tbuckley/cabot-search huggingface dataset:
Interindividual variation in carcinogen metabolism and bladder cancer risk.
Authors: P Vineis, G Ronco
Journal: Environmental Health Perspectives (1992)

Epidemiological studies indicate that subjects of the genetically based slow acetylator phenotype may be at higher risk for bladder cancer than fast acetylators, particularly when they are exposed to carcinogenic arylamines: N-acetylation is a detoxification step in the metabolism of some arylamines. We describe two collaborative studies on tobacco smoking, in which markers of internal dose (arylamine-hemoglobin adducts) and markers of genetically-based metabolic polymorphism have been coupled. In the first investigation, we found that hemoglobin adducts formed by mononuclear arylamines have high reciprocal correlation coefficients, as do adducts from binuclear arylamines. This tendency of adducts with structurally similar arylamines to correlate reciprocally explains a large proportion of the residual variance seen after controlling for smoking habits (number and type of cigarettes). In the second study, the concentration of 4-amino-biphenyl-hemoglobin adducts varied according to three independent determinants: number of cigarettes, type of tobacco (air or flue cured), and acetylator phenotype (slow and fast). The dose-response relationship between the amount of tobacco smoked and level of 4-aminobiphenyl-hemoglobin adducts in the slow acetylators (with an immediate steep increase of the adducts) was different from that in the fast acetylators (with a more regular increase). These findings from
Ethics at the Bedside
Authors: Gregory A. Plotnikoff
Journal: JAMA (1991)

In the past few years, numerous academic medical centers have established in-house ethics consultation services for assistance in life-and-death decision making and the resolution of moral conflicts. Until now, however, little knowledge gained from such experience has been shared with the general medical and lay public. In<i>Ethics at the Bedside</i>, Charles M. Culver, MD, PhD, McInerny Professor of Medical Ethics and professor of psychiatry, Dartmouth Medical School, brings together some of the nation's most experienced, knowledgeable, and widely recognized consultants to share with the reader a difficult or complex case. Each contributor presents a story rich in intellectual excitement and clinical drama. Written as narratives rather than academic essays, the stories lead the reader through the process of identifying the morally relevant facts and applying the pertinent moral concepts amidst the exigencies and uncertainties of clinical medicine. The result is 12 outstanding essays that the medical professional and intelligent
Methotrexate in Rheumatoid Arthritis
Authors: PETER TUGWELL
Journal: Annals of Internal Medicine (1987)

Evidence on the safety and efficacy of methotrexate as a second- or third-line agent for treating patients with rheumatoid arthritis is reviewed. Four placebo-controlled clinical trials have documented short-term benefit from methotrexate; combining the four studies using meta-analysis shows that, although true remission is rare, patients receiving methotrexate had a 26% (95% confidence interval [Cl], 17% to 35%) greater improvement in their inflamed joint count and a 39% (95% Cl, 26% to 51.5%) greater improvement in pain than did controls receiving nonsteroidal anti-inflammatory agents with or without prednisone. With respect to longterm benefit, improvement usually occurs within 1 month, reaching a maximum at 6 and then leveling off for the duration of treatment; in some patients, the benefit may wane after an initial satisfactory response in the first 4 to 6 months. In one third of those given methotrexate, treatment had to be discontinued because of adverse effects, less than 1% of which were life threatening. Careful baseline and follow-up monitoring is recommended until more data on the safety of methotrexate are available.
Abstract 587: Phenethyl isothiocyanate suppresses inhibitor of apoptosis family protein expression in prostate cancer cells in culture and <i>in vivo</i>
Authors: Kozue Sakao, Sudhakar Desineni, Eun-Ryeong Hahm, Shivendra V. Singh
Journal: Cancer Research (2012)

