tbuckley/cabot-search huggingface dataset:
Abstract 3428: Genome-stabilizing functions of NM23 in metastatic melanoma
Authors: Stuart G. Jarrett, Marian Novak, Glenn Merlino, Andrzej Slominski, David M. Kaetzel
Journal: Cancer Research (2012)

Abstract The metastasis suppressor protein NM23-H1 exhibits two enzymatic activities in vitro with potential roles in the maintenance of genomic integrity: a nucleoside diphosphate kinase (NDPK) activity that maintains balance in nucleotide pools and a 3′-5′ exonuclease (3′-5′ EXO) activity that could provide proofreading during DNA repair and replication. Studies were conducted in cell culture and in vivo to determine the extent to which NM23-H1 expression contributes to maintenance of genomic integrity, as well as suppression of melanoma initiation and progression. Expression of NM23-H1, and possibly NM23-H2, was shown to be necessary for timely repair of UVR-induced (6-4) photoproducts (6-4PP) in melanoma cell lines, as well as in transgenic mouse-derived melanocytes and embryo fibroblasts, as determined by immunoslot-blot assay. NM23 protein expression also suppressed the incidence of both spontaneous and UVR-induced mutations as determined using the 6-thioguanine resistance colony-forming assay. Point mutations that either selectively or tandemly disrupted the NDPK and 3′-5′ EXO activities of NM23-H1 exhibited compromised DNA repair and mutation-suppressing activities, consistent with contributions of both enzymatic functions. UVR induced rapid (&amp;lt; 5 min) translocation of NM23-H1 to the nucleus, where it colocalized closely in concert with 6-4PPs, strongly suggesting direct participation in the repair of those lesions. Consistent with this proposed function, transgenic mice engineered to be hemizygous-null in expression of both NM23-M1 and NM23-M2 (the mouse homologs of NM23-H1 and NM23-H2, respectively) were rendered susceptible to UVR-induced melanoma and epithelioid follicular cyst formation. Moreover, this NM23-deficient genotype conferred an aggressively metastatic phenotype to the HGF-expressing transgenic mouse model of UVR-inducible melanoma. Metastasis of highly-pigmented cells to draining lymph nodes and the lungs was seen in most cases, with lesions also occasionally seen in liver, brain and bone. Taken together, these results demonstrate a critical role for NM23 proteins in DNA repair and suppressing mutations under basal and genotoxic conditions. Importantly, they highlight for the first time a tumor suppressor function in the context of UVR-induced melanoma in vivo, and suggest a novel metastasis suppressor activity through suppression of metastasis-driving mutations. 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 3428. doi:1538-7445.AM2012-3428
Vaccines and their real or perceived adverse effects
Authors: T O Jefferson, R. Rabinovich, J. Tuomilehto, H. Bedford, D. Elliman, J. B. Classen, D. C Classen
Journal: BMJ (1999)

Editor—In responding to Jefferson’s editorial about vaccination and its adverse effects Classen and Classen say that present immunisation schedules may exacerbate the development of type 1 diabetes and that early immunisation with a cocktail of vaccines may prevent the development of diabetes.1,2

The authors cite their unpublished reanalysis of the Finnish trial of Haemophilus influenzae type b vaccine.3 Their conclusions are at odds with the analyses and conclusions of the investigator (JT) presented at a National Institutes of Health workshop and were published recently.4 The Finnish investigators’ review of the data could not attribute the risk of type 1 diabetes in Finnish children to differences in the timing of childhood vaccination in the vaccine trial. The incidence of type 1 diabetes in Finland has risen over several decades, and the risk seems to have been almost linear since the early 1950s. Given the disparity of conclusions, it was suggested that Classen and Classen’s analysis be sent to an independent statistician. We are not aware that this has been done.

The authors quote the aim of the National Institutes of Health workshop as being “to discuss our data” when in fact the title was “an evaluation of the possible role of vaccines and infectious diseases in insulin dependent (type 1) diabetes mellitus.” Two independent reviews of available data specific to vaccines were presented by the Cochrane reviewers and the Johns Hopkins Vaccine Safety Institute; neither found an association such as that reported, and both indicated concerns about methodological issues in statistical analysis and the design and conduct of these studies. The conclusion of the workshop, presented in June 1998, was that studies in humans do not indicate an increase in type 1 diabetes attributable to any vaccine or the timing of immunisation.

