tbuckley/cabot-search huggingface dataset:
Physicians' Silent Decisions: Because Patient Autonomy Does Not Always Come First
Authors: Simon N. Whitney, Laurence B. McCullough
Journal: The American Journal of Bioethics (2007)

Physicians make some medical decisions without disclosure to their patients. Nondisclosure is possible because these are silent decisions to refrain from screening, diagnostic or therapeutic interventions. Nondisclosure is ethically permissible when the usual presumption that the patient should be involved in decisions is defeated by considerations of clinical utility or patient emotional and physical well-being. Some silent decisions—not all—are ethically justified by this standard. Justified silent decisions are typically dependent on the physician's professional judgment, experience and knowledge, and are not likely to be changed by patient preferences. We condemn the inappropriate exclusion of the patient from the decision-making process. However, if a test or treatment is unlikely to yield a net benefit, disclosure and discussion are at times unnecessary. Appropriate silent decisions are ethically justified by such considerations as patient benefit or economy of time.
Noninvasive quantitation of valvular regurgitation by gated equilibrium radionuclide angiography.
Authors: S G Sorensen, R A O'Rourke, T K Chaudhuri
Journal: Circulation (1980)

R-wave synchronous equilbrium radionuclide angiography (RNA) is a noninvasive method that provides time-activity curve count information proportional to ventricular volumes and is used for relative volume comparisons within the left or right ventricle to derive the ejection fraction. Comparison of the ventricular count output between both ventricles may permit quantitation of the relative amount of valvular regurgitation, i.e., the regurgitant fraction. We performed resting gated RNA in 30 consecutive patients undergoing cardiac catheterization and quantitative contrast ventriculography for aortic or mitral valvular regurgitation. RNA regurgitant fraction correlated well with cardiac catheterization regurgitant fraction (r = 0.85). In 11 patients imaged before and 1-4 months after successful valve replacement, the regurgitant fraction declined from 0.68 +/- 0.11 to -0.09 +/- 0.13 (p &lt; 0.001). In 20 control patients without valvular regurgitation, the calculated regurgitant fraction did not exceed 0.20. We conclude that valvular regurgitation may be accurately detected, quantitative and followed serially after therapeutic intervention using gated RNA.
Cardiac AAV9-S100A1 Gene Therapy Rescues Post-Ischemic Heart Failure in a Preclinical Large Animal Model
Authors: Sven T. Pleger, Changguang Shan, Jan Ksienzyk, