tbuckley/cabot-search huggingface dataset:
Companies Waver in Efforts To Target Transforming Growth Factor in Cancer
Authors: K. Garber
Journal: JNCI Journal of the National Cancer Institute (2009)

ore than 30 years after its discovery, transforming growth factor ␤ (TGF-␤ ) engages developmental biologists, immunologists, cell biologists, and cancer researchers.New findings are reported weekly for this multifunctional cytokine family.In cancer, researchers continue to deconstruct TGF-␤ ' s dual role as a tumor suppressor and promoter.Interest in its biology is greater than ever.Unfortunately, the same can't be said about therapies targeting TGF-␤ in cancer.Earlier this decade, spurred by reports that TGF-␤ inhibition was safe and effective in animal models, many drug and biotech companies launched programs to develop TGF-␤ inhibitors.But several of these programs have recently been abandoned, and most companies that remain in the race are proceeding slowly and cautiously ( see sidebar).The future of TGF-␤ therapy, once so bright, is now in doubt. From the StartTGF-␤ and cancer were linked from the start.In 1978, Joe De Larco, Ph.D., and George Todaro, M.D., at the National Cancer Institute partially purifi ed a substance that allowed normal cells to form colonies in soft agar unsupported by any solid structure -a defi ning trait of cancer cells.They called the mysterious substance sarcoma growth factor.One fraction of sarcoma growth factor proved responsible for this anchorage-independent growth.Called TGF-␤ , it was purifi ed in 1981 by Anita Roberts, Ph.D., in the NCI lab of Mike
The control of Ca release from the cardiac sarcoplasmic reticulum: regulation versus autoregulation
Authors: D.A Eisner, A.W Trafford, M.E Dñaz, C.L Overend, S.C O'Neill
Journal: Cardiovascular Research (1998)

This review discusses the mechanism and regulation of Ca release from the cardiac sarcoplasmic reticulum. Ca is released through the Ca release channel or ryanodine receptor (RyR) by the process of calcium-induced Ca release (CICR). The trigger for this release is the L-type Ca current with a small contribution from Ca entry on the Na–Ca exchange. Recent work has shown that CICR is controlled at the level of small, local domains consisting of one or a small number of L-type Ca channels and associated RyRs. Ca efflux from the s.r. in one such unit is seen as a 'spark' and the properties of these sparks produce controlled Ca release from the s.r. A major factor controlling the amount of Ca released from the s.r. and therefore the magnitude of the systolic Ca transient is its Ca content. The Ca content depends on both the properties of the s.r. and the cytoplasmic Ca concentration. Changes of s.r. Ca content and the Ca released affect the sarcolemmal Ca and Na–Ca exchange currents and this acts to control cell Ca loading and the s.r. Ca content. The opening probability of the RyR can be regulated by various physiological mediators as well as pharmacological compounds. However, it is shown that, due to compensatory changes of s.r. Ca, modifiers of the RyR only produce transient effects on systolic Ca. We conclude that, although the RyR can be regulated, of much greater importance to the control of Ca efflux from the s.r. are effects due to changes of s.r. Ca content.
Colonoscopy withdrawal time and adenoma detection rate in screening colonoscopy: the optimum average withdrawal time is 10 min
Authors: T. J. W. Lee, R. G. Blanks, C. J. Rees, K. C. Wright, C. Nickerson, S. M. Moss, A. Chilton, A. F. Goddard, J. Patnick, R. J. Q. McNally, M. D. Rutter
Journal: Gut (2011)