Abstract Bioactive food components continue to gain traction for possible chemoprevention of prostate cancer, which is a leading cause of cancer-related death among American men. Phenethyl isothiocyanate (PEITC) is one such compound that is under active investigation for chemoprevention of prostate cancer as well as other types of malignancies, including colon, lung, and breast cancers. PEITC occurs naturally as a thioglucoside conjugate (gluconasturtiin) in a variety of edible cruciferous vegetables (e.g., watercress), and is generated upon cutting or chewing of cruciferous vegetables due to myrosinase-catalyzed breakdown of the gluconasturtiin. Initial evidence supporting prostate cancer protective effect of cruciferous vegetables emerged from population-based case control studies. In vivo chemopreventive efficacy of PEITC against prostate cancer has now been demonstrated in a transgenic mouse model (Transgenic Adenocarcinoma of Mouse Prostate mice; hereafter abbreviated as TRAMP mice). Post-initiation cancer chemopreventive response to PEITC is associated with apoptosis induction but the mechanism of cell death is not fully understood. The present study was undertaken to determine the role of inhibitor of apoptosis (IAP) family proteins in regulation of PEITC-induced apoptosis. The IAP family proteins play critical roles in apoptosis regulation by inhibiting caspases. Elevated expression of IAP proteins, including X-linked inhibitor of apoptosis (XIAP) and Survivin has been reported in human prostate cancers. Exposure of PC-3 and LNCaP human prostate cancer cells to PEITC resulted in downregulation of XIAP and Survivin proteins and suppression of Survivin mRNA expression. PEITC administration to Transgenic Adenocarcinoma of Mouse Prostate mice caused modest but significant downregulation of XIAP and Survivin proteins in the dorsolateral prostate. Proapoptotic response to PEITC was significantly attenuated by ectopic expression of XIAP and Survivin proteins. In addition, Survivin overexpression conferred modest but significant protection against PEITC-mediated inhibition of PC-3 cell migration. In conclusion, these results indicate that cellular responses to PEITC, including apoptosis induction and inhibition of cell migration, in prostate cancer cells are mediated by downregulation of XIAP and/or Survivin, which may serve as valid biomarkers to assess PEITC response in future clinical investigations. This investigation was supported by the USPHS grant RO1 CA101753-08. 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 587. doi:1538-7445.AM2012-587
D2-04: MERIT: a prospective study of putative relationships between tumour biomarkers and clinical benefit from erlotinib in advanced non-small cell lung cancer (NSCLC)
Authors: Eng-Huat Tan, Rodryg Ramlau, Anna Pluzanska, Han-Pin Kuo, Barbara Klughammer, Mark Kockx, Maximo Carreras, Verena Lutz, Laurent Essioux, Jose Baselga
Journal: Journal of Thoracic Oncology (2007)
Aromatase Inhibitors — A Triumph of Translational Oncology
Authors: Sandra M. Swain
Journal: New England Journal of Medicine (2005)

Great strides have been made in the diagnosis and treatment of early-stage breast cancer, thanks to advances in molecular medicine, interdisciplinary treatment, and rapid electronic communication. Hormonal therapy, the first and most successful targeted therapy for breast cancer, has saved many thousands of lives. Moreover, screening and adjuvant (postoperative) therapy have increased survival among women with breast cancer.1,2 The improvement in survival can be attributed to both adjuvant tamoxifen therapy and adjuvant chemotherapy and has been found in all subgroups of patients regardless of the presence or absence of tumor cells in draining lymph nodes, including women who are . . .
Differential Associations of Oral Glucose Tolerance Test–Derived Measures of Insulin Sensitivity and Pancreatic β-Cell Function With Coronary Artery Calcification and Microalbuminuria in Type 2 Diabetes
Authors: Claire K. Mulvey, Ann M. McNeill, Cynthia J. Girman, Timothy W. Churchill, Karen Terembula, Jane F. Ferguson, Rachana Shah, Nehal N. Mehta, Atif N. Qasim, Michael R. Rickels, Muredach P. Reilly
Journal: Diabetes Care (2013)

OBJECTIVE We evaluated relationships of oral glucose tolerance testing (OGTT)-derived measures of insulin sensitivity and pancreatic β-cell function with indices of diabetes complications in a cross-sectional study of patients with type 2 diabetes who are free of overt cardiovascular or renal disease. RESEARCH DESIGN AND METHODS A subset of participants from the Penn Diabetes Heart Study (n = 672; mean age 59 ± 8 years; 67% male; 60% Caucasian) underwent a standard 2-h, 75-g OGTT. Insulin sensitivity was estimated using the Matsuda Insulin Sensitivity Index (ISI), and β-cell function was estimated using the Insulinogenic Index. Multivariable modeling was used to analyze associations between quartiles of each index with coronary artery calcification (CAC) and microalbuminuria. RESULTS The Insulinogenic Index and Matsuda ISI had distinct associations with cardiometabolic risk factors. The top quartile of the Matsuda ISI had a negative association with CAC that remained significant after adjusting for traditional cardiovascular risk factors (Tobit ratio -0.78 [95% CI -1.51 to -0.05]; P = 0.035), but the Insulinogenic Index was not associated with CAC. Conversely, the highest quartile of the Insulinogenic Index, but not the Matsuda ISI, was associated with lower odds of microalbuminuria (OR 0.52 [95% CI 0.30-0.91]; P = 0.022); however, this association was attenuated in models that included duration of diabetes. CONCLUSIONS Lower β-cell function is associated with microalbuminuria, a microvascular complication, while impaired insulin sensitivity is associated with higher CAC, a predictor of macrovascular complications. Despite these pathophysiological insights, the Matsuda ISI and Insulinogenic Index are unlikely to be translated into clinical use in type 2 diabetes beyond established clinical variables, such as obesity or duration of diabetes.
The Normal Lung: The Basis for Diagnosis and Treatment of Pulmonary Disease
Authors: William R. Barclay
Journal: JAMA (1976)

This small book, slightly more than 300 pages, is an outstanding publication. Beautifully written and illustrated, it reflects the editorial expertise of its author. The book is easy to read, captures and holds the reader's interest, and is readily understandable. The excellent diagrams and pictures, which are used extensively, make even rather difficult subject material easy to follow. Since physicians are primarily concerned with the diagnosis and treatment of disease, the title,<i>The Normal Lung</i>, might detract from the book's appeal, but if so, this will be unfortunate. The volume gives a background and an insight that will greatly strengthen diagnostic ability and will help develop a rational approach to therapy. The book begins by describing the prenatal and postnatal growth and development of the lung, and it ends by describing the effects of the aging process on the lung. The chapters in between deal with metabolism, circulation, diffusion of
The Value of Urine Creatinine Analysis in the Evaluation of Schilling Tests
Authors: LTC JAMES D. HEIRONIMUS, LTC RONALD D. BORCHERT, COL FREDERICK L. WEILAND
Journal: Clinical Nuclear Medicine (1990)

We performed a prospective study to assess the clinical value of evaluating the adequacy of 24-hour urine specimens submitted for Schilling tests. A total of 121 specimens were evaluated of which 51 had abnormal vitamin B12 excretion values. Of those 51, there were 23 with apparently inadequate total creatinine content (implying a collection of less than 24 hours). Six of 12 specimens with less than 600 ml had adequate total creatinine content as well as normal vitamin B12 excretion. Compared with evaluation of specimen volume alone, these data support the inexpensive urine creatinine assay as a valuable source of information regarding the adequacy of 24-hour urine collections thereby improving the specificity of the Schilling test.
Edward Beresford Davies
Authors: A. Broadhurst
Journal: BMJ (2002)

Former consultant psychiatrist Addenbrooke's and Fulbourn Hospitals, Cambridge (b Liverpool 1913; q Cambridge/Middlesex Hospital 1947; MD, FRCPsych, DPM), died from myeloid leukaemia on 13 August 2001.

He was one of Cambridge's most distinguished psychiatrists and a statesman-like figure. His observations of the effects of battle stress during wartime service in the Royal Air Force strengthened his intention to become a psychiatrist. In 1960 he organised one of the first international conferences on antidepressant treatment. He used psychotropic medication when it was indicated but he was also a skilful psychotherapist. Edward started the Lithium Club, a national charity for all who needed to take lithium. His first wife, Hendriette, predeceased him after 55 years of marriage.
Modulation of skeletal muscle sodium channels by human myotonin protein kinase.
Authors: J P Mounsey, P Xu, J E John, L T Horne, J Gilbert, A D Roses, J R Moorman
Journal: Journal of Clinical Investigation (1995)

