal: Cardiovascular Research (2014)

Disease mechanisms regarding hypertrophic cardiomyopathy (HCM) are largely unknown and disease onset varies. Sarcomere mutations might induce energy depletion for which until now there is no direct evidence at sarcomere level in human HCM. This study investigated if mutations in genes encoding myosin-binding protein C (MYBPC3) and myosin heavy chain (MYH7) underlie changes in the energetic cost of contraction in the development of human HCM disease. Energetic cost of contraction was studied in vitro by measurements of force development and ATPase activity in cardiac muscle strips from 26 manifest HCM patients (11 MYBPC3mut, 9 MYH7mut, and 6 sarcomere mutation-negative, HCMsmn). In addition, in vivo, the ratio between external work (EW) and myocardial oxygen consumption (MVO2) to obtain myocardial external efficiency (MEE) was determined in 28 pre-hypertrophic mutation carriers (14 MYBPC3mut and 14 MYH7mut) and 14 healthy controls using [11C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging. Tension cost (TC), i.e. ATPase activity during force development, was higher in MYBPC3mut and MYH7mut compared with HCMsmn at saturating [Ca2+]. TC was also significantly higher in MYH7mut at submaximal, more physiological [Ca2+]. EW was significantly lower in both mutation carrier groups, while MVO2 did not differ. MEE was significantly lower in both mutation carrier groups compared with controls, showing the lowest efficiency in MYH7 mutation carriers. We provide direct evidence that sarcomere mutations perturb the energetic cost of cardiac contraction. Gene-specific severity of cardiac abnormalities may underlie differences in disease onset and suggests that early initiation of metabolic treatment may be beneficial, in particular, in MYH7 mutation carriers.
Effect of Aminoglutethimide on Blood Pressure and Steroid Secretion in Patients with Low Renin Essential Hypertension
Authors: Addison A. Taylor, Jerry R. Mitchell, Frederic C. Bartter, Wayne R. Snodgrass, Randolph J. McMurtry, John R. Gill, Ronald B. Franklin
Journal: Journal of Clinical Investigation (1978)

An inhibitor of adrenal steroid biosynthesis, aminoglutethimide, was administered to seven patients with low renin essential hypertension, and the antihypertensive action of the drug was compared with its effects on adrenal steroid production. In all patients aldosterone concentrations in plasma and urine were within normal limits before the study. Mean arterial pressure was reduced from a pretreatment value of 117±2 (mean±SE) mm Hg to 108±3 mm Hg after 4 days of aminoglutethimide therapy and further to 99±3 mm Hg when drug administration was stopped (usually 21 days). Body weight was also reduced from 81.6±7.2 kg in the control period to 80.6±7.0 kg after 4 days of drug treatment and to 80.1±6.7 kg at the termination of therapy. Plasma renin activity was not significantly increased after 4 days of treatment but had risen to the normal range by the termination of aminoglutethimide therapy. Mean plasma concentrations of deoxycorticosterone and cortisol were unchanged during aminoglutethimide treatment whereas those of 18-hydroxydeoxycorticosterone, progesterone, 17α-hydroxyprogesterone, and 11-deoxycortisol were increased as compared to pretreatment values. In contrast, aminoglutethimide treatment reduced mean plasma aldosterone concentrations to about 30% of control values. Excretion rates of 16β-hydroxydehydroepiandrosterone, 16-oxo-androstenediol, 17-hydroxycorticosteroids and 17-ketosteroids, and the secretion rate of 16β-hydroxydehydroepiandrosterone were not significantly altered by aminoglutethimide treatment whereas the excretion rate of aldosterone was reduced from 3.62±0.5 (mean±SE) in the control period to 0.9±0.2 μg/24 h after 4 days and to 1.1±0.3 μg/24 h at the termination of aminoglutethimide treatment.
Rapid Encoding of New Memories by Individual Neurons in the Human Brain
Authors: Matias J. Ison, Rodrigo Quian Quiroga, Itzhak Fried
Journal: Neuron (2015)

