tbuckley/cabot-search huggingface dataset:
Abstract LB-487: Pim protein kinase inhibitors induce the unfolded protein response and sensitize prostate cancer cells to killing by ABT-737-mediated apoptosis
Authors: Jin H. Song, Andrew S. Kraft
Journal: Cancer Research (2012)

Abstract Pim serine/threonine kinases contribute to prostate tumorigenesis and therapeutic resistance, yet anticancer efficacy of Pim kinase inhibitors on prostate cancer is unknown. We demonstrate for the first time that a genetically engineered decrease in Pim kinase levels or the addition of Pim kinase small molecule inhibitors (e.g. SMI-4a) to human prostate cancer cells, including LNCaP and PC-3, causes ER stress and activates the unfolded protein response (UPR) stimulating increases in eIF-2α phosphorylation, ATF-4, CHOP proteins, and cleavage of XBP-1. Because (1) Bcl-2 family proteins reside on the ER lumen and play an important role in regulation of XBP-1 splicing, (2) Bcl-2 family members are over expressed in prostate cancer to enhance Pim kinase anti-cancer activity, and (3) Pim kinase inhibitors decrease Mcl-1 and increase Noxa protein, we treated prostate cancer cell lines with SMI-4a plus the Bcl-2 family antagonist ABT-737, a small molecule antagonist of Bcl-2 family members. Strikingly, the addition of ABT-737 to Pim inhibitors triggered a robust apoptosis of prostate cancer cells in vitro and in vivo. Pim inhibitors decreased levels of the Bcl-2 family member Mcl-1, both by blocking 5′-cap dependent translation and decreasing protein half life. Additionally, Pim inhibition transcriptionally increased levels of the BH3 protein Noxa by activating the UPR, lead to eIF2α phosphorylation and increased expression of CHOP. Increased levels of Noxa also inactivated the remaining levels of Mcl-1 protein activity. Notably, these specific protein changes were essential to the apoptotic process because ABT-737 did not inhibit Mcl-1 protein activity and Mcl-1 overexpression blocked the apoptotic activity of ABT-737. We find that the Pim kinase inhibitors and ABT-737 are highly synergistic in killing prostate cancer both in vitro and when used together in a subcutaneous animal model of prostate cancer therapy. Our results therefore suggest that this combination treatment could be developed as a potential therapy for human prostate cancer where overexpression of Pim kinases and antiapoptotic Bcl-2 family members drives tumor cell resistance to current anticancer therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-487. doi:1538-7445.AM2012-LB-487
Serial liver biopsy findings in methotrexate-treated psoriasis
Authors: A.P. Warin, J.W. Landells, G.M. Levene, H. Baker
Journal: British Journal of Dermatology (1974)

Journal Article Serial liver biopsy findings in methotrexate‐treated psoriasis Get access A.P. Warin, A.P. Warin The London Hospital, and St John's Hospital for Diseases of the skin, London Search for other works by this author on: Oxford Academic Google Scholar J.W. Landells, J.W. Landells The London Hospital, and St John's Hospital for Diseases of the skin, London Search for other works by this author on: Oxford Academic Google Scholar G.M. Levene, G.M. Levene The London Hospital, and St John's Hospital for Diseases of the skin, London Search for other works by this author on: Oxford Academic Google Scholar H. Baker H. Baker The London Hospital, and St John's Hospital for Diseases of the skin, London Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 91, Issue s10, 1 July 1974, Pages 15–17, https://doi.org/10.1111/j.1365-2133.1974.tb12477.x Published: 01 July 1974
An intronic mutation in a lariat branchpoint sequence is a direct cause of an inherited human disorder (fish-eye disease).
Authors: J A Kuivenhoven, H Weibusch, P H Pritchard, H Funke, R Benne, G Assmann, J J Kastelein
Journal: Journal of Clinical Investigation (1996)