In myotonic muscular dystrophy, abnormal muscle Na currents underlie myotonic discharges. Since the myotonic muscular dystrophy gene encodes a product, human myotonin protein kinase, with structural similarity to protein kinases, we tested the idea that human myotonin protein kinase modulates skeletal muscle Na channels. Coexpression of human myotonin protein kinase with rat skeletal muscle Na channels in Xenopus oocytes reduced the amplitude of Na currents and accelerated current decay. The effect required the presence of a potential phosphorylation site in the inactivation mechanism of the channel. The mutation responsible for human disease, trinucleotide repeats in the 3' untranslated region, did not prevent the effect. The consequence of an abnormal amount of the kinase would be altered muscle cell excitability, consistent with the clinical finding of myotonia in myotonic dystrophy.
REINFARCTION-SPECIFIC MAGNETIC RESONANCE IMAGING CONTRAST AGENT
Authors: Robert Kirschner, Akos Varga-Szemes, Levente Toth, Tamas Simor, Pal Suranyi, Balazs Ruzsics, Pal Kiss, Attila Toth, Robert Baker, Brigitta C. Brott, Silvio Litovsky, Ada Elgavish, Gabriel A. Elgavish
Journal: Journal of the American College of Cardiology (2010)
Solomon A. Berson
Authors: Ronald A. Arky, F.J. Ingelfinger
Journal: New England Journal of Medicine (1972)

On April 11 this year, Dr. Solomon A. Berson died suddenly and prematurely while attending a meeting in Atlantic City. This woeful event interrupted at its height the fecund career of a man who, in collaboration with Dr. Rosalyn Yalow, made contributions that not only revolutionized an entire phase of laboratory practice but also affected some of the fundamental principles of medicine. Of the many Berson-Yalow achievements, probably none are more outstanding than their pioneering efforts in developing the technic of radioimmune assay, a method that permits the precise measurement of minute concentrations of many metabolically active peptide hormones and . . .
Integrated exposure uptake biokinetic model for lead in children: empirical comparisons with epidemiologic data.
Authors: K Hogan, A Marcus, R Smith, P White
Journal: Environmental Health Perspectives (1998)

The concept of model validation is evolving in the scientific community. This paper addresses the comparison of observed and predicted estimates as one component of model validation as applied to the integrated exposure uptake biokinetic (IEUBK) model for lead in children. The IEUBK model is an exposure (dose)-response model that uses children's environmental lead exposures to estimate risk of elevated blood lead (typically > 10 micrograms/dl) through estimation of lead body burdens in a mass balance framework. We used residence-specific environmental lead measurements from three epidemiologic datasets as inputs for the IEUBK model to predict blood lead levels, and compared these predictions with blood lead levels of children living at these residences. When the IEUBK modeling focused on children with representative exposure measurements, that is, children who spent the bulk of their time near the locations sampled, there was reasonably close agreement between observed and predicted blood lead distributions in the three studies considered. Geometric mean observed and predicted blood lead levels were within 0.7 microgram/dl, and proportions of study populations expected to be above 10 micrograms/dl were within 4% of those observed.
Transforming Growth Factor-β Gene Family Members and Bone*
Authors: MICHAEL CENTRELLA, MARK C. HOROWITZ, JOHN M. WOZNEY, THOMAS L. MCCARTHY
Journal: Endocrine Reviews (1994)

EARLY efforts to purify a bone-derived growth factor from rat bone culture medium revealed its biological and biochemical similarity to transforming growth factor-β type 1 (TGF-β1) extracted from human blood platelets. Cartilage inducing factors (CIF-A and CIF-B) from bovine bone matrix were then identified as TGF-β isoforms, and it soon became evident that bone cells synthesize TGF-βs and that bone matrix was a major repository of these factors in the organism. The TGF-β supergene family comprises at least five closely related proteins termed TGF-β1 through TGF-β5 in addition to a growing number of more distant but highly homologous growth regulators. Several of the closely related TGF-β isoforms occur in many animals, and appear to control development, growth, and differentiation in humans as well as a variety of other species. More importantly from the skeletal tissue perspective, some of the less closely related gene family members, activin-A and the bone morphogenetic proteins (BMPs), are also expressed by bone cells, stored in bone matrix, and increase bone cell activity in vivo and in vitro.
Multiple Roles of p53-Related Pathways in Somatic Cell Reprogramming and Stem Cell Differentiation
Authors: Lan Yi, Chiwei Lu, Wenwei Hu, Yvonne Sun, Arnold J. Levine
Journal: Cancer Research (2012)