The creation of memories about real-life episodes requires rapid neuronal changes that may appear after a single occurrence of an event. How is such demand met by neurons in the medial temporal lobe (MTL), which plays a fundamental role in episodic memory formation? We recorded the activity of MTL neurons in neurosurgical patients while they learned new associations. Pairs of unrelated pictures, one of a person and another of a place, were used to construct a meaningful association modeling the episodic memory of meeting a person in a particular place. We found that a large proportion of responsive MTL neurons expanded their selectivity to encode these specific associations within a few trials: cells initially responsive to one picture started firing to the associated one but not to others. Our results provide a plausible neural substrate for the inception of associations, which are crucial for the formation of episodic memories.
Effect of hypoxia and carbon monoxide on muscle oxygenation during exercise.
Authors: K Maehara, M Riley, P Galassetti, T J Barstow, K Wasserman
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

We used near-infrared spectroscopy (NIRS) to test the hypothesis that reducing oxygen availability during exercise would affect the rate of muscle oxyhemoglobin (O2Hb) desaturation when performing work above the lactic acidosis threshold (LAT), but not below it. Seven healthy men each performed two constant work intensities (60%LAT and the LAT plus 40% of the difference between the LAT and VO2max [40%delta]) four times under the following conditions: (1) 10 min air; (2) 5 min 15%O2 + 5 min air; (3) 5 min air + 5 min 15%O2; (4) 5 min after carbon monoxide (CO) loading to increase the carboxyhemoglobin (COHb) saturation to 15%. During each test, cardiorespiratory parameters and muscle oxygenation measured with NIRS were continuously monitored. Forearm venous blood lactate was measured every 2 to 3 min. Hypoxia and CO accelerated muscle deoxygenation only for exercise above the LAT; for exercise below the LAT, neither progressive deoxygenation nor lactate accumulation occurred after initital, rapid muscle deoxygenation. The rate of decrease in muscle oxygenation between 3 to 5 min of exercise correlated with the increase in VO2 (r = 0.61, p < 0.01) and blood lactate (r = 0.70, p < 0.01) over the same period. These results support the hypothesis that progressive muscle deoxygenation occurs above the LAT and that the rate of deoxygenation is sensitive to oxygen delivery.
The Nordic Football Injury Audit: higher injury rates for professional football clubs with third-generation artificial turf at their home venue
Authors: Karolina Kristenson, John Bjørneboe, Markus Waldén, Thor Einar Andersen, Jan Ekstrand, Martin Hägglund
Journal: British Journal of Sports Medicine (2013)

Background Previously, no difference in acute injury rate has been found when playing football on artificial turf (AT) compared with natural grass (NG). Aim To compare acute injury rates in professional football played on AT and NG at the individual player level; and to compare, at club level, acute and overuse injury rates between clubs that have AT at their home venue (AT clubs) and clubs that have NG (NG clubs). Methods 32 clubs (AT, n=11; NG, n=21) in the male Swedish and Norwegian premier leagues were followed prospectively during the 2010 and 2011 seasons. Injury rate was expressed as the number of time loss injuries/1000 h and compared with rate ratio (RR) and 99% CI. Results No statistically significant differences were found in acute injury rates on AT compared with NG during match play (RR 0.98, 99% CI 0.79 to 1.22) or training (RR 1.14, 99% CI 0.86 to 1.50) when analysing at the individual player level. When analysing at the club level, however, AT clubs had a significantly higher acute training injury rate (RR 1.31, 99% CI 1.04 to 1.63) and overuse injury rate (RR 1.38, 99% CI 1.14 to 1.65) compared with NG clubs. Conclusions At the individual player level, no significant differences were found in acute injury rates when playing on AT compared with NG. However, clubs with AT at their home venue had higher rates of acute training injuries and overuse injuries compared with clubs that played home matches on NG.
Regulation of E-box DNA binding during in vivo and in vitro activation of rat and human hepatic stellate cells
Authors: K J Vincent
Journal: Gut (2001)