The first step in the splicing of an intron from nuclear precursors of mRNA results in the formation of a lariat structure. A distinct intronic nucleotide sequence, known as the branchpoint region, plays a central role in this process. We here describe a point mutation in such a sequence. Three sisters were shown to suffer from fish-eye disease (FED), a disorder which is caused by mutations in the gene coding for lecithin:cholesterol acyltransferase (LCAT). Sequencing of the LCAT gene of all three probands revealed compound heterozygosity for a missense mutation in exon 4 which is reported to underlie the FED phenotype, and a point mutation located in intron 4 (IVS4:T-22C). By performing in vitro expression of LCAT minigenes and reverse transcriptase PCR on mRNA isolated from leukocytes of the patient, this gene defect was shown to cause a null allele as the result of complete intron retention. In conclusion, we demonstrated that a point mutation in a lariat branchpoint consensus sequence causes a null allele in a patient with FED. In addition, our finding illustrates the importance of this sequence for normal human mRNA processing. Finally, this report provides a widely applicable strategy which ensures fast and effective screening for intronic defects that underlie differential gene expression.
Carcinogenicity studies of Estonian oil shale soots.
Authors: A I Võsamäe
Journal: Environmental Health Perspectives (1979)

Several series of chronic experiments in white mice and white rats were carried out in order to determine the carcinogenicity of Estonian oil shale soot as well as the soot from oil shale fuel oil. All the investigated samples of soot showed a relatively low (from 14 to 1200 ppm) benzo(a)pyrene content. The benzene extract of oil shale soot, painted on the skin of white mice, proved to be strongly carcinogenic: in most of the animals skin tumors developed. The benzene extract of shale fuel oil exerted a considerably weaker carcinogenic action than the extract of soot of solid shale. The effect of oil shale soots as well as of tars extracted from oil shale soot on the bronchial mucosa and lung respiratory tissue was studied in white rats. Lung tumors were induced in a considerable number of cases in a series of experiments, where the tarry material from solid fuel soot, containing 1070 ppm benzo(a)pyrene, as a suspension in an aqueous solution of Tween 40, was administered by repeated intratracheal instillation. Lung tumor incidence among various control and experimental groups of rats is presented. The peculiarities of oil shale combustion are described.
So nearly a disaster
Authors: T R Wiggin
Journal: BMJ (1994)

My African houseboy, Linus, and I were due some annual leave, and what better place to go than the number one tourist spot in Cameroon - Kribi- “on-sea.” My sister in law had thoughtfully sent us both new swimming trunks so that we would be well dressed for the beach, and we had been practising for the rigours of the ocean by swimming regularly in the numerous rivers that flow through the hills and grasslands of the north west province, where we work.

Kribi was all we had heard it to be. Hot sun, cool breezes, golden sands, swaying palm trees, tarred roads to get there - a complete difference from the quagmire tracks we were used to. It did not take us long to find our digs and get down to the beach for Linus's first Atlantic swim.

The beach was packed with local people, enjoying cooling off after a busy day at the Kribi harbour and market, making for a tremendous community atmosphere with all the laughing and shouting, splashing and other tomfoolery that goes with the seaside. The sea was perfect: waves just strong enough to ride in up the beach, but never too high, and with no undercurrent to pull you down. Linus stuck to our rule of always keeping the water lower than his chest.

So went the first two days of our holiday. Swimming, relaxing, and investigating the many rock pools; …
Therapeutic Dilemma for Restless Legs Syndrome
Authors: Sudhansu Chokroverty
Journal: New England Journal of Medicine (2014)