Dr J B Classen has filed a European and American patent on his schedule that may have widespread implications should his views be implemented. He applies for a patent on immunisation schedules to be administered from birth, both to reduce the likelihood of type 1 diabetes developing and to protect individuals from communicable diseases.5 The safety or efficacy of one particular paediatric schedule (annex 5 of the application5) has not been shown.

The applications can be obtained for a small fee from the Search and Advisory Service, Patent Office, Cardiff Road, Newport, Gwent NP9 1RH. The full list of references for this letter is on the BMJ’s website.6 We agree that the public should be made aware of what is going on.
Noninvasive ECG Imaging of Electrophysiologically Abnormal Substrates in Infarcted Hearts
Authors: John E. Burnes, Bruno Taccardi, Robert S. MacLeod, Yoram Rudy
Journal: Circulation (2000)

Background —Myocardial infarction and subsequent remodeling create substrates with altered electrophysiological (EP) properties that are highly arrhythmogenic. Existing ECG methods cannot always detect the existence of such substrates nor provide any detailed information about their EP characteristics. A noninvasive method with such capabilities is greatly needed for identifying patients at risk of arrhythmias and for guidance and evaluation of therapy. Recently, we developed a noninvasive ECG imaging modality that can reconstruct epicardial EP information from body surface potentials. We extended its application to hearts with structural disease and examined its ability to detect and characterize abnormal EP substrates. Methods and Results —Epicardial potentials were recorded with a 490-electrode sock from an open-chest dog. Recordings were obtained from a normal heart and from the same heart 2 hours after left anterior descending coronary artery occlusion and ethanol injection to create an infarct. Body surface potentials were generated from these epicardial potentials in a human torso model. Realistic geometry errors and measurement noise were added to the torso data, which were then used to noninvasively reconstruct epicardial potentials and electrograms (EGMs), with excellent accuracy. EP characteristics associated with the infarct substrate were reconstructed, including (1) a negative region over the infarct, (2) EGMs with large predominant negative deflections (eg, Q-wave EGMs), (3) Q-wave EGMs with superimposed RS deflections reflecting local activation of surviving myocardium within the infarct border zone, (4) reduced magnitudes of EGM negative derivatives, and (5) negative QRS integrals of EGMs over the infarct. Conclusions —ECG imaging can noninvasively detect and map abnormal EP substrates associated with infarction and structural heart disease.
P04.18 * PROGNOSIS IMPACT OF THE REGIONAL DISTRIBUTION OF MGMT GENE METHYLATION ACCORDING TO THE CPGISLAND METHYLATOR PHENOTYPE AND AGE IN HIGH-GRADE GLIOMAS
Authors: P. Mur, A. R. de Lope, T. Hernandez-Iglesias, F. Diaz, T. Ribalta, C. Fiano, J. F. Garcia, J. A. Rey, M. Mollejo, B. Melendez
Journal: Neuro-Oncology (2014)

Clinical and molecular prognostic factors in gliomas include age, IDH mutation, the glioma CpG island methylator phenotype (G-CIMP) and promoter methylation of the O6-methylguanine DNA-methyltransferase (MGMT) gene, among others. Clinical trials supported the predictive value of MGMT promoter methylation for benefit from alkylating chemotherapy in elderly GBM patients. In this study, methylation data were obtained from 46 oligodendroglial samples with the Illumina 450K platform, and were analyzed with external data to reach a total 247 glioma samples. MGMT gene methylation analysis with this platform revealed two significant survival-associated CpG regions, one within the promoter (cg12981137) and the other within the gene body (cg07933035), both significantly associated with better overall survival (OS) and strongly correlated with the G-CIMP+ status. However, although around 50% of G-CIMP- tumors were MGMT methylated on these CpG sites, their prognostic relevance were not observed in these patients. Only the gene body methylation was prognostic, but in the context of age, showing significant differences of OS in elderly patients. The absence of the MGMT promoter prognostic value in G-CIMP- tumors was validated in an independent series of 59 chemoradiated GBM patients by MSP and qMSP assays. Our study suggests that the prognostic value of MGMT methylation should be reviewed in the context of specific G-CIMP profiles and age groups. Further analysis on the impact of MGMT methylation on gene and protein expression is necessary for better clinical treatment settings. The routine use of MGMT methylation for the individual treatment of patients should be still viewed with caution.
Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: The Primary Immune Deficiency Treatment Consortium experience
Authors: William T. Shearer, Elizabeth Dunn, Luigi D. Notarangelo, Christopher C. Dvorak, Jennifer M. Puck, Brent R. Logan, Linda M. Griffith, Donald B. Kohn, Richard J. O'Reilly, Thomas A. Fleisher, Sung-Yun Pai, Caridad A. Martinez, Rebecca H. Buckley, Morton J. Cowan
Journal: Journal of Allergy and Clinical Immunology (2013)
Nonlinearity of dose-response functions for carcinogenicity.
Authors: D G Hoel, C J Portier
Journal: Environmental Health Perspectives (1994)

