tbuckley/cabot-search huggingface dataset:
Abstract LB-326: Structural basis of lipid-binding and regulation in PI3Kα
Authors: Michelle S. Miller, Oleg Schmidt-Kittler, David M. Bolduc, Evan T. Brower, Daniele Chaves-Moreira, Marc Allaire, Kenneth W. Kinzler, Ian G. Jennings, Philip E. Thompson, Philip A. Cole, L. Mario Amzel, Bert Vogelstein, Sandra B. Gabelli
Journal: Cancer Research (2014)

Abstract PI3Kα is a well-established target for the development of novel cancer therapeutics. Currently, all inhibitors in clinical trials target the highly conserved ATP-binding site, which has made the development of PI3K selective inhibitors difficult, with many inhibitors displaying cross-reactivity against protein kinases. We have used X-ray crystallography and fluorescence quenching studies to characterize the lipid-binding site of PI3Kα and the structural basis of regulation by nSH2. A newly determined p110α/niSH2 crystal structure is the first to reveal the nSH2 domain in complex with wild-type p110α, allowing investigation of the mechanisms of nSH2 regulation. Key interactions between the nSH2 domain and the activation loop suggest a mechanism by which the kinase domain is kept in an inactive conformation until activation by phosphopeptide binding. Key differences in nSH2 domain binding to p110α were identified between the wild-type and oncogenic mutant, p110αH1047R. Increased buried surface area and two unique salt-bridges are suggestive of tighter regulatory control in the wild-type PI3Kα compared with the oncogenic mutant. A second structure reveals the details of PI3K binding to a lipid substrate mimetic, diC4-PIP2. Unexpectedly, we found an additional lipid-binding site, and this striking observation was confirmed by fluorescence quenching experiments. The identification of multiple lipid binding sites provides additional targets that may enable more selective inhibition among the various isoforms, or even between mutant and wild-type forms of PI3Kα. Citation Format: Michelle S. Miller, Oleg Schmidt-Kittler, David M. Bolduc, Evan T. Brower, Daniele Chaves-Moreira, Marc Allaire, Kenneth W. Kinzler, Ian G. Jennings, Philip E. Thompson, Philip A. Cole, L. Mario Amzel, Bert Vogelstein, Sandra B. Gabelli. Structural basis of lipid-binding and regulation in PI3Kα. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-326. doi:10.1158/1538-7445.AM2014-LB-326
A Piece of My Mind
Authors: Stuart N. Speer
Journal: JAMA (1993)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Safety and efficacy of nimodipine in resuscitation of patients outside hospital.
Authors: R O Roine, M Kaste, A Kinnunen, P Nikki
Journal: BMJ (1987)

Safety and efficacy of nimodipine in resuscitation of patients outside hospitalThe extent of brain injury after cardiac arrest depends not only on the duration of the arrest but also on the time taken until the circulation is fully restored.Postischaemic hypoperfusion may contribute to brain damage after cerebral ischaemia,' and there is no treatment to protect the brain against anoxic-ischaemic injury.Outcome in patiens resuscitated after cardiac arrest outside hospital Group treated with nimodipine Controls
Ventricular tachycardia after in vivo DC shock ablation in dogs. Electrophysiologic and histologic correlation.
Authors: R N Hauer, J M de Bakker, A A de Wilde, W Straks, J T Vermeulen, M J Janse
Journal: Circulation (1991)

BACKGROUND DC shock catheter ablation for the treatment of ventricular tachycardia (VT) may induce VT episodes that disappear within days. METHODS AND RESULTS A 30-J cathodal shock was delivered to the endocardial left ventricular wall in 15 closed-chest dogs. All dogs had VT during the first day after ablation. Eleven of these dogs were studied on the first day. Extensive epicardial and endocardial activation mapping in vivo, in Langendorff-perfused hearts, and in tissue blocks in a tissue bath localized the site of origin of VT to subendocardial Purkinje fibers in a border zone surrounding the central necrotic ablation lesion. Intracellular recording showed that this zone consisted of a subendocardial superficial layer (SSL) of cells with abnormal characteristics, a resting membrane potential (RMP) of -58 +/- 11 mV (mean +/- SD), and an action potential amplitude (APA) of 61 +/- 20 mV. In addition, the steepness of phase 0 of the action potential was markedly reduced. In three dogs abnormal automaticity was found in a very small area. Immediately below the SSL, cells were normal with an RMP of -78 +/- 5 mV and an APA of 107 +/- 8 mV. Histology confirmed a thin SSL with edematous and necrotic cells, hemorrhage, and infiltration. The other four dogs were studied at 1 week after ablation when VT was absent. Microelectrode impalement in the SSL was either impossible or showed nearly normal action potential characteristics. Histological examination showed a markedly thickened fibrotic subendocardial layer at places where impalement was impossible. Normal subendocardium was found in other areas of the border zone. CONCLUSIONS Our results indicate that VT after DC shock ablation originates from cells with abnormal automaticity in the superficial subendocardial border zone around the central ablation lesion. Within 1 week edematous and necrotic cells in this border zone are replaced by a fibrotic layer, and this transition is associated with the disappearance of VT.
On the Detection and Treatment of Foreign Bodies in the Bladder: With Remarks on the Use of the Endoscope
Authors: E. Lund
Journal: BMJ (1869)

knowledge, might have been predicated; viz., that a larger proportion of these diseases terminate in health under restorative treatment than under depleting remedies.The propriety of the substitution of food and moderate quantities of stimulants, as routine practice, for the lancet, rests on the firm basis ofresults; and this firm basis is established with- out regard to the answer that may be given by science to the question, * Too narrow a limit must not be given to the twenty-five years, as the writer intended rather to fix a time within which the illustrations given had become part of the stock knowledge of the profession, than fix with accuracy dates when each fact was published by its discoverer.
Cloning pioneer denies intentionally falsifying results
Authors: Jane Parry
Journal: BMJ (2006)

Disgraced Korean stem cell researcher Professor Hwang Woo-suk has apologised to the Korean people after a report by an investigating committee at Seoul National University into his work concluded that two landmark stem cell papers were based on faked data.

He denied, however, that he intentionally falsified the research and said that given six more months and a supply of human ova he could produce tailored embryonic stem cells.

On 11 January Professor Hwang appeared in public for the first time since his resignation on 23 December from his post as professor of the college of veterinary medicine at Seoul National University. “I ask …
Geriatric Conditions and Disability: The Health and Retirement Study
Authors: Christine T. Cigolle, Kenneth M. Langa, Mohammed U. Kabeto, Zhiyi Tian, Caroline S. Blaum
Journal: Annals of Internal Medicine (2007)

Background: Geriatric conditions, such as incontinence and falling, are not part of the traditional disease model of medicine and may be overlooked in the care of older adults. The prevalence of geriatric conditions and their effect on health and disability in older adults has not been investigated in population-based samples. Objective: To investigate the prevalence of geriatric conditions and their association with dependency in activities of daily living by using nationally representative data. Design: Cross-sectional analysis. Setting: Health and Retirement Study survey administered in 2000. Participants: Adults age 65 years or older (n = 11 093, representing 34.5 million older Americans) living in the community and in nursing homes. Measurements: Geriatric conditions (cognitive impairment, falls, incontinence, low body mass index, dizziness, vision impairment, hearing impairment) and dependency in activities of daily living (bathing, dressing, eating, transferring, toileting). Results: Of adults age 65 years or older, 49.9% had 1 or more geriatric conditions. Some conditions were as prevalent as common chronic diseases, such as heart disease and diabetes. The association between geriatric conditions and dependency in activities of daily living was strong and significant, even after adjustment for demographic characteristics and chronic diseases (adjusted risk ratio, 2.1 [95% CI, 1.9 to 2.4] for 1 geriatric condition, 3.6 [CI, 3.1 to 4.1] for 2 conditions, and 6.6 [CI, 5.6 to 7.6] for ≥3 conditions). Limitations: The study was cross-sectional and based on self-reported data. Because measures were limited by the survey questions, important conditions, such as delirium and frailty, were not assessed. Survival biases may influence the estimates. Conclusions: Geriatric conditions are similar in prevalence to chronic diseases in older adults and in some cases are as strongly associated with disability. The findings suggest that geriatric conditions, although not a target of current models of health care, are important to the health and function of older adults and should be addressed in their care.
Diseases of the Newborn
Authors: Lewis A. Leavitt
Journal: JAMA (1972)

