tbuckley/cabot-search huggingface dataset:
NEXT-GENERATION NEUROPATHOLOGY - IMPROVING DIAGNOSTIC ACCURACY FOR BRAIN TUMORS USING DNA METHYLATION ARRAY-BASED MOLECULAR PROFILING
Authors: D. T. W. Jones, D. Capper, M. Sill, V. Hovestadt, P. Lichter, D. Zagzag, M. A. Karajannis, K. D. Aldape, A. Korshunov, A. von Deimling, S. M. Pfister
Journal: Neuro-Oncology (2014)

BACKGROUND: The current World Health Organisation (WHO) classification of central nervous system tumors comprises over 100 entities. Most of these are defined by purely histological criteria, with varying and sometimes overlapping spectra. Histological diagnosis is often challenging, however, especially in cases with limited or non-representative biopsy material. Thus, molecular technologies that can complement standard pathology testing have the potential to greatly enhance diagnostic precision and improve clinical decision-making. DNA methylation profiling, acting as a 'fingerprint' of cellular origin and molecular alterations, is one such promising technology. METHODS: We have assembled a reference dataset of more than 2,000 methylation profiles using the Illumina HumanMethylation450 (450k) array, currently representing over 50 brain tumor entities or subgroups. The array platform is suitable for both frozen and paraffin-embedded material, with minimal DNA input required. Each new diagnostic case receives an entity prediction with an associated probability score as a confidence measure. Genome-wide copy number profiles (e.g. for scoring 1p/19q loss or gene amplifications) and target gene methylation data (e.g. MGMT) generated from the array provide important additional information. RESULTS: In addition to the reference cohort, more than 500 diagnostic samples from Heidelberg University Hospital and external institutions have been processed. Approximately 5-10% of cases displayed a discrepancy between histological and molecular diagnoses. Careful re-examination of these often resulted in refinement of the original diagnosis, and improved patient care.Furthermore, samples collected for the reference cohort have led to significant improvements in our understanding of the biology of several tumor types, including the identification of further subgroups for several entities and associations with recurrent copy number changes and/or mutations. CONCLUSIONS: Our understanding of the molecular alterations underlying brain tumors has grown enormously in recent years, and it is crucial that this is translated into the clinic promptly. DNA methylation profiling is one tool with the potential to become an important part of the diagnostic armoury of neuropathologists. This relatively inexpensive and robust method is well suited to complement standard histopathologic techniques and improve diagnostic accuracy, thereby optimising patient management. We are currently expanding our pipeline to include additional diagnostic centres, allowing for further refinement and validation as well as broader international access. SECONDARY CATEGORY: Tumor Biology.
Comparison of two twice-daily doses of budesonide/formoterol maintenance and reliever therapy
Authors: M. Aubier, R. Buhl, T. Ekström, J. Ostinelli, C.P. van Schayck, O. Selroos, J. Haughney
Journal: European Respiratory Journal (2010)

The aim of this study was to compare two budesonide/formoterol maintenance doses within the budesonide/formoterol maintenance and reliever therapy concept and to identify possible patient characteristics at baseline which would predict a better response to a higher than standard maintenance dose. A total of 8,424 patients with symptomatic asthma when using an inhaled corticosteroid (ICS) with or without a long-acting β 2 -agonist were randomised to budesonide/formoterol 160/4.5 μg, one (1×2) or two (2×2) inhalations b.i.d . Patients used the same inhaler as needed for symptom relief. The primary outcome variable was time to first severe asthma exacerbation. In the total study population, the time to first severe asthma exacerbation was prolonged by 18% with 2×2 versus 1×2 (hazard ratio 0.82; p = 0.03). Lung function (peak expiratory flow) was the only statistically significant predictor of a better response to 2×2. The mean daily ICS doses were 737 and 463 μg in the 2×2 and 1×2 groups, respectively. In a real-life setting, budesonide/formoterol maintenance and reliever therapy at the 2×2 maintenance dose did prolong time to first severe exacerbation but at a higher medication load. Patients with low lung function benefited most from the higher maintenance dose.
γ-H2AX Foci as a Biomarker for Patient X-Ray Exposure in Pediatric Cardiac Catheterization
Authors: Laurence Beels, Klaus Bacher, Daniël De Wolf, Joke Werbrouck, Hubert Thierens
Journal: Circulation (2009)