Carcinogenesis data for 315 chemicals were obtained from the National Cancer Institute-National Toxicology Program (NCI-NTP) bioassay programs and were analyzed to examine the shape of carcinogenesis dose-response curves. Tumor site data were more often consistent with a quadratic response than with a linear response, suggesting that the routine use of linear dose-response models will often overestimate risk. Information from in vivo short-term mutagenicity and genotoxicity assays was also obtained for most of these rodent bioassays. It was found that there were no clear relationships between the shape of the carcinogenesis dose-response curve and the result of the short-term test. These observations argue against the concept that carcinogens that are positive in a short-term assay be regulated using a linear dose-response curve and those that are negative be regulated using a sublinear dose-response curve or a safety factor approach.
Comments on "Is sperm motility maturation affected by static magnetic fields?".
Authors: A Lerchl
Journal: Environmental Health Perspectives (1997)

In the paper titled "Is Sperm Motility Maturation Affected by Static Magnetic Fields?" (1), the authors conclude that "sperm production is unaffected because no changes were observed in testicular or epididymal weights after exposure to static magnetic fields."This conclusion, however, is not sup- ported by the data presented.With five animals per group and the standard deviations (SD) given (Table 2 of their paper), a calculation of the power of such comparisons is possible.With values of a = 0.05 and a = 0.80, the minimal detectable dif- ference (DD) is larger than the maximal observed difference (OD), for each parameter (see Table 1).The results of the study are therefore unable to prove the nonexistence of an effect of static magnetic fields, at least with respect to the weight data.
Clinical benefit of high dose IL-2 (HD IL-2) therapy: evidence for improved overall survival in patients with stable disease
Authors: Tasha Hughes, Gail Iodice, Sanjib Basu, Steven Bines, Howard Kaufman
Journal: Journal for ImmunoTherapy of Cancer (2013)

Meeting abstracts HD IL-2 is an approved immunotherapy for advanced melanoma and renal cell carcinoma with a reported objective response rate (ORR) up to 20%. Patients with stable disease (SD) following treatment are not considered objective responders and thus are not included in reported response
Diuretics and Blood Lipids
Authors: MICHAEL H. ALDERMAN
Journal: Annals of Internal Medicine (1981)

Letters1 June 1981Diuretics and Blood LipidsMICHAEL H. ALDERMAN, M.D., MARGARET E. STANBACK, M.P.H.MICHAEL H. ALDERMAN, M.D.Search for more papers by this author, MARGARET E. STANBACK, M.P.H.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-94-6-822_3 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: The elegant study reported by Grimm and colleagues (1) on "Effects of Thiazide Diuretics on Plasma Lipids and Lipoproteins in Mildly Hypertensive Patients" in the January 1981 issue confirms previous findings (2-5) that, in the short term, diuretic therapy is associated with increases in total serum cholesterol and lipid fractions (low-density lipoproteins [LDL] and very low density lipoproteins [VLDL]). Moreover, the authors present a new observation that high-density lipoprotein (HDL) levels modestly rise (not significant) among patients on diuretic therapy in 6 weeks of treatment.But although the findings of this thorough and well-designed study are in...References1. GRIMMLEONHUNNINGHAKELENZHANNANBLACKBURN RADKPH. Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hypertensive patients: a double-blind controlled trial. Ann Intern Med. 1981;94:7-11. LinkGoogle Scholar2. PERRY H. Treatment of mild hypertension, Veterans Administration—NHLBI Study Group for Cooperative Studies on Antihypertensive Therapy: Mild Hypertension. Circ Res. 1977;40(Suppl I):I-180-9. Google Scholar3. AMESHILL RP. Elevation of serum lipids during diuretic therapy of hypertension. Am J Med. 1976;61:748-57. CrossrefMedlineGoogle Scholar4. AMESHILL RP. Increase in serum-lipids during treatment of hypertension with chlorthalidone. Lancet. 1976;1:721-3. CrossrefMedlineGoogle Scholar5. AMESHILL RP. Raised serum lipid concentrations during diuretic treatment of hypertension: a study of predictive indexes. Clin Sci Mol Med. 1978;55(Suppl 4):311s-4s. Google Scholar6. HELGELANDHJERMANNHOLMELEREN AJIP. Serum triglycerides and serum uric acid in untreated and thiazide treated patients with mild hypertension. Am J Med. 1978;64:34-8. CrossrefMedlineGoogle Scholar7. GLÜCKWEIDMANNMORDASINI ZPR. The effect of diuretic therapy on serum lipoproteins: an undesirable effect? Schweiz Med Wochenschr. 1979;109(4):104-8. MedlineGoogle Scholar8. HELGELANDHJERMANNLERENENGERHOLME AJPSI. High density lipoprotein cholesterol and antihypertensive drugs: The Oslo Study. Br Med J. 1978;2:403. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: The New York Hospital—Cornell Medical Center New York, NY 10021 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 June 1981Volume 94, Issue 6Page: 822-823KeywordsBlood plasmaCholesterolDiureticsHigh density lipoproteinLipidsLipoproteinsLow density lipoproteinVery low density lipoprotein Issue Published: 1 June 1981 PDF downloadLoading ...
Thrombophlebitis with intravenous naftidrofuryl oxalate.
Authors: V F Standing, P A Wiggins, D Pratt, R C Kester
Journal: BMJ (1977)

grey and breathless in her cot.A tachycardia of 240/min was noted which settled over the following four hours.Examination showed no evidence of cardiac failure.A chest x-ray was normal.An ECG the next morning revealed a sinus tachycardia of 180, min.Her subsequent progress was unevent- ful and she was discharged home on her 65th day weighing 2 42 kg.She failed to keep her follow-up appointmmnt and we later learnt that she had been found dead in her cot unexpectedly at home at the age of 10 weeks.Post-mortem examination revealed no abnormalities.
IMPROVEMENT IN EXERCISE TOLERANCE AFTER CARDIAC REHABILITATION IN PATIENTS WITH ACUTE STEMI RECEIVED DIFFERENT MODES OF REVASCULARIZATION IN HONG KONG
Authors: Chor Cheung Tam, Hon Wah Raymond Chan, Sheung Wai Li, Wing Sze Chan, Kam Bick Lam, Yin Yu Ho, Kitty Fong, Ka Lam Wong, Yiu Tung Wong, Arthur Yung, Stephen Lee
Journal: Journal of the American College of Cardiology (2013)
Human Mesenchymal Stem Cells Form Purkinje Fibers in Fetal Sheep Heart
Authors: Judith A. Airey, Graça Almeida-Porada, Evan J. Colletti, Christopher D. Porada, Jason Chamberlain, Matthew Movsesian, John L. Sutko, Esmail D. Zanjani
Journal: Circulation (2004)

Background— We have investigated the usefulness of a model of cardiac development in a large mammal, sheep, for studies of engraftment of human stem cells in the heart. Methods and Results— Adult and fetal human mesenchymal stem cells were injected intraperitoneally into sheep fetuses in utero. Hearts at late fetal development were analyzed for engraftment of human cells. The majority of the engrafted cells of human origin formed segments of Purkinje fibers containing exclusively human cells. There were no differences in engraftment of human mesenchymal stem cells from adult bone marrow, fetal brain, and fetal liver. On average, 43.2% of the total Purkinje fibers in random areas (n=11) of both ventricles were of human origin. In contrast, ≈0.01% of cardiomyocytes were of human origin. Conclusions— Human mesenchymal stem cells preferentially engraft at high levels in the ventricular conduction system during fetal development in sheep. These findings raise the possibility that stem cells contribute to normal development of the fetal heart.
Assessing the options available to Lord Darzi
Authors: Martin Roland
Journal: BMJ (2008)

Time to look at both the system and the patient as a whole

The Department of Health in the United Kingdom is undertaking a major review of National Health Service policy (“the Darzi review”). Which options are most likely to produce an effective, efficient, and patient centred health service? The UK has made major progress in reducing avoidable deaths and improving care for chronic diseases.1 2 However, many areas still have considerable room for improvement.

Strong primary care is associated with reduced costs and improved outcomes.3 The review therefore needs to strengthen primary care. The UK system of universal registration with a single general practice promotes equity, provides a “medical home” for coordinating care, and is an effective mechanism for holding providers to account for the quality of care provided. This must be retained, even though patients may occasionally consult other practitioners—for example, a doctor near their workplace.