Since its initial publication 11 years ago, Schaffer's<i>Diseases of the Newborn</i>has been a standard reference for physicians working in the nursery. Its success depended on a highly readable exposition coupled with extensive practical comments from the author's personal experience. Those familiar with its predecessors will find the third edition more current in information but unchanged in style and format. Dr. Mary Ellen Avery joins Dr. Schaffer as coauthor of this edition. The book is a comprehensive compendium of newborn diseases arranged by organ system. Pertinent and instructive photographs and illustrations are widely used. Well-described case histories add depth to the presentation of clinical entities. Written for the physician who wants practical, diagnosis-and-treatment-oriented information, the authors emphasize clinical signs and symptoms, and differential diagnosis. Discussion of pathophysiology is short but to the point. An up-to-date list of references follows each chapter. There are helpful appendices which include outlined procedures
Increased Adhesiveness of Isolated Monocytes to Endothelium Is Prevented by Vitamin C Intake in Smokers
Authors: Christian Weber, Wolfgang Erl, Kim Weber, Peter C. Weber
Journal: Circulation (1996)

Background To explore pathophysiological mechanisms of cigarette smoking involved in atherogenesis, we compared adhesiveness of isolated blood monocytes with endothelium and plasma levels of the aqueous phase antioxidant vitamin C in nonsmokers and smokers before and after supplementation, using a novel monocyte adhesion assay with fixed human endothelial cells. Methods and Results Monocyte adhesion to unstimulated human umbilical vein endothelial cells ranged from 0.17% to 0.51% in the nonsmoker group (0.37±0.09%, mean±SD, n=13). In smokers with a 1 to 2 packs per day consumption, monocyte adhesion was increased to 0.71±0.17% (mean±SD, n=10, P &lt;.001), ranging from 0.46% to 0.99%. Increased adhesiveness was mediated by the integrin CD11b/CD18, as shown by inhibition with a monoclonal antibody to CD11b but not associated with altered CD11b surface expression. Plasma vitamin C levels were reduced in smokers (48.2±14.1 μmol/L) versus nonsmokers (67.7±17.6 μmol/L; P &lt;.025), while no significant differences were found in retinol, vitamin E, or β-carotene levels. This confirms that the radical scavenger vitamin C reacts sensitively to oxidative stress induced by cigarette smoke in human plasma. Consistently, dietary supplementation with vitamin C (2 g per day) for 10 days raised plasma levels to 82.6±11.0 μmol/L (n=10, P &lt;.001) in smokers and decreased monocyte adhesion to values found in nonsmokers (0.38±0.18%, P &lt;.001). In contrast, vitamin C intake did not affect monocyte adhesiveness in nonsmokers (0.37±0.14%, n=6) despite increasing plasma levels to 82.9±11.8 μmol/L. Conclusions Our data show that cigarette smoking increases CD11b-dependent monocyte adhesiveness in humans. Restoring reduced plasma vitamin C concentrations in smokers by oral supplementation decreased monocyte adhesion to values found in nonsmokers.
Human immunodeficiency virus 1. Predominance of a group-specific neutralizing epitope that persists despite genetic variation.
Authors: I Berkower, G E Smith, C Giri, D Murphy
Journal: The Journal of Experimental Medicine (1989)

HIV-1 is known to show a high degree of genetic diversity, which may have major implications for disease pathogenesis and prevention. If every divergent isolate represented a distinct serotype, then effective vaccination might be impossible. However, using a sensitive new plaque-forming assay for HIV-1, we have found that most infected patients make neutralizing antibodies, predominantly to a group-specific epitope shared among three highly divergent isolates. This epitope persists among divergent isolates and rarely mutates, despite the rapid overall mutation rate of HIV-1, suggesting that it may participate in an essential viral function. These findings, plus the rarity of reinfections among these patients, suggest that HIV-1 may be more susceptible to a vaccine strategy based on a group-specific neutralizing epitope than was previously suspected.
CEREBROSPINAL MENINGITIS IN NEW YORK CITY DURING 1904 AND 1905.
Authors: J. S. BILLINGS
Journal: JAMA (1906)

During the past forty years there have been four outbreaks of epidemic cerebrospinal meningitis in New York City. The first and, up to that of 1904 and 1905, the most severe epidemic was in 1872, when there were 782 deaths—a death rate of 8.70 per 10,000. In 1881 and 1893 the outbreaks were not so severe; the number of deaths were, respectively, 461 and 469, and the death rates 3.70 and 2.67. The latest epidemic, the severest in the history of the city, began in the early months of 1904 and continued through 1905. During 1904 there were 1,083 deaths and a death rate of 4.6; during 1905, 1,511 deaths and a death rate of 6.3. The winters of 1872, 1881, 1893 and 1904 were what are known as "hard winters;" being cold, with considerable snow. The disease has always been abnormally prevalent for a year or two after each
Evolution of Genomic Diversity in the Breast Cancer Cell Line MCF-7.
Authors: P. den Hollander, I. Osadchey, O. Hampton, O. Hampton, C. Coarfa, A. Milosavljevic, A. Milosavljevic, A. Lee
Journal: Cancer Research (2009)

Abstract Background: Tumors arise from an accumulation of genetic changes via a multi-step process. Genetic rearrangements can potentially lead to fusions with consequent deregulation of a gene, or the generation of new genes (through the fusion of two genes) that maybe functionally important in tumor development and progression. Our knowledge of rearrangements in solid tumors is limited and it is likely that solid tumors are defined by fusion genes that are not yet discovered. We recently reported 157 genomic breakpoints that were identified in a BAC library generated from MCF-7 cells (termed MCF-7/BAC), and could be confirmed by PCR across breakpoint joins as likely somatic mutations. To gain insight into the heterogeneity of genomic breakpoints in breast cancer cell lines, we studied these 157 validated breakpoints in a two common MCF-7 sublines.Methods: DNA was isolated from MCF-7/ATCC and MCF-7/B and genomic breakpoints were amplified by PCR and visualized by gel electrophoresis. Breakpoints were called present or absent based upon amplification of a product at the predicted size. By mapping the breakpoints to specific stages in the evolution of MCF-7 we reconstructed the sequence of chromosomal rearrangement events in the cancer genomesResults: MCF-7/B harbored only 91 of the breakpoints from the original 157 identified from MCF-7/BAC, and MCF-7/ATCC only shared 40. MCF-7 had 3 breakpoints that were found in MCF-7/BAC but not in MCF-7/B. Thus, of the original 157 breakpoints, 37 (23.6%) were shared all three sublines. MCF-7/ATCC contained the least breakpoints, which might indicate that MCF-7/ATCC is ancestral to MCF-7/B and MCF-7/BAC. Consistent with this, of the 157 genomic breakpoints in MCF-7/BAC, 50.3% contained genes, while this was enriched in the MCF-7/ATCC to 72.5%. Interestingly, two breakpoints involving genes in double strand break repair are retained in all three sublines, indicating that these breakpoints might originate from an ancestral cell line, and that deficient double strand break repair might be the underlying cause of genomic instability in these cell lines.Discussion: These preliminary results imply that MCF-7/ATCC maybe ancestral to other MCF-7 sublines. We are now expanding our data set with six other MCF-7 sublines to reconstruct the phylogeny of this breast cancer cell lines. With this information we may get a better understanding of the evolution and heterogeneity of genomic instability and rearrangements in breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3171.
Impact of organochlorine contamination on levels of sex hormones and external morphology of common snapping turtles (Chelydra serpentina serpentina) in Ontario, Canada.
Authors: S R de Solla, C A Bishop, G Van der Kraak, R J Brooks
Journal: Environmental Health Perspectives (1998)