Since the tantalizing description by Willis in 1672 and the modern exposition by Ekbom in 1945,1 we have enhanced our understanding of the common yet uncommonly recognized entity of restless legs syndrome (RLS). RLS is a sensorimotor neurologic disorder with an unknown natural history that profoundly disturbs sleep and quality of life. The condition was not viewed as a true disease by some until 2011, when it was renamed Willis–Ekbom disease. Four essential diagnostic criteria have been established: the urge to move the legs (with or without uncomfortable leg sensations), beginning or worsening of symptoms during quiescence, relief on moving . . .
The Cystic Fibrosis Transmembrane Conductance Regulator Gene
Authors: Lap-Chee Tsui
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Since identification of the gene responsible for cystic fibrosis (CF) in 1989, significant progess has been made in elucidating the mutational basis for this severe, autosomal recessive disease. Such advances have been of major importance in furthering our understanding of the basic defect in CF. Studies of the protein product of the CF gene, referred to as the CF transmembrane conductance regulator (CFTR), indicate that the protein is a Cl− channel but may have additional functions. The most common mutation of the CF gene (ΔF508), which leads to the deletion of a single amino acid on the protein molecule, occurs in approximately 70% of CF chromosomes, but the CF Genetic Analysis Consortium has documented over 300 other sequence alterations of the CF gene. In addition to single amino acid deletions, other types of mutations include missense, nonsense (stop codon), frameshift, and splice-junction mutations. Studies of potential correspondences among these different mutational types and predicted functional domains of the CFTR molecule may provide important clues to the physiologic role of normal CFTR and how a defective protein might lead to the CF phenotype. Analyses of genotype-phenotype relationships have shown strong correlations between particular mutations and pancreatic function. However, associations between genotype and severity of CF pulmonary disease are not clear-cut, suggesting that the pulmonary phenotype is strongly influenced by other genetic or environmental factors.
Therapeutic Endoscopic Retrograde Cholangiopancreatography without Fluoroscopy in Four Critically Ill Patients Using Wire-Guided Intraductal Ultrasound
Authors: S. Stavropoulos, A. Larghi, E. Verna, P. Stevens
Journal: Endoscopy (2005)

Emergent endoscopic retrograde cholangiopancreatography cannot be performed at the bedside in critically ill patients in an intensive care unit because of the requirement for fluoroscopy. Moving such patients to a safe location where fluoroscopy is available can pose practical problems, and can lead to delayed intervention, which may adversely affect the outcome. We report the use of intraductal ultrasound to facilitate therapeutic biliary interventions in four critically ill patients in an intensive care unit. Cannulation was performed endoscopically at the bedside using a sphincterotome and a guide wire. Intraductal ultrasound, rather than fluoroscopy, was then used to confirm the location of the wire within the common bile duct prior to performing endoscopic sphincterotomy or stent placement. This technique was successful in all four patients.
IS THE HUMAN PERSONALITY MORE PLASTIC IN INFANCY AND CHILDHOOD?
Authors: IAN STEVENSON
Journal: American Journal of Psychiatry (1957)

The article reviews data, much of rather recent origin, bearing on the assumption that human personality is more plastic in infancy and childhood than in adulthood. The available data permit the following conclusions: l. We have no compelling evidence of a predictable relationship between child training practices and later personality. 2. Severe psychological stresses can have as marked effects in adulthood as in infancy and childhood, sometimes having greater effects in adulthood than in childhood. 3. Important personality changes occur after childhood (in the absence of treatment) including the disappearance of marked psychological disorders. 4. Infants reared according to ostensibly ideal methods of infant care show no greater immunity to mental illness than do other children reared differently. Infants reared under apparently inadequate or harmful circumstances do not necessarily develop psychological disorders. 5. Resemblances between patterns of behavior in children and adults can be explained without the hypothesis of a special impressionability or vulnerability of personality in childhood. 6. The initial immobility and the prolonged physical dependency of children upon adults places them at a special disadvantage in that they cannot readily change their environments to obtain new experiences. A lack of new experiences may give to the personality a pattern which appears more fixed than it really is. The assumption that the human personality is more plastic in infancy and childhood than in adulthood remains unproven. Neither is it disproven. We need much further research in this area and this research may eventually show that the human personality is more plastic during childhood in some respects, but not in others.
The function and representation of concepts
Authors: Sangeet S. Khemlani, Geoffrey Goodwin
Journal: Behavioral and Brain Sciences (2010)

Machery has usefully organized the vast heterogeneity in conceptual representation. However, we believe his argument is too narrow in tacitly assuming that concepts are comprised of only prototypes, exemplars, and theories, and also that its eliminative aspect is too strong. We examine two exceptions to Machery's representational taxonomy before considering whether doing without concepts is a good idea.
NATURE AND TREATMENT OF PSYCHIC AND EMOTIONAL FACTORS IN DISEASE
Authors: J. RAMSAY HUNT
Journal: JAMA (1927)

In the practice of medicine and the management of the various complex situations which arise, all will agree that the psychologic aspects of each case should receive serious consideration. Not only are psychic factors important from the standpoint of etiology and diagnosis, but also they are often of the greatest value in determining treatment. Many disorders which affect human beings are purely psychogenic and respond only to psychologic treatment, while in many others emotional and psychic influences play an important role. Furthermore, it is the mind which bears the burden of every illness and directs the adjustment of the individual to pain, deformity and invalidism in all its various forms, so that any clinical method which ignores this master function of the body is gravely defective and may lead to serious error in interpretation and treatment.  ANATOMY OF NEURAL FUNCTION  The importance of mind in the sphere of medicine will
Improved Visual Evoked Potential Latencies In Poorly Controlled Diabetic Patients After Short-Term Strict Metabolic Control
Authors: Olivier Ziegler, Bruno Guerci, Michel Algan, Philippe Lonchamp, Michel Weber, Pierre Drouin
Journal: Diabetes Care (1994)

OBJECTIVE To determine whether short-term strict control of blood glucose can improve abnormal visual evoked potentials (VEPs) in poorly controlled diabetic patients with no overt diabetic complications. RESEARCH DESIGN AND METHODS VEPs (P100 wave latencies) were recorded in 12 poorly controlled diabetic patients (7 with insulin-dependent diabetes mellitus and 5 with non-insulin-dependent diabetes mellitus) before and after at least 3 days of near normoglycemia obtained by continuous subcutaneous insulin infusion (CSII). Exclusion criteria were overt diabetic neuropathy or retinopathy. The control subjects were 12 healthy subjects matched for age and sex. Fifty-two other subjects formed a reference control population. The intra-individual coefficient of variation for P100 latency was &amp;lt; 3%. RESULTS The P100 latencies were longer in diabetic patients than in control subjects (means of both eyes ± SD: 116.8 ± 10.1 vs. 106.2 ± 4.5 ms, P &amp;lt; 0.01), and 4 of the 12 diabetic patients had abnormal VEPs. After 3 days of close blood glucose control (mean blood glucose profile fell from 13.7 ± 2.2 mmol/l to 6.8 ± 1.2 mmol/l, P &amp;lt; 0.01), the mean P100 latencies were significantly shorter (112.5 ± 7.6 ms, P &amp;lt; 0.01) but were still significantly longer than control values. The longer the initial P100 latency, the greater the decrease after CSII. There was no correlation between the fall in blood glucose and improvement in VEPs. CONCLUSIONS Short-term blood glucose normalization is associated with improved P100 wave latency in uncomplicated diabetic patients. These data suggest that abnormal VEPs are partly reversible and include functional disturbances related to glucose metabolism.
Approaches to conflict resolution
Authors: Ewan W Anderson
Journal: BMJ (2005)

The potential for conflict is almost limitless, and it is impossible to prepare a recipe for resolution that will fit every occasion.Conflict may be on any scale from an individual to entire states; and no one can be an expert on all forms of conflict resolution.The most that can be asked is that aid workers have an awareness of the issues and can, if required, make some positive contribution to resolution.
Artificially Sweetened Beverages
Authors: David S. Ludwig
Journal: JAMA (2009)

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
Thrombomodulin and tissue factor pathway inhibitor levels as risk factors in patients with essential hypertension
Authors: Th.K. Makris, P.G. Krespi, G.P. Anastasiadis, T. Dodouras, P. Triposikiadis, A.N. Hatzizaharias, A. Perrakis, M.K. Kynakids
Journal: Journal of the American College of Cardiology (1998)
Prodromata of myocardial infarction and sudden death.
Authors: A A Alonzo, A B Simon, M Feinleib
Journal: Circulation (1975)