<h3>Introduction</h3> Increasing colonoscopy withdrawal time has previously been shown to be associated with increasing adenoma detection rate (ADR). Current guidelines recommend a minimum withdrawal time of 6 min. The optimum mean withdrawal time for adenoma detection is not known. <h3>Methods</h3> The mean withdrawal time in negative complete colonoscopies (nc-CWT) was estimated for 147 colonoscopists in the NHS Bowel Cancer Screening Programme; colonoscopists were grouped in four levels of nc-CWT (&lt;7, 7–8.9, 9–10.9 and ≤11 min). Logistic regression was used to analyse the relationship between CWT and ADR. <h3>Results</h3> The study examined data from 31,088 procedures by 147 colonoscopists undertaken between August 2006 and August 2009. The mean ADR in each group was 42.5% in colonoscopists with a mean nc-CWT &lt;7 min, 45.5% in the 7–8.9-min group (p = 0.002 for difference compared to lowest nc-CWT group), 47.3% in the 9–10.9-min group (p &lt; 0.001) and 47.1% in the ≤11-min group (p &lt; 0.001). In multivariable analysis, the ADR of colonoscopists with an nc-CWT of around 10 min was 11% higher than those with an nc-CWT of around 6 min (p &lt; 0.001). Both the proportion of adenomas less than 1 cm in size and the proportion of adenomas detected in the proximal colon increased for longer withdrawal times. Advanced adenoma detection was not affected by increasing withdrawal times. <h3>Conclusion</h3> Increasing average nc-CWT is shown to be associated with increasing ADR up to 10 min. Beyond 10 min no significant further increase in adenoma yield is seen. This is evidence of the 'ceiling effect' of withdrawal time on adenoma detection. Inadequate bowel preparation quality increases mean withdrawal time in complete colonoscopies but this is not associated with any change in ADR. The increase in adenoma detection as a result of longer withdrawal is due to detection of more small and right sided lesions, no increase in detection of large or advanced adenomas is seen. We recommend, on the basis of the findings of this study, that the optimal average nc-CWT per colonoscopist for screening colonoscopy is around 10 min.
TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells
Authors: Stephan R Krutzik, Belinda Tan, Huiying Li, Maria Teresa Ochoa, Philip T Liu, Sarah E Sharfstein, Thomas G Graeber, Peter A Sieling, Yong-Jun Liu, Thomas H Rea, Barry R Bloom, Robert L Modlin
Journal: Nature Medicine (2005)
Evolution of the Multifunctional Protein Tyrosine Phosphatase Family
Authors: Birgit Pils, Jörg Schultz
Journal: Molecular Biology and Evolution (2004)

The protein tyrosine phosphatase (PTP) family plays a central role in signal transduction pathways by controlling the phosphorylation state of serine, threonine, and tyrosine residues. PTPs can be divided into dual specificity phosphatases and the classical PTPs, which can comprise of one or two phosphatase domains. We studied amino acid substitutions at functional sites in the phosphatase domain and identified putative noncatalytic phosphatase domains in all subclasses of the PTP family. The presence of inactive phosphatase domains in all subclasses indicates that they were invented multiple times in evolution. Depending on the domain composition, loss of catalytic activity can result in different consequences for the function of the protein. Inactive single-domain phosphatases can still specifically bind substrate and protect it from dephosphorylation by other phosphatases. The inactive domains of tandem phosphatases can be further subdivided. The first class is more conserved, still able to bind phosphorylated tyrosine residues and might recruit multiphosphorylated substrates for the adjacent active domain. The second has accumulated several variable amino acid substitutions in the catalytic center, indicating a complete loss of tyrosine-binding capabilities. To study the impact of substitutions in the catalytic center to the evolution of the whole domain, we examined the evolutionary rates for each individual site and compared them between the classes. This analysis revealed a release of evolutionary constraint for multiple sites surrounding the catalytic center only in the second class, emphasizing its difference in function compared with the first class. Furthermore, we found a region of higher conservation common to both domain classes, suggesting a new regulatory center. We discuss the influence of evolutionary forces on the development of the phosphatase domain, which has led to additional functions, such as the specific protection of phosphorylated tyrosine residues, substrate recruitment, and regulation of the catalytic activity of adjacent domains.
POSaM: a fast, flexible, open-source, inkjet oligonucleotide synthesizer and microarrayer
Authors: Christopher Lausted, Timothy Dahl, Charles Warren, Kimberly King, Kimberly Smith, Michael Johnson, Ramsey Saleem, John Aitchison, Lee Hood, Stephen R Lasky
Journal: Genome biology (2004)

DNA arrays are valuable tools in molecular biology laboratories. Their rapid acceptance was aided by the release of plans for a pin-spotting microarrayer by researchers at Stanford. Inkjet microarraying is a flexible, complementary technique that allows the synthesis of arrays of any oligonucleotide sequences de novo. We describe here an open-source inkjet arrayer capable of rapidly producing sets of unique 9,800-feature arrays.
STUDIES IN GLOMERULONEPHRITIS
Authors: Harold Kniest Faber
Journal: The Journal of Experimental Medicine (1917)