Recent research has suggested that contaminants in the environment may influence sex differentiation and reproductive endocrine function in wildlife. Concentrations of organochlorine contaminants (total polychlorinated biphenyls, pesticides) were higher in the blood plasma of snapping turtles from contaminated sites than in those from reference sites. The ratio of the precloacal length to the posterior lobe of the plastron (PPR) is sexually dimorphic in snapping turtles. There were significant reductions in the PPR at three contaminated sites versus two reference sites. The magnitude of the response was such that a significantly higher proportion of PPRs of males from a contaminated site (Cootes Paradise) overlapped with those of females than PPRs of males from a reference site (Lake Sasajewun). Observers can incorrectly identify the sex of turtles at the contaminated site based on secondary sexual characteristics alone. Unlike the changes to the morphology, there were few changes in 17 beta-estradiol or testosterone levels, and where differences occurred, there was more variation among reference sites than between the reference and contaminated sites. Our results suggest that environmental contaminants may affect sexually dimorphic morphology in snapping turtles without affecting circulating testosterone or estrogen levels in the adults.
STUDIES ON REGENERATION OF BACTERIOPHAGE
Authors: Gregory Shwartzman
Journal: The Journal of Experimental Medicine (1926)

The investigations of the influence of oxygen on the bacteriophage phenomenon recorded in this paper show that this factor plays an important role which is due exclusively to its ability to induce certain changes in the behavior of bacterial cells towards lytic principle. At certain H ion concentrations both aerobic and anaerobic cultures can be made resistant in the absence of lytic principle. The resistance thus acquired is of a stable nature under suitable conditions. If the lytic principle is added to aerobic or anaerobic types of resistant strains the cultures are able to regenerate it to a certain extent. However they do not undergo any visible lysis themselves even under the action of lytic principles which were passed through several generations of these types. The principles regenerated by both types of resistant cultures are identical in action with each other as well as with the stock lytic principle. These experiments suggest a new method of investigation into the hitherto unexplained nature of resistance of bacteria towards bacteriophage.
Acute failure of artificial heart valves.
Authors: K. Taylor
Journal: BMJ (1988)

mg).A recent trial of short term use in patients who have had acute myocardial infarctions has shown that 160 mg aspirin daily reduces mortality after five weeks by a fifth.9Despite the lack of evidence from clinical trials many patients with transient ischaemic attack and stroke are treated with 75 mg daily (a dose enshrined in the current British National Formulary), with the risk that they may be receiving an inadequate dose, albeit a safe one.On the basis of properly conducted clinical trials patients with transient ischaemic attacks and minor ischaemic strokes and no previous problems of peptic ulceration should be treated with 300 mg aspirin daily.The dose may be reduced to 150 mg and then 75 mg if I Antiplatelet Trialists' Collaboration.Secondary prevention of vascular disease by prolonged antiplatelet treatment.
SOME OF THE CAUSES OF THERAPEUTIC UNCERTAINTY IN THE TREATMENT OF CHILDREN.Read in the Section on Diseases of Children at the Forty-fifth Annual Meeting of the American Medical Association, held at San Francisco, June 5-8, 1894.
Authors: A. C. COTTON
Journal: JAMA (1894)

The limited time for the presentation of this subject prevents more than passing mention of a few of the many causes that tend to increase the uncertainty of our results in the treatment of sick children. One frequent cause of failure, faulty diagnosis, whether due to a lack of appreciation of the physiologic peculiarities incident to this stage of development, or to insufficient care in ascertaining the pathologic condition and history, we will dismiss with the mere mention; and, although in the practice of medicine, two negatives<i>may</i>make an affirmative, we will relegate the use of wrong remedial agents to the company of wrong diagnoses. A most common cause of therapeutic uncertainties is our forgetfulness of the difference between the actions of remedies in infant and adult organisms; or rather, shall I say, because we have never learned those physiologic actions in children. As students of materia medica we