tbuckley/cabot-search huggingface dataset:
Proportion of Breast Cancer Cases in the United States Explained by Well-Established Risk Factors
Authors: M. P. Madigan, R. G. Ziegler, J. Benichou, C. Byrne, R. N. Hoover
Journal: JNCI Journal of the National Cancer Institute (1995)

Few estimates of the fraction of cases of breast cancer attributable to recognized risk factors have been published. All estimates are based on selected groups, making their generalizability to the U.S. population uncertain.Our goal was to estimate the fraction of breast cancer cases in the United States attributable to well-established risk factors (i.e., later age at first birth, nulliparity, higher family income, and first-degree family history of breast cancer), using data from the first National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study (NHEFS), the survey and follow-up of a probability sample of the U.S. population.From a cohort of 7508 female participants surveyed in the early 1970s, and followed up between 1982 and 1984 and again in 1987, 193 breast cancer cases were accrued for study. We calculated incidence rates, relative risks (RRs), and population attributable risks (PARs) for breast cancer risk factors and extended our results to the U.S. female population by using sample weights from the NHANES I survey.Our PAR estimates suggest that later age at first birth and nulliparity accounted for a large fraction of U.S. breast cancer cases, 29.5% (95% confidence interval [CI] = 5.6%-53.3%); higher income contributed 18.9% (95% CI = -4.3% to 42.1%), and family history of breast cancer accounted for 9.1% (95% CI = 3.0%-15.2%). Taken together, these well-established risk factors accounted for approximately 47% (95% CI = 17%-77%) of breast cancer cases in the NHEFS cohort and about 41% (95% CI = 2%-80%) in the U.S. population.The RRs for most of these risk factors were modest, but their prevalence as a group was high, leading to estimates that suggest that a substantial proportion of breast cancer cases in the United States are explained by well-established risk factors.Elucidation of the determinants underlying recognized factors and study of other factors that may confer risk or protection are needed in efforts to advance understanding of breast cancer etiology and to aid in devising strategies for prevention.
Diuretics and Cholesterol Elevation
Authors: W. McFate Smith
Journal: JAMA (1979)

<h3>To the Editor.—</h3> In his article titled "Prazosin and Clonidine for Moderately Severe Hypertension," Walter M. Kirkendall, MD (240:2553, 1978), describes the cholesterol-raising effect of the diuretics chlorthalidone and polythiazide, citing also the reports of Ames and Hill<sup>1</sup>and of Schnaper et al.<sup>2</sup>Although noting that the former observed this effect for hydrochlorothiazide also, Dr Kirkendall asserts that "the effect of thiazide diuretics is not as well established," apparently based on failure of the data from the Framingham Heart Study<sup>3</sup>to show such an association. Two observations are relevant to this question: The first is that it is not surprising for there to be failure to recognize such an effect (5% to 10% change) in an uncontrolled community study not designed to be sensitive to such questions. Uncontrollable variation in drug use (both dosage and duration) as well as nonrandom dietary intervention could easily obscure such aneffect.
Pulmonary arterial hypertension in patients with sleep apnoea syndrome
Authors: E Bady
Journal: Thorax (2000)

Pulmonary arterial hypertension (PAH) in patients with sleep apnoea syndrome (SAS) is classically ascribed to associated chronic obstructive pulmonary disease (COPD). The aim of this retrospective study was to evaluate the possible occurrence of PAH as a complication of SAS in patients without COPD.Right heart catheterisation was performed in 44 patients with SAS and without COPD confirmed by polysomnography (apnoea index >5/h) admitted for the administration of nasal continuous positive airway pressure (CPAP).Precapillary PAH, defined as mean pulmonary arterial pressure of >20 mm Hg with pulmonary capillary wedge pressure <15 mm Hg, was observed in 12/44 (27%) patients with SAS. There were no significant differences in apnoea index between patients with (PAH+) and those without PAH (PAH-) (42.6 (26.3) versus 35.8 (21.7) apnoeas/h). The PAH+ group differed significantly from the PAH- group in the following respects: lower daytime arterial oxygen tension (PaO(2)) (9.6 (1.1) versus 11.3 (1.5) kPa, p=0.0006); higher daytime arterial carbon dioxide tension (PaCO(2)) (5.8 (0.5) versus 5.3 (0.5) kPa, p=0.002); more severe nocturnal hypoxaemia with a higher percentage of total sleep time spent at SaO(2) <80% (32.2 (28.5)% versus 10.7 (18.8)%, p=0.005); and higher body mass index (BMI) (37.4 (6) versus 30.3 (6.7) kg/m(2), p=0.002). The PAH+ patients had significantly lower values of vital capacity (VC) (87 (14)% predicted versus 105 (20)% predicted, p=0.005), forced expiratory volume in one second (FEV(1)) (82 (14)% predicted versus 101 (17)% predicted, p=0.001), expiratory reserve volume (40 (16)% predicted versus 77 (41)% predicted, p=0.003), and total lung capacity (87 (13)% predicted versus 98 (18)% predicted, p=0.04). Stepwise multiple regression analysis showed that mean pulmonary artery pressure (PAPm) was positively correlated with BMI and negatively with PaO(2).Pulmonary arterial hypertension is frequently observed in patients with SAS, even when COPD is absent, and appears to be related to the severity of obesity and its respiratory mechanical consequences.
Three Patients with Full Facial Transplantation
Authors: Bohdan Pomahac, Julian Pribaz, Elof Eriksson, Ericka M. Bueno, J. Rodrigo Diaz-Siso, Frank J. Rybicki, Donald J. Annino, Dennis Orgill, Edward J. Caterson, Stephanie A. Caterson, Matthew J. Carty, Yoon S. Chun, Christian E. Sampson, Jeffrey E. Janis, Daniel S. Alam, Arturo Saavedra, Joseph A. Molnar, Thomas Edrich, Francisco M. Marty, Stefan G. Tullius
Journal: New England Journal of Medicine (2011)

Unlike conventional reconstruction, facial transplantation seeks to correct severe deformities in a single operation. We report on three patients who received full-face transplants at our institution in 2011 in operations that aimed for functional restoration by coaptation of all main available motor and sensory nerves. We enumerate the technical challenges and postoperative complications and their management, including single episodes of acute rejection in two patients. At 6 months of follow-up, all facial allografts were surviving, facial appearance and function were improved, and glucocorticoids were successfully withdrawn in all patients.
Pacemaker Activity During Vagal Escape Rhythms
Authors: ANDREW G. WALLACE, WILLARD M. DAGGETT
Journal: Circulation Research (1964)

In dogs, bipolar electrograms were recorded from the SA node and His bundle to localize pacemaker sites during vagal escape and to study the effects of isoproterenol on escape mechanisms. Vagal escape can result from the development of pacemaker activity above the A-V node, within the region of the A-V node, and below the common bundle of His. Isoproterenol shortened the period of asystole prior to the onset of vagal escape, increased the rate of escape rhythms at all pacemaker sites, and occasionally changed the pacemaker to a higher focus in the conduction system.
Pigmented Hyperplasia of Epidermis Following Feeding of l -Dopa to Elderly Rats
Authors: B. Maat
Journal: JNCI Journal of the National Cancer Institute (1977)

In view of clinical data supporting a casual relationship between long-term L-dopa administration and recurrence of melanoma, long-term L-dopa administration to aged rats was performed to investigate its effect on the incidence of malignant melanoma. Of the treated animals, 11% showed local pigmented epidermal hyperplasia, compared with 0.5% of the control animals, but the number of expected melanomas was not increased by L-dopa treatment.
Ontogenesis of thyrotropin-releasing hormone in the human fetal pancreas. A combined radioimmunological and immunocytochemical study.
Authors: P Leduque, S Aratan-Spire, P Czernichow, P M Dubois
Journal: Journal of Clinical Investigation (1986)