1. Rabbits in which a mild grade of glomerular damage has been produced by small doses of diphtheria toxin develop a severe glomerulonephritis corresponding to the extracapillary form described by Volhard and Fahr after inoculations with sublethal quantities of Bacillus coli. 2. Similar, though not completely identical lesions are produced when diphtheria toxin is followed by intravenous injections of Vaughan's split protein (poisonous part) of Bacillus coli. 3. The inference is drawn that under the experimental conditions described Bacillus coli undergoes bacteriolysis and produces glomerular lesions through the toxic groups contained within its protein molecule.
Narcolepsy and excessive daytime sleepiness
Authors: Adam Zeman, Tom Britton, Neil Douglas, Andrew Hansen, Jane Hicks, Robin Howard, Andrew Meredith, Ian Smith, Gregory Stores, Sue Wilson, Zenobia Zaiwalla
Journal: BMJ (2004)

Excessive daytime sleepiness is common,1 yet opportunities to learn about sleep medicine in medical school are rare; a survey in 1998 indicated that undergraduate courses devoted a median of five minutes to sleep and its disorders.2 In this review we provide an update on the biology, diagnosis, and management of narcolepsy—an important, yet often misdiagnosed, cause of sleepiness that has seen exciting recent advances. We also briefly outline the other principal causes of daytime sleepiness and aim to equip the general reader with a practical approach to the assessment of patients who complain of excessive daytime sleepiness.

This paper is based on a literature search conducted to produce evidence based guidelines on the diagnosis and management of narcolepsy in adults and children.3 We searched Medline, Embase, the Cochrane Collaboration, and two specialist sleep literature resources for abstracts with the key word “narcolepsy.” We read the full text of relevant papers and hand searched these for other relevant material. A multidisciplinary working party prepared the guidelines, and a group of 10 independent experts later reviewed them. These guidelines can be downloaded from the news section of http://www.sleeping.org.uk/ (accessed July 2004).

Narcolepsy is a chronic neurological disorder affecting sleep regulation and causing excessive sleepiness and, in most cases, cataplexy (brief attacks of weakness on emotional arousal).3 4 The excessive sleepiness of narcolepsy comprises both a background feeling of sleepiness present much of the time and a strong, sometime irresistible, urge to sleep recurring at intervals through the day. This desire is heightened by conducive, monotonous circumstances, but naps at inappropriate times—such as during meals—are characteristic. The naps of narcolepsy usually last from minutes to an hour and occur a few times each day. Cataplexy refers to partial or generalised, almost invariably bilateral, loss of skeletal muscle tone and …
Effect of Diet and Cold Exposure on Norepinephrine Turnover in Brown Adipose Tissue of the Rat
Authors: James B. Young, Elizabeth Saville, Nancy J. Rothwell, Michael J. Stock, Lewis Landsberg
Journal: Journal of Clinical Investigation (1982)

Brown adipose tissue (BAT) is an important site of adaptive changes in thermogenesis in the rat. The sympathetic nervous system, which richly supplies BAT, is thought to play an important role in the regulation of BAT thermogenesis because catecholamines stimulate and beta adrenergic blocking agents inhibit oxygen consumption in this tissue. The present studies were carried out to assess directly sympathetic activity in BAT in response to cold exposure and to changes in dietary intake, both of which alter heat production in the rat. Sympathetic activity was determined from the rate of norepinephrine (NE) turnover in interscapular brown adipose tissue (IBAT) after preliminary experiments validated the use of NE turnover techniques in IBAT. Acute exposure to 4°C increased NE turnover in IBAT 4- to 12-fold compared with ambient temperature controls, depending upon the interval over which the turnover measurement was made, while in the heart NE turnover doubled in response to the same cold stimulus. In animals exposed to cold continuously for 10 d before study, NE turnover measurements in IBAT and in the heart were elevated comparably to those obtained during acute exposure. Alterations in feeding were also associated with changes in NE turnover in IBAT. Fasting for 2 d decreased NE turnover in IBAT (-35% from 29.2±4.2 ng NE/h to 18.9±5.9) and in heart (-52%). In animals fed a “cafeteria” diet, a model of voluntary overfeeding in the rat, NE turnover was increased in both IBAT (+108% from 24.8±4.5 ng NE/h to 51.7±6.8) and heart (+66%). Because ganglionic blockade exerted a greater effect on NE turnover in IBAT in cafeteria-fed rats than in controls, the increase in NE turnover in IBAT with this overfeeding regimen reflects enhanced central sympathetic outflow. Thus NE turnover techniques can be satisfactorily applied to the assessment of sympathetic nervous system activity in IBAT.
Care-Related Distress: A Nationwide Study of Parents Who Lost Their Child to Cancer
Authors: Ulrika Kreicbergs, Unnur Valdimarsdóttir, Erik Onelöv, Olle Björk, Gunnar Steineck, Jan-Inge Henter
Journal: Journal of Clinical Oncology (2005)

Palliative care is an important part of cancer treatment. However, little is known about how care-related factors affect bereaved intimates in a long-term perspective. We conducted a population-based, nationwide study addressing this issue, focusing on potential care-related stressors in parents losing a child to cancer.In 2001, we attempted to contact all parents in Sweden who had lost a child to cancer in 1992 to 1997. The parents were asked, through an anonymous postal questionnaire, about their experience of the care given and to what extent these experiences still affect them today.Information was supplied by 449 (80%) of 561 eligible parents. Among 196 parents of children whose pain could not be relieved, 111 (57%) were still affected by it 4 to 9 years after bereavement. Among 138 parents reporting that the child had a difficult moment of death, 78 (57%) were still affected by it at follow-up. The probability of parents reporting that their child had a difficult moment of death was increased (relative risk = 1.4; 95% CI, 1.0 to 1.8) if staff were not present at the moment of death. Ten percent of the parents (25 of 251 parents) were not satisfied with the care given during the last month at a pediatric hematology/oncology center; the corresponding figure for care at other hospitals was 20% (33 of 168 parents; P = .0163).Physical pain and the moment of death are two important issues to address in end-of-life care of children with cancer in trying to reduce long-term distress in bereaved parents.
p53-Independent Negative Regulation of p21/Cyclin-Dependent Kinase–Interacting Protein 1 by the Sonic Hedgehog-Glioma-Associated Oncogene 1 Pathway in Gastric Carcinoma Cells
Authors: Miki Ohta, Keisuke Tateishi, Fumihiko Kanai, Hirotsugu Watabe, Shintaro Kondo, Bayasi Guleng, Yasuo Tanaka, Yoshinari Asaoka, Amarsanaa Jazag, Jun Imamura, Hideaki Ijichi, Tsuneo Ikenoue, Masataka Sata, Makoto Miyagishi, Kazunari Taira, Minoru Tada, Takao Kawabe, Masao Omata
Journal: Cancer Research (2005)