Activation of hepatic stellate cells (HSCs) to a myofibroblastic phenotype is a key event in liver fibrosis. Identification of transcription factors with activities that are modulated during HSC activation will improve our understanding of the molecular events controlling HSC activation.To determine if changes in E-box DNA binding activity occur during in vitro and in vivo activation of rat and human HSCs and to investigate mechanisms underlying any observed changes.Nuclear extracts were prepared from rat HSCs isolated and cultured from normal and carbon tetrachloride injured rat livers and from HSCs isolated from human liver. EMSA analysis of E-box DNA binding activity was performed on nuclear extracts to determine changes during HSC activation. Western and northern blot analysis of MyoD and Id1 basic helix-loop-helix (bHLH) proteins was performed to confirm expression in HSC.HSC activation was associated with inducible expression of two low mobility E-box binding complexes that were immunoreactive with an anti-MyoD antibody. MyoD mRNA expression was found at similar levels in freshly isolated and activated HSCs; in contrast, MyoD protein expression was elevated in activated HSCs. Activation of rat HSCs was accompanied by reduced expression of the inhibitory bHLH protein Id1.In vitro and in vivo activation of rat and human HSCs is accompanied by induction of MyoD binding to E-box DNA sequences which appears to be mechanistically associated with elevated MyoD protein expression and reduced expression of the inhibitory Id1 protein. Clarification of the role of MyoD and Id1 proteins in HSC activation and liver fibrogenesis is now required.
Global workspace theory emerges unscathed
Authors: Murray Shanahan, Bernard Baars
Journal: Behavioral and Brain Sciences (2007)

Abstract Our aim in this reply is to defend Global Workspace theory (GWT) from the challenge of Block's article. We argue that Block's article relies on an outdated and imprecise concept of access, and perpetuates a common misunderstanding of GWT that conflates the global workspace with working memory. In the light of the relevant clarifications, Block's conclusion turns out to be unwarranted, and the basic tenets of GWT emerge unscathed.
Controlling the spread of carbapenemase-producing Gram-negatives: therapeutic approach and infection control
Authors: Y. Carmeli, M. Akova, G. Cornaglia, G.L. Daikos, J. Garau, S. Harbarth, G.M. Rossolini, M. Souli, H. Giamarellou
Journal: Clinical Microbiology and Infection (2010)
Naturally Occurring Neomorphic PIK3R1 Mutations Activate the MAPK Pathway, Dictating Therapeutic Response to MAPK Pathway Inhibitors
Authors: Lydia W.T. Cheung, Shuangxing Yu, Dong Zhang, Jie Li, Patrick K.S. Ng, Nattapon Panupinthu, Shreya Mitra, Zhenlin Ju, Qinghua Yu, Han Liang, David H. Hawke, Yiling Lu, Russell R. Broaddus, Gordon B. Mills
Journal: Cancer Cell (2014)
Rectal reservoir and sensory function studied by graded isobaric distension in normal man.
Authors: S Akervall, S Fasth, S Nordgren, T Oresland, L Hulten
Journal: Gut (1989)

The rectal expansion and concomitant sensory function on graded, isobaric, rectal distension within the interval 5-60 cm H2O was investigated in 36 healthy young volunteers. Anal pressure and electromyography (EMG) from the external anal sphincter were simultaneously recorded. Rectal distension caused an initial rapid expansion followed by transient, often repeated, reflex rectal contractions and a slow gradual increase of rectal volume. The maximal volume displaced by the first reflex rectal contraction was 18 (13) ml, which was less than 10% of the volume at 60 s. The pressure threshold for appreciation of rectal filling was 12 cm H2O (95% CL 5-15 cm H2O) and coincided with the threshold for rectoanal inhibition. Urge to defecate was experienced at 28 cm H2O (15-50 cm H2O) distension pressure, which was close to the threshold for maximal rectal contraction, also coinciding with the appearance of the external anal sphincter reflex. The interindividual variation of rectal volume on distension with defined pressures varied widely, indicating a considerable variation of rectal compliance in normal man. No correlation was found between rectal volume and sex or anthropometric variables. The relative variations in pressure thresholds for eliciting rectal sensation and rectoanal reflexes were less than the corresponding threshold volumes. It was concluded that the dynamic rectal response to distension reflects a well graded reflex adjustment ideal for a reservoir.
Pulmonary arterial aneurysm presenting as an endobronchial mass.
Authors: P M Gibbs, A Hami
Journal: Thorax (1995)