The ontogenesis of pancreatic thyrotropin-releasing hormone (TRH) in the human fetal gland was studied by radioimmunoassay or immunocytochemistry. The highest TRH concentrations (1,508.5 +/- 382.3 pg/mg wet wt) were detected between 6 and 8 wk of gestation. From 9 to 12 wk, TRH declined to 365.2 +/- 127.4 pg/mg wet wt and remained low thereafter (96.1 +/- 28.9 pg/mg wet wt). The immunocytochemical procedure was performed on semithin and thin sections from 12- to 19-wk-old human fetuses. At the light microscope level, TRH was found interspersed among the islet cell clusters (12 wk), and later (16 wk) inside the typical islets of Langerhans. Consecutive semithin sections treated by TRH and insulin antisera showed the same immunoreactive cells. Electron microscopy showed TRH in B cell secretory granules. These results are consistent with an eventual implication of TRH in the endocrine regulation of metabolism or in the fetal development of pancreas.
Human Amyloidogenic Light Chains Directly Impair Cardiomyocyte Function Through an Increase in Cellular Oxidant Stress
Authors: Daniel A. Brenner, Mohit Jain, David R. Pimentel, Bo Wang, Lawreen H. Connors, Martha Skinner, Carl S. Apstein, Ronglih Liao
Journal: Circulation Research (2004)

Primary amyloidosis is a systemic disorder characterized by the clonal production and tissue deposition of immunoglobulin light chain (LC) proteins. Congestive heart failure remains the greatest cause of death in primary amyloidosis, due to the development of a rapidly progressive amyloid cardiomyopathy. Amyloid cardiomyopathy is largely unresponsive to current heart failure therapies, and is associated with a median survival of less than 6 months and a 5-year survival of less than 10%. The mechanisms underlying this disorder, however, remain unknown. In this report, we demonstrate that physiological levels of human amyloid LC proteins, isolated from patients with amyloid cardiomyopathy (cardiac-LC), specifically alter cellular redox state in isolated cardiomyocytes, marked by an increase in intracellular reactive oxygen species and upregulation of the redox-sensitive protein, heme oxygenase-1. In contrast, vehicle or control LC proteins isolated from patients without cardiac involvement did not alter cardiomyocyte redox status. Oxidant stress imposed by cardiac-LC proteins further resulted in direct impairment of cardiomyocyte contractility and relaxation, associated with alterations in intracellular calcium handling. Cardiomyocyte dysfunction induced by cardiac-LC proteins was independent of neurohormonal stimulants, vascular factors, or extracellular fibril deposition, and was prevented through treatment with a superoxide dismutase/catalase mimetic. This study suggests that cardiac dysfunction in amyloid cardiomyopathy is directly mediated by LC protein-induced cardiomyocyte oxidant stress and alterations in cellular redox status, independent of fibril deposition. Antioxidant therapies or treatment strategies aimed at eliminating circulating LC proteins may therefore be beneficial in the treatment of this fatal disease.
Cytokine-Induced Modulation of Cardiac Function
Authors: Sumanth D. Prabhu
Journal: Circulation Research (2004)

Cytokines act in an autocrine and/or paracrine fashion to induce a diverse variety of biological responses. Several cardiac diseases are associated with cytokine activation, and such activation significantly influences several physiologic parameters, including cardiac mechanical function. This review summarizes the current concepts regarding the modulation of myocardial function by cytokines and provides rationale for the sometimes-conflicting results in the literature regarding underlying mechanisms and patterns of dysfunction. Although traditionally considered cardiodepressant mediators, contractile responses are complex and bimodal, with an early response (within minutes) of variable direction, stimulatory or depressant, depending on the ambient physiologic milieu and relative contributions of the underlying signaling pathways that are activated. These pathways include sphingomyelinase-, nitric oxide (NO)-, and phospholipase A2-dependent signaling with resultant combined effects on contraction and the Ca 2+ transient. This is subsequently followed by a profoundly cardiodepressant late response lasting hours to days, depending on the production of secondary mediators and the combined influence of NO generated from inducible NO synthase, reactive oxygen species, and alterations in β-adrenergic receptor signaling. The interrelationships between these pathways and the time-dependence of their activation are important considerations in the evaluation of cytokine-dependent dysfunction during both acute cardiac injury and chronic cardiac pathologies.
Does Insulin Glargine Increase the Risk of Cancer Compared With Other Basal Insulins?
Authors: Jean-Paul Fagot, Pierre-Olivier Blotière, Philippe Ricordeau, Alain Weill, François Alla, Hubert Allemand
Journal: Diabetes Care (2012)

To explore in France the relationship between insulin glargine use and overall and specific cancer risks in type 2 diabetic patients compared with other basal insulins.Data were extracted from French health insurance information system (Système National d'Information Inter-Régimes de l'Assurance Maladie) linked with data from the French Hospital Discharge database (Programme de Médicalisation des Systèmes d'Information). Included were 70,027 patients aged 40-79 years who started a basal insulin in 2007-2009. Cox proportional hazards models with age as time-scale were used to calculate multivariate-adjusted hazard ratios for associations between type of basal insulin and risk of overall cancer, breast cancer, and seven other cancer sites.The median follow-up was 2.67 years in patients exposed to insulin glargine. Absolute event rates for all cancer in patients exposed to glargine versus other basal insulin users were 1,622 and 1,643 per 100,000 person-years, respectively. No significant association was observed between glargine exposure and overall cancer incidence after adjustment for sex, with a hazard ratio of 0.97 (95% CI 0.87-1.07), or after additional adjustment for any other hypoglycemic agent use and duration of diabetes. No increased risk of breast cancer was observed for glargine users compared with other basal insulins users, with a fully adjusted hazard ratio of 1.08 (0.72-1.62).In a large cohort of patients newly treated by basal insulin, no increased risk of any cancer was observed in insulin glargine users compared with other basal insulin users. Because follow-up did not exceed 4 years, longer-term studies are needed.
POLIOVIRUS PRECIPITINS
Authors: George L. Le Bouvier
Journal: The Journal of Experimental Medicine (1957)

Antigens present in poliovirus concentrates react with antibodies present in the serum of hyperimmunized monkeys to give type-specific precipitates. One or more bands of precipitate can be formed wherever such homotypic reactants, diffusing into an agar gel, meet in sufficient concentration and in equivalent proportions. No qualitative differences have been detected between the type-specific reactions given by different strains of the same virus type; and no precipitates have been seen which could be called "group-specific." Non-specific precipitates have occasionally been observed. Type-specific poliovirus precipitins are found in the serum of poliomyelitis patients. Their concentration has been measured by a standardized method. They tend to develop in parallel with neutralizing antibodies against the same virus type, increasing in amount during the first weeks of illness in those patients who show concurrent neutralizing antibody rises. The precipitation reaction has proved valuable in the antigenic analysis of polioviruses. Its general adoption as a diagnostic procedure is perhaps unlikely; but it may be well worth applying for special purposes.
Expression of Matrix Metalloproteinases and Endogenous Inhibitors Within Ascending Aortic Aneurysms of Patients With Marfan Syndrome
Authors: John S. Ikonomidis, Jeffery A. Jones, John R. Barbour, Robert E. Stroud, Leslie L. Clark, Brooke S. Kaplan, Ahmed Zeeshan, Joseph E. Bavaria, Joseph H. Gorman, Francis G. Spinale, Robert C. Gorman
Journal: Circulation (2006)

Background— Marfan syndrome (MFS) is known to cause ascending thoracic aortic aneurysms (ATAAs). Transforming growth factor beta (TGF-β) has recently been implicated in this process. Imbalances between the matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) have also been shown to contribute to aneurysm formation. Whether and to what degree MMP, TIMP, and TGF-β signaling profiles are altered in ATAAs in MFS compared with non-MFS patients remains unknown. Methods and Results— ATAA samples taken during aortic replacement from age-matched MFS (n=9) and non-MFS (n=18) patients were assessed for representative subtypes of all MMP classes, all 4 known TIMPs, and type 2 TGF-β receptors (TGFBR2). Results were expressed as a percentage (mean±SEM) of reference control samples (100%; n=18) obtained from patients without ATAA. In MFS, decreased MMP-2 (76±7; P &lt;0.05 versus control), increased MMP-12 (161±27% versus control; P &lt;0.05), and increased MT1-MMP (248±64% versus 91±21 non-MFS and control; P &lt;0.05) were observed. TIMP-3 (74±23%) was reduced compared with control values ( P &lt;0.05) and TIMP-2 was elevated (128±31%) compared with non-MFS (73±19%; P &lt;0.05). In non-MFS samples, MMP-1 (70±16%), MMP-3 (77±18%), MMP-8 (75±11%), MMP-9 (69±14%), and MMP-12 (85±15%) were decreased compared with control ( P &lt;0.05). TIMPs 1 to 3 were reduced in non-MFS compared with control values ( P &lt;0.05). TGFBR2 were increased in MFS (193±32%) compared with non-MFS (95±16%) and controls ( P &lt;0.05). Conclusions— A unique MMP and TIMP portfolio was observed in ATAAs from MFS compared with non-MFS patients. In addition, MFS samples showed evidence of increased TGF-β signaling. These differences suggest disparate mechanisms of extracellular matrix remodeling between these 2 groups of patients.
PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12/CXCR4 signaling
Authors: M Katie Conley-LaComb, Allen Saliganan, Pridvi Kandagatla, Yong Q Chen, Michael L Cher, Sreenivasa R Chinni
Journal: Molecular Cancer (2013)

Abstract Introduction The chemokine CXCL12, also known as SDF-1, and its receptor, CXCR4, are overexpressed in prostate cancers and in animal models of prostate-specific PTEN deletion, but their regulation is poorly understood. Loss of the tumor suppressor PTEN (phosphatase and tensin homolog) is frequently observed in cancer, resulting in the deregulation of cell survival, growth, and proliferation. We hypothesize that loss of PTEN and subsequent activation of Akt, frequent occurrences in prostate cancer, regulate the CXCL12/CXCR4 signaling axis in tumor growth and bone metastasis. Methods Murine prostate epithelial cells from PTEN +/+ , PTEN +/− , and PTEN −/− (prostate specific knockdown) mice as well as human prostate cancer cell lines C4-2B, PC3, and DU145 were used in gene expression and invasion studies with Akt inhibition. Additionally, HA-tagged Akt1 was overexpressed in DU145, and tumor growth in subcutaneous and intra-tibia bone metastasis models were analyzed. Results Loss of PTEN resulted in increased expression of CXCR4 and CXCL12 and Akt inhibition reversed expression and cellular invasion. These results suggest that loss of PTEN may play a key role in the regulation of this chemokine activity in prostate cancer. Overexpression of Akt1 in DU145 resulted in increased CXCR4 expression, as well as increased proliferation and cell cycle progression. Subcutaneous injection of these cells also resulted in increased tumor growth as compared to neo controls. Akt1 overexpression reversed the osteosclerotic phenotype associated with DU145 cells to an osteolytic phenotype and enhanced intra-osseous tumor growth. Conclusions These results suggest the basis for activation of CXCL12 signaling through CXCR4 in prostate cancer driven by the loss of PTEN and subsequent activation of Akt. Akt1-associated CXCL12/CXCR4 signaling promotes tumor growth, suggesting that Akt inhibitors may potentially be employed as anticancer agents to target expansion of PC bone metastases.
Structural Variation in the Human Genome and its Role in Disease
Authors: Paweł Stankiewicz, James R. Lupski
Journal: Annual Review of Medicine (2010)

During the last quarter of the twentieth century, our knowledge about human genetic variation was limited mainly to the heterochromatin polymorphisms, large enough to be visible in the light microscope, and the single nucleotide polymorphisms (SNPs) identified by traditional PCR-based DNA sequencing. In the past five years, the rapid development and expanded use of microarray technologies, including oligonucleotide array comparative genomic hybridization and SNP genotyping arrays, as well as next-generation sequencing with "paired-end" methods, has enabled a whole-genome analysis with essentially unlimited resolution. The discovery of submicroscopic copy-number variations (CNVs) present in our genomes has changed dramatically our perspective on DNA structural variation and disease. It is now thought that CNVs encompass more total nucleotides and arise more frequently than SNPs. CNVs, to a larger extent than SNPs, have been shown to be responsible for human evolution, genetic diversity between individuals, and a rapidly increasing number of traits or susceptibility to traits; such conditions have been referred to as genomic disorders. In addition to well-known sporadic chromosomal microdeletion syndromes and Mendelian diseases, many common complex traits including autism and schizophrenia can result from CNVs. Both recombination- and replication-based mechanisms for CNV formation have been described.