Abstract The activation of Hedgehog (Hh) signaling has been implicated in the growth of various tumor types, including gastric carcinoma. However, the precise mechanisms of Hh activation and suppression of tumor growth by the blockade of Hh signaling in gastric carcinoma cells remain unknown. The aim of this study was to elucidate the mechanism of abnormal Hh signaling and the key molecules contributing to dysregulated growth of gastric carcinoma. The Sonic hedgehog (Shh) ligand and its receptor Patched were expressed in all five gastric carcinoma cell lines examined (MKN1, MKN7, MKN45, MKN74, and AGS cells). The blockade of Hh signaling with anti-Shh antibody inhibited the growth of all five gastric carcinoma cell lines. Shh was overexpressed (mean, 12.8-fold) in 8 of 14 (57.0%) cancerous tissue samples from patients with gastric carcinoma as compared with expression in the surrounding noncancerous tissues. The disruption of glioma-associated oncogene 1 (Gli1) by small interfering RNA induced an increase in p21/cyclin-dependent kinase–interacting protein 1 (CIP1), interfered with the G1-S transition, and suppressed cell proliferation. The stimulation or inhibition of Hh signaling did not affect p53 activity and the induction of p21/CIP1 expression and the G1 arrest by inhibition of Hh signaling were not affected by the p53 status. These findings suggest that the overexpression of Shh contributes to constitutive Hh activation and that this signaling pathway negatively regulates p21/CIP1 through a Gli1-dependent and p53-independent mechanism in gastric carcinoma cells.
Decision Making in Adolescents With Behavior Disorders and Adults With Substance Abuse
Authors: Monique Ernst, Steven J. Grant, Edythe D. London, Carlo S. Contoreggi, Alane S. Kimes, Loretta Spurgeon
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: The study assessed the validity of the Gambling Task as a test of decision-making ability in adolescents and examined whether adolescents with behavior disorders, who are at risk for substance abuse, have deficits in decision making similar to those exhibited by adults with substance abuse. METHOD: Performance on the Gambling Task in two testing sessions separated by 1 week was assessed in 64 12–14-year-old adolescents (31 healthy, 33 with externalizing behavior disorders) and 52 adults (22 healthy, 30 with substance abuse). RESULTS: The healthy adolescents and the healthy adults had similar performance on the Gambling Task. Adolescents with behavior disorders performed more poorly than healthy adolescents, but only in the second testing session. In adults, overall Gambling Task performance did not differ between the healthy and substance abuse groups at either testing session, indicating no difference in learning of decision-making strategies between groups. However, adults with substance abuse performed more poorly than healthy adults during an early stage of the task, when participants presumably begin to understand the rewards and penalties involved in the task but are not yet sure of the actual risk of incurring penalities. CONCLUSIONS: The Gambling Task can be used with adolescents. Testing with the Gambling Task revealed a deficit in decision making in adolescents with behavior disorders, who are at risk for substance abuse. This deficit may represent a vulnerability factor for the development of substance abuse.
Myocardial ischaemia and the cardiac nervous system
Authors: J Armour
Journal: Cardiovascular Research (1999)

The intrinsic cardiac nervous system has been classically considered to contain only parasympathetic efferent postganglionic neurones which receive inputs from medullary parasympathetic efferent preganglionic neurones. In such a view, intrinsic cardiac ganglia act as simple relay stations of parasympathetic efferent neuronal input to the heart, the major autonomic control of the heart purported to reside solely in the brainstem and spinal cord. Data collected over the past two decades indicate that processing occurs within the mammalian intrinsic cardiac nervous system which involves afferent neurones, local circuit neurones (interconnecting neurones) as well as both sympathetic and parasympathetic efferent postganglionic neurones. As such, intrinsic cardiac ganglionic interactions represent the organ component of the hierarchy of intrathoracic nested feedback control loops which provide rapid and appropriate reflex coordination of efferent autonomic neuronal outflow to the heart. In such a concept, the intrinsic cardiac nervous system acts as a distributive processor, integrating parasympathetic and sympathetic efferent centrifugal information to the heart in addition to centripetal information arising from cardiac sensory neurites. A number of neurochemicals have been shown to influence the interneuronal interactions which occur within the intrathoracic cardiac nervous system. For instance, pharmacological interventions that modify β-adrenergic or angiotensin II receptors affect cardiomyocyte function not only directly, but indirectly by influencing the capacity of intrathoracic neurones to regulate cardiomyocytes. Thus, current pharmacological management of heart disease may influence cardiomyocyte function directly as well as indirectly secondary to modifying the cardiac nervous system. This review presents a brief summary of developing concepts about the role of the cardiac nervous system in regulating the normal heart. In addition, it provides some tentative ideas concerning the importance of this nervous system in cardiac disease states with a view to stimulating further interest in neural control of the heart so that appropriate neurocardiological strategies can be devised for the management of heart disease.
Biology of language: Principle predictions and evidence
Authors: Friedemann Pulvermüller, Bettina Mohr, Hubert Preissl
Journal: Behavioral and Brain Sciences (1996)

Abstract Müller's target article aims to summarize approaches to the question of how language elements (phonemes, morphemes, etc.) and rules are laid down in the brain. However, it suffers from being too vague about basic assumptions and empirical predictions of neurobiological models, and the empirical evidence available to test the models is not appropriately evaluated. (1) In a neuroscientific model of language, different cortical localizations of words can only be based on biological principles. These need to be made explicit. (2) Evidence for and against word class differences could be evaluated more rigorously. (3) All (and only) humans are able to learn languages with complex syntactic structures; it is, therefore, not appropriate to deny innateness and universality of syntactic principles. The real question appears to be the following: Which neurobiological principles are the linguistic principles based on?