A sample of 160 hospitalized, acute myocardial infarction patients and 138 individuals who died prior to hospitalization from acute coronary heart disease were studied to determine the incidence and duration of prodromal symptoms and action taken to cope with the symptoms. Seventy percent of the in-hospital subsample (IHS) and 64% of the out-hospital subsample (OHS) reported prodromata. The OHS reported a significantly longer median duration of symptoms than the IHS (29 versus 10.5 days). Sixty-seven percent of the IHS reported new or accelerated anginal symptoms as the most frequently occurring symptom, in contrast to 35% for the OHS. Twenty-seven percent of the IHS and 36% of the OHS consulted a physician about symptoms. Individuals in both subgroups, especially chronically diseased patients, considered their symptoms manageable. Likewise, when contacted, their physicians may have viewed these symptoms as manageable. Patients with a high risk of myocardial infarction and sudden death were significantly more likely to have consulted physicians during the prodromal phase than low-risk patients. A clearly delineated prodromal syndrome is needed so that both lay and medical communities can effectively respond to and intervene during the prodromal phase of acute myocardial infarction and sudden cardiac death.
Abnormal Function of Endocrine Pancreas and Anterior Pituitary in Friedreich's Ataxia
Authors: THOMAS D. BIRD
Journal: Annals of Internal Medicine (1978)

A family had three siblings affected with classic Friedreich's ataxia. One sibling died at age 20 with fulminant diabetic ketoacidosis. The other two affected siblings are identical twin sisters without clinical diabetes but with an abnormality in the metabolism of exogenously administered glucose. These twins also have abnormal hypothalamic-pituitary control of prolactin and possibly of growth-hormone secretion. This study extends the previous reports of endocrine deficiencies associated with Friedreich's ataxia. The mechanisms underlying this association are undetermined but could represent pleiotropic effects of the Friedreich's ataxia gene or secondary manifestations of the primary central nervous system degeneration, or both.
Immunohistological and ultrastructural analysis of the intimal thickening in coarctation of human aorta
Authors: M Jimenez
Journal: Cardiovascular Research (1999)

Objectives: The histological nature and characteristics of aortic coarctation are not clearly defined, the aim of this study is to analyse intimal thickening in aortic coarctation. Methods: In order to characterize the components of intimal thickening in coarctation, narrowed segments of aorta obtained after surgery from ten children were examined immunocytochemically and by electron microscopy. Results: Histological analysis of aortic coarctation demonstrated a widened subendothelial region with separation of endothelial cells from the internal elastic lamina. Masson's trichrome staining showed a marked increase in extracellular matrix and cell numbers in the intimal thickening compared with normal aorta. Cellular component analysis demonstrated invagination of the intima by smooth muscle actin-positive cells, with a fragmentation of the internal elastic lamina. No proliferating smooth muscle and inflammatory cells were identified in the intima. In order to characterize the smooth muscle cell phenotypes, various smooth muscle cell markers were sought using specific monoclonal antibodies: α-smooth muscle actin, smooth muscle-myosin heavy chain, heavy caldesmon, desmin. In moderate coarcted aorta, at least two distinct smooth muscle phenotypes were identified. In the juxtamedial part of the intima smooth muscle, cells were differentiated and expressed all smooth muscle markers; in the subendothelial part of the intimal thickening, the majority of smooth muscle cells expressed only α-smooth muscle actin and appeared dedifferentiated. In regions of marked stenosis, a strong expression of smooth muscle-myosin heavy chain, and heavy caldesmon in the intimal thickening pointed to the presence of redifferentiated smooth muscle cells, not still expressing desmin. Electron microscopic examination also revealed a variety of smooth muscle cell phenotypes in the intimal thickening. In the superficial layer, smooth muscle cells appeared to be in the synthetic state, while in the deeper part, both synthetic and contractile components were identified. Conclusions: These observations indicated that human coarctation was characterized by intimal recruitment of non-proliferating smooth muscle cells with dedifferentiated phenotype. However, the presence of smooth muscle cells with an intermediate phenotype in the narrowest part of the coarctation suggest that the redifferentiation process could participate in the pathogenesis of aortic coarctation.