The inactivation of p53 functions enhances the efficiency and decreases the latency of producing induced pluripotent stem cells (iPSC) in culture. The formation of iPSCs in culture starts with a rapid set of cell divisions followed by an epigenetic reprogramming of the DNA and chromatin. The mechanisms by which the p53 protein inhibits the formation of iPSCs are largely unknown. Using a temperature sensitive mutant of the p53 (Trp53) gene, we examined the impact of the temporal expression of wild type p53 in preventing stem cell induction from somatic cells. We also explored how different p53 mutant alleles affect the reprogramming process. We found that little or no p53 activity favors the entire process of somatic cell reprogramming. Reactivation of p53 at any time point during the reprogramming process not only interrupted the formation of iPSCs, but also induced newly formed stem cells to differentiate. Among p53-regulated genes, p21 (Cdkn1a), but not Puma (Bbc3) played a partial role in iPSCs formation probably by slowing cell division. Activation of p53 functions in iPSCs induced senescence and differentiation in stem cell populations. High rate of birth defects and increases in DNA methylation at the IGF2-H19 loci in female offspring of p53 knockout mice suggested that the absence of p53 may give rise to epigenetic instability in a stochastic fashion. Consistently, selected p53 missense mutations showed differential effects on the stem cell reprogramming efficiency in a c-Myc dependent manner. The absence of p53 activity and functions also contributed to an enhanced efficiency of iPSC production from cancer cells. The production of iPSCs in culture from normal and cancer cells, although different from each other in several ways, both responded to the inhibition of reprogramming by the p53 protein.
Left ventricular function in acute myocardial infarction
Authors: Paul Hamosh, Jay N. Cohn
Journal: Journal of Clinical Investigation (1971)

Left ventricular catheterization was carried out in 40 patients with acute myocardial infarction. Left ventricular end-diastolic pressure (LVEDP) was elevated in 85% of the patients studied. In 14 patients with apparently uncomplicated infarcts, LVEDP averaged 15 mm Hg, and cardiac index (2.98 liter/min/m(2)), stroke volume (38.3 ml/m(2)), and stroke work (49.2 g-m/m(2)) were within normal limits. In 12 patients with clinical signs of left ventricular failure, LVEDP averaged 29.9 mm Hg, cardiac index was at the lower limit of normal (2.79 liter/min/m(2)), but stroke volume (31.6 ml/m(2)) and stroke work (37.3 g-m/m(2)) were reduced. In 14 patients with clinical signs of shock, LVEDP averaged significantly lower than in the heart failure group (21.1 mm Hg), but cardiac index (1.59 liter/min/m(2)), stroke volume (16.5 ml/m(2)), and stroke work (11.1 g-m/m(2)) were markedly reduced. A large presystolic atrial "kick" (average amplitude 9.5 mm Hg) was an important factor in the high LVEDP in the patients with heart failure but not in those with shock. The first derivative of left ventricular pressure was significantly lower in shock than in the nonshock group. Although right atrial pressure (RAP) and LVEDP were significantly correlated (r = 0.49), wide discrepancies in individual patients rendered the RAP an unreliable indicator of the magnitude of left ventricular filling pressure. THESE DATA SHOW THE FOLLOWING: (a) LVEDP is usually elevated in acute myocardial infarction, even in absence of clinical heart failure; (b) cardiac output apparently is supported by increased LVEDP and compensatory tachycardia; (c) in patients with shock, left ventricular function usually is markedly impaired, but inadequate compensatory cardiac dilatation or tachycardia could contribute to the reduced cardiac output in some individuals; (d) lower LVEDP in shock than in heart failure may represent differences in left ventricular compliance.
Immunization Action Month—October 1973
Authors: John J. Witte
Journal: JAMA (1973)

The control and prevention of communicable diseases through immunization is a well established component of good medical care. During recent years, the availability and wide usage of vaccines have accounted for dramatic reductions in the morbidity and mortality from a number of once-feared diseases. Smallpox has disappeared from the United States (as well as from most of the world) because of effective vaccination programs. Epidemics of poliomyelitis no longer occur, thanks to extensive use of effective vaccines. The occurrence of diphtheria, pertussis, and tetanus has been substantially reduced as a result of systematic and comprehensive immunization. The use of measles vaccine has accounted for a sharp decline in the number of rubeola cases and deaths.  This record of achievement is impressive and we can feel assured that major problems from these diseases are no longer a factor in modern medical practice. Or, can we? Although no large epidemics of poliomyelitis