Much has been written about “polyclinics”—facilities that group together primary care practitioners with diagnostic and specialist services. Despite lack of clarity about their purpose, several are already planned. Part of the debate about polyclinics relates to a perceived need to merge …
Human leukoagglutinating antibody evokes cooperative leukotriene synthesis in pulmonary microvasculature. Model of transfusion-related acute lung injury.
Authors: F Grimminger, B Kreusler, U Schneider, E von Witzleben, D Walmrath, J Neppert, W Seeger
Journal: Circulation Research (1991)

Leukoagglutinating antibodies have been implicated in the development of transfusion-related acute lung injury. In the present study, human neutrophil leukotriene generation was provoked by an anti-5b immunoglobulin G, isolated from a multiparous donor plasma that caused noncardiogenic lung edema during transfusion therapy. In 5b-positive polymorphonuclear neutrophils (PMNs), the antibody stimulated marked arachidonic acid metabolism, dependent on the presence of plasma as the complement source. Quantity and profile of lipid mediators (leukotriene B4 and its omega-oxidation products, 5-hydroxyeicosatetraenoic acid, and nonenzymatic hydrolysis products of leukotriene A4) corresponded to those repeatedly described after PMN in vitro stimulation with the artificial calcium ionophore A23187. Anti-5b challenge of PMNs sequestered in the microvasculature of perfused rabbit lungs did, however, induce a markedly modified metabolite profile. Nonenzymatic hydrolysis products of leukotriene A4 were not detected, and 5-hydroxyeicosatetraenoic acid was markedly reduced. In contrast, cysteinyl leukotrienes were measured as predominant compounds, with rapid appearance of leukotriene C4 and more protracted generation of leukotriene E4. Leukotriene B4 and its omega-oxidation products were released with similar kinetics, but in lower amounts, as compared with the isolated PMN stimulation. Anti-5b challenge of PMNs coincubated with pulmonary artery endothelial cells in vitro, but not stimulation of either cell type alone, provoked marked generation of cysteinyl leukotrienes. These findings suggest modulation of PMN 5-lipoxygenase metabolism in favor of leukotriene A4 transfer to adjacent acceptor cells with subsequent enzymatic conversion to cysteinyl leukotrienes under conditions of lung vascular sequestration. Endothelial cells appear to serve as predominant cooperative cells under circumstances of blood-free lung perfusion. PMN-related transcellular eicosanoid synthesis may be involved in the pathogenesis of transfusion-evoked acute lung injury.
Doctors hear about "minimally disruptive medicine" and the medical uses of YouTube
Authors: N. Hawkes
Journal: BMJ (2010)

When Sharon Straus, co-chair of Knowledge Translation Canada, made a presentation to a group of bankers and businessmen, they were bewildered. She explained that well established medical evidence, backed by double blind trials and systematic reviews, was often ignored by doctors.

“You say there’s evidence and these doctors aren’t using it?” asked one of those present. “Why don’t you just fire them?”

Professor Straus was speaking on the second day of Evidence 2010, an international conference at BMA House devoted to understanding why medical practice so often deviates from medical evidence, and what might be done to narrow the gap. 

Victor Montori from the Mayo Clinic in Rochester, Minnesota, set the scene by quoting a figure of $290bn (£181.4bn; €208bn), the money estimated by the New England Healthcare Institute to go to waste in the US healthcare system every year as a result of patients not taking medicines as prescribed.

“Only half of clinicians prescribe the right drugs, and half the patients who are prescribed them stop taking them,” he said. …
High court is to review UK government's failure to stop export of death row drug
Authors: C. Dyer
Journal: BMJ (2010)

Campaigners against the death penalty have won the right to launch a legal action to try to stop the export of an anaesthetic manufactured in Britain that is to be used in the execution of an inmate on death row in the United States.

Reprieve, a human rights organisation that supports prisoners, is trying to prevent the export of thiopental sodium, which prison authorities in Tennessee need if they want to go ahead with the execution of Edmund Zagorski.

Vince Cable, the UK …
Dynamics of pigmentation induction by repeated ultraviolet exposures: dose, dose interval and ultraviolet spectrum dependence
Authors: S.A. Miller, S.G. Coelho, B.Z. Zmudzka, H.F. Bushar, Y. Yamaguchi, V.J. Hearing, J.Z. Beer
Journal: British Journal of Dermatology (2008)

The dynamics of ultraviolet (UV)-induced melanogenesis have been well characterized for single UV exposures. However, our knowledge of the effects of repeated UV exposures on the development of new pigmentation is limited.