The case is presented of a 25 year old man with haemoptysis who exsanguinated following endoscopic fine needle aspiration of an endobronchial mass. Necroscopic examination revealed an aneurysm of the proximal left pulmonary artery.
Utility of A1C for Diabetes Screening in the 1999–2004 NHANES Population
Authors: Catherine Buell, Duclie Kermah, Mayer B. Davidson
Journal: Diabetes Care (2007)

Thirty percent of people with diabetes are undiagnosed (1), and up to 25% already have microvascular complications at diagnosis (2). The American Diabetes Association recommends screening adults ≥45 years of age, especially those with a BMI ≥25 kg/m2, at 3-year intervals with a fasting plasma glucose (FPG) measurement (3). However, physicians infrequently use an FPG for screening. For example, in a large health maintenance organization within the University of Michigan health system, 184 physicians at 22 separate locations screened 5,752 (69%) of 8,286 people without diabetes over a 3-year period. Ninety-five percent of the screening tests were random glucose measurements, 3% were FPGs, and 2% were A1Cs (4). Random glucose levels depend on the length of time after the previous meal and the carbohydrate content of that meal. There is no agreement on what random glucose values should lead to further investigations.

Because A1C levels reflect average glycemia during the preceding 3–4 months, meal issues are not a factor. To determine what A1C level should lead to further tests to diagnose diabetes, we examined the 1999–2004 National Health and Nutrition Examination Survey (NHANES) population of those not known to have diabetes to determine the sensitivity and specificity with which various A1C levels identified people with diabetes.

NHANES oversampled African-American and Hispanic individuals to obtain enough data for analysis in this minority subset. Accordingly, results were weighted to reflect the …
Effects of heterogeneous myocardial perfusion on coronary venous H2 desaturation curves and calculations of coronary flow
Authors: Francis J. Klocke, Robert C. Koberstein, David E. Pittman, Ivan L. Bunnell, David G. Greene, Douglas R. Rosing
Journal: Journal of Clinical Investigation (1968)

The present investigation was intended to evaluate myocardial inert gas desaturation curves for manifestations of heterogeneous coronary perfusion. The test gas was hydrogen (H(2)) and blood H(2) analyses were performed with a gas chromatograph capable of detecting small but prolonged venous-arterial H(2) differences produced by areas of reduced flow. Curves were initially obtained after 4-min left ventricular infusions of H(2)-saturated saline in six patients with arteriographically proven coronary artery disease, three patients with normal coronary arteries, and nine closed-chest dogs. The dogs were studied before and after embolic occlusion of a portion of the left coronary artery. Although the slopes of their semilogarithmically plotted venous desaturation curves varied with time before embolization, they showed more distinct deviations from single exponentials after embolization (after H(2) concentrations had fallen below 15% of their initial values). The human curves divided similarly, those from coronary artery patients deviating appreciably from single exponentials. A similar separation was also evident in studies of coronary venous-arterial H(2) differences after 20 min of breathing 2% H(2): data were obtained in four dogs before and after coronary embolization, and in three normal patients, and five patients with coronary artery disease. Additional data indicated that the findings were not the result of right atrial admixture in sampled coronary venous blood, although admixture occurred frequently when blood was sampled in the first 2 cm of the coronary sinus (as seen in the frontal projection). Finally, average coronary flows calculated from a given set of data varied significantly with different methods of calculation. Areas of below-average flow seemed likely to be overlooked when single rate constants of desaturation, relatively insensitive analytical techniques, or relatively short periods of saturation and (or) desaturation are employed.