Background— A better knowledge of patient x-ray dose and the associated radiation risk in pediatric interventional cardiology is warranted in view of the extensive use of x-rays and the higher radiosensitivity of children. In the present study, γ-H2AX foci were used as a biomarker for radiation-induced effects. Patient-specific dose was assessed and radiation risks were estimated according to the linear-no-threshold model, commonly used in radiation protection, and the γ-H2AX foci data. Methods and Results— In 49 pediatric patients (median age, 0.75 years) with congenital heart disease who underwent cardiac catheterization procedures, blood samples were taken before and shortly after the procedure. γ-H2AX foci were determined in peripheral blood T lymphocytes. In each patient, a net increase in γ-H2AX foci, representing DNA double-strand breaks induced by interventional x-rays, was observed. In addition, a patient-specific Monte Carlo simulation of the procedure was performed, resulting in individual blood, organ, and tissue doses. Plotting of γ-H2AX foci versus blood dose indicated a low-dose hypersensitivity. Median effective doses calculated according to the International Commission on Radiological Protection 60 and 103 publications are 5.6 and 6.4 mSv, respectively. The lifetime-attributable risk of cancer mortality was calculated from the linear-no-threshold model and the γ-H2AX foci data. This resulted in lifetime-attributable risk values of 1% and 4%, respectively, for the patient population under study. Conclusions— γ-H2AX foci as a biomarker for DNA damage indicate that radiation risk estimates according to the linear-no-threshold hypothesis are possibly underestimates. Great care should be taken to minimize and optimize patient radiation exposure.
Pharmacokinetic Problems in Peritoneal Drug Administration: Tissue Penetration and Surface Exposure
Authors: R. L. Dedrick, M. F. Flessner
Journal: JNCI Journal of the National Cancer Institute (1997)

Both theory and clinical studies demonstrate that drug concentrations in the peritoneal cavity can greatly exceed concentrations in the plasma following intraperitoneal administration. This regional advantage has been associated with clinical activity, including surgically documented complete responses in ovarian cancer patients with persistent or recurrent disease following systemic therapy, and has produced a survival advantage in a recent phase III trial. Two pharmacokinetic problems appear to limit the effectiveness of intraperitoneal therapy: poor tumor penetration by the drug and incomplete irrigation of serosal surfaces by the drug-containing solution. We have examined these problems in the context of a very simple, spatially distributed model. If D is the diffusivity of the drug in a tissue adjacent to the peritoneal cavity and k is the rate constant for removal of the drug from the tissue by capillary blood, the model predicts that (for slowly reacting drugs) the characteristic penetration distance is ( D/k ) 1/2 and the apparent permeability of the surface of a peritoneal structure is ( D/k ) 1/2 . The permeabilityarea product used in classical pharmacokinetic calculations for the peritoneal cavity as a whole is the sum of the products of the tissue-specific permeabilities and the relevant superficial surface areas. Since the model is mechanistic, it provides insight into the expected effect of procedures such as pharmacologic manipulation or physical mixing. We observe that large changes in tissue penetration may be difficult to achieve but that we have very little information on the transport characteristics within tumors in this setting or their response to vasoactive drugs. Enhanced mixing is likely to offer significant potential for improved therapy; however, procedures easily applicable to the clinical setting have not been adequately investigated and should be given high priority. Clinical studies indicate that an increase in irrigated area may be achieved in many patients by individualizing the dialysate volume and consideration of patient position.
Extracellular matrix derived from hair and skin fibroblasts stimulates human skin melanocyte tyrosinase activity
Authors: J.A. BUFFEY, A.G. MESSENGER, M. TAYLOR, A.T.T. ASHCROFT, G.E. WESTGATE, S.MAC NEIL
Journal: British Journal of Dermatology (1994)

Journal Article Extracellular matrix derived from hair and skin fibroblasts stimulates human skin melanocyte tyrosinase activity Get access J.A. BUFFEY, J.A. BUFFEY University Department of Medicine, Clinical Sciences Centre, Northern General Hospital, Sheffield S5 7AU, U.K. Search for other works by this author on: Oxford Academic Google Scholar A.G. MESSENGER, A.G. MESSENGER University Department of Dermatology, Royal Hallamshire Hospital, Sheffield S10, U.K. Search for other works by this author on: Oxford Academic Google Scholar M. TAYLOR, M. TAYLOR University Department of Dermatology, Royal Hallamshire Hospital, Sheffield S10, U.K. Search for other works by this author on: Oxford Academic Google Scholar A.T.T. ASHCROFT, A.T.T. ASHCROFT University Department of Dermatology, Royal Hallamshire Hospital, Sheffield S10, U.K. Search for other works by this author on: Oxford Academic Google Scholar G.E. WESTGATE, G.E. WESTGATE Unilever Research, Colworth House, Colworth, U.K. Search for other works by this author on: Oxford Academic Google Scholar S.MAC NEIL S.MAC NEIL University Department of Medicine, Clinical Sciences Centre, Northern General Hospital, Sheffield S5 7AU, U.K. Dr S.Mac Neil. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 131, Issue 6, 1 December 1994, Pages 836–842, https://doi.org/10.1111/j.1365-2133.1994.tb08586.x Published: 01 December 1994 Article history Accepted: 13 April 1994 Published: 01 December 1994
RESTRICTION OF GENE EXPRESSION IN B LYMPHOCYTES AND THEIR PROGENY
Authors: Patricia P. Jones, John J. Cebra
Journal: The Journal of Experimental Medicine (1974)

Fluorescent antibody staining with antibodies to the f and g locus allotype markers present on rabbit alpha-chains revealed that the alpha-chain is the heavy chain on the Peyer's patch lymphocytes which previously had been shown to be the precursors of IgA-producing plasma cells. In addition, lymphocytes which had been stripped of membrane Ig with pronase and then cultured overnight to allow the sole expression of endogenous membrane Ig were found to have either the micro-chain or the alpha-chain on their membranes, but not both. These results suggest that most lymphocytes are restricted to the synthesis of one class of heavy chains at a time and that the commitment to synthesizing that particular heavy chain is maintained during the differentiation of lymphocytes into plasma cells. The proportion of lymphocytes with membrane alpha-chains is higher in the Peyer's patch and appendix, two gut-associated lymphoid tissues (GALT), than in other lymphoid tissues. Since the GALT are enriched sources of precursors for IgA-producing plasma cells compared to nongut-associated tissues, the presence of cells bearing membrane alpha-chains correlates well with the relative abilities of these tissues to generate IgA plasma cells.
What Predicts Progression and Regression of Urinary Albumin Excretion in the Nondiabetic Population?
Authors: Auke H Brantsma, Jarir Atthobari, Stephan J L Bakker, Dick de Zeeuw, Paul E de Jong, Ronald T Gansevoort
Journal: Journal of the American Society of Nephrology (2007)

An increase or decrease in urinary albumin excretion (UAE) is associated with, respectively, a higher or lower risk for renal and cardiovascular disease, independent of widely known cardiovascular risk factors. This study aimed to identify factors that are associated with changes in UAE in the nondiabetic population using data of the Prevention of Renal and Vascular End stage Disease (PREVEND) Study, a community-based prospective cohort study. Data of the 6647 nondiabetic participants who completed the first (1997 through 2001) and second (2001 through 2003) screening were used. Change in UAE was categorized as regression (n = 650), stable (n = 5240), or progression (n = 757) on the basis of change in class during follow-up, with classes being a UAE <15, 15 to 30, 30 to 300, and >300 mg/24 h. With the use of stepwise forward multinomial regression analysis changes in BP, fasting glucose concentration, and start of antihypertensive drugs were found to be the most important modifiable variables associated with the risk for progression and regression (P < 0.01 for likelihood ratio test). The odds ratios to develop regression or progression of UAE during follow-up were 0.64 (95% confidence interval [CI] 0.57 to 0.73) and 1.91 (95% CI 1.72 to 2.12), respectively, per 10-mmHg increase in BP during follow-up, 0.89 (95% CI 0.80 to 0.98) and 1.09 (95% CI 1.01 to 1.17), respectively, per 1-mmol/L increase of fasting glucose levels during follow-up, and 1.57 (95% CI 1.21 to 2.06) and 0.70 (95% CI 0.51 to 0.95), respectively, for start of antihypertensive drugs during follow-up. These associations were independent of baseline BP, glucose, body mass index, estimated GFR, and UAE and changes in high-sensitivity C-reactive protein during follow-up. In conclusion, changes in glucose concentration and BP and start of antihypertensive drugs (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in >50% of cases) are associated with progression and regression of UAE in the nondiabetic population. Although associations do not necessarily suggest causality, it is hypothesized that in the general population, the most important ways to reduce UAE are by lowering glucose concentration and BP (including start of antihypertensive medication), even in normotensive, nondiabetic individuals.
Extracorporeal photochemotherapy does not suppress T- or B-cell responses to novel or recall antigens
Authors: K R Suchin, M Cassin, R Washko, G Nahass, M Berkson, B Stouch, B R Vowels, A H Rook
Journal: Journal of the American Academy of Dermatology (1999)

Extracorporeal photopheresis (ExP) is an effective therapy for several conditions including cutaneous T-cell lymphoma, scleroderma, and allograft rejection. Experimental animal models suggest that ExP may induce antigen-specific immunosuppression.Our purpose was to determine the effect of photopheresis on humoral and cell-mediated immunity in human subjects.Recall and primary immune responses of patients with scleroderma receiving monthly ExP treatments were assessed by delayed type hypersensitivity skin tests, T-cell proliferative responses after immunizations with tetanus toxoid and keyhole limpet hemocyanin, and serum antibody titers against common viral pathogens.After 6 months of ExP, viral antibody titers and delayed type hypersensitivity responses were not significantly different from baseline values in all 7 patients tested. T-cell responses to tetanus toxoid remained normal in 3 of 3 patients tested for a minimum of 6 months after booster immunization. Immunization with the protein antigen keyhole limpet hemocyanin after initiation of ExP therapy resulted in sustained T-cell proliferative responses up to 6 months in 3 of 3 patients.These results, along with the observation of no increased incidence of opportunistic infections or neoplasms, suggest that ExP is not broadly immunosuppressive and does not prevent primary responses to vaccination or other antigenic challenges.
Molecular Pathways: Targeting Hsp90—Who Benefits and Who Does Not
Authors: Maurizio Scaltriti, Shaheenah Dawood, Javier Cortes
Journal: Clinical Cancer Research (2012)

Many kinases and hormone receptors, important for cancer cell proliferation and survival, bind to and are dependent on the Hsp90 cycle for their folding and maturation. This provides the rationale for the development of small-molecule ATP competitors that, inhibiting Hsp90 function, lead to degradation of the "client" proteins. After continual efforts to improve the pharmacologic properties and the tolerability of these molecules, several Hsp90 inhibitors have exhibited activity in both preclinical models and in the clinical setting. As is the case with many other targeted agents, patient selection seems to be the major limitation to the success of these compounds. ERBB2-positive patients with breast cancer are exquisitely sensitive to Hsp90 inhibition. This is because ERBB2 is indispensable for growth and survival of this subtype of cancer, and at the same time ERBB2 is a client protein strictly dependent on Hsp90 for its maturation and stability. Extensive preclinical work identifying other ERBB-like client proteins will likely lead to the ability to enhance selection of appropriate patients for enrollment in more rational clinical trials. Hsp90 inhibition has also been reported to synergize with other therapeutic agents. Several ongoing studies testing different combinations of Hsp90 inhibitors with other targeted agents will confirm whether Hsp90 inhibition can potentiate the efficacy of targeted therapy and/or prevent the emergence of drug resistance.
The Effect of In Vivo Hydrocortisone on Subpopulations of Human Lymphocytes
Authors: Anthony S. Fauci, David C. Dale
Journal: Journal of Clinical Investigation (1974)

This study was designed to determine the effect of in vivo hydrocortisone on subpopulations of lymphoid cells in normal humans. Subjects received a single intravenous dose of either 100 mg or 400 mg of hydrocortisone, and blood was drawn at hourly intervals for 6 h, and then again at 10 and 24 h after injection. Profound decreases in absolute numbers of circulating lymphocytes and monocytes occurred at 4-6 h after both 100 mg and 400 mg of hydrocortisone. Counts returned to normal by 24 h. The relative proportion of circulating thymus-derived lymphocytes as measured by the sheep red blood cell rosette assay decreased maximally by 4 h and returned to base line 24 h after hydrocortisone. There was a selective depletion of functional subpopulations of lymphocytes as represented by differential effects on in vitro stimulation with various mitogens and antigens. Phytohaemagglutinin response was relatively unaffected, while responses to concanavalin A were significantly diminished. Responses to pokeweed mitogen were unaffected by 100 mg of hydrocortisone, but greatly diminished by 400 mg of hydrocortisone. In vitro responses to the antigens streptokinase-streptodornase and tetanus toxoid were markedly diminished by in vivo hydrocortisone. Reconstitution of monocyte-depleted cultures with autologous monocytes partially corrected the diminished response to antigens. This transient selective depletion of monocytes and subsets of human lymphocytes by a single dose of hydrocortisone is most compatible with a redistribution of these cells out of the circulation into other body compartments.
Mycoplasma Infections of Man
Authors: Robert M. Chanock
Journal: New England Journal of Medicine (1965)

Mycoplasma pneumoniae. History. In the late 1930's and early 1940's a broad group of nonbacterial pneumonias was first recognized and given the name of primary atypical pneumonia.83 , 84 The name was applied to pneumonia that was unlike the typical lobar disease caused by Diplococcus pneumoniae. A description of primary atypical pneumonia as a clinical syndrome was necessary at the time since the etiologic agents involved were not known. In 1943 it was first noted that in many patients with the atypical pneumonia syndrome cold agglutinins developed during the course of illness.85 Since that time a test for such antibody has been . . .
Smallpox and Smallpox Vaccination Policy
Authors: J M Lane, J D Millar, J M Neff
Journal: Annual Review of Medicine (1971)

campaigns. The introduction of heat-stable lyophilized smallpox vaccine, coupled with the World Health Organization'S drive against the disease, has made vaccination widespread and effective. In the past 25 years, smallpox has been eliminated from North America, Western Europe, Russia, China, North Africa, the Middle East, much of Southeast Asia, most of the new countries of sub-Saharan Africa, and all of South and Central America except parts of Brazil. Formal smallpox eradication campaigns have been initiated in all endemic countries. Figure 1 presents maps of the distribution of endemic smallpox in 1945 and in the first eight months of 1970 (1). In the United States , defense against smallpox has been based upon four principles. First is routine vaccination of the popUlation. Second is vaccina­ tion of travelers. Third is inspection of vaccination certificates of returning travelers and immigrants. Fourth is investigation of suspect smallpox cases, with rapid isolation and control of smallpox importations. Approximately 15 million smallpox vaccinations are performed in the United States each year, about six million of which are primary vaccinations. The total cost of the United States for smallpox prevention, including vaccine production, vacci­ nation fees, time lost from work or school for vaccination, maintenance of the foreign quarantine system, research on smallpox and vaccinia, and med­ ical costs of vaccination complications, is an estimated $147,000,000 (2). There is disagreement about the need for and effectiveness of current United States policies. Kempe has emphasized the dangers of smallpox vac­ cination (3). Dick believes that, in Great Britain, routine population vacci­ nation is less effective and more costly than surveillance of disease intro­ ductions and outbreak control (4). The United States Public Health Ser­ vice's Advisory Committee on Immunization Practices, and the American Academy of Pediatrics Committee on the Control of Infectious Diseases recommend routine childhood vaccination. Most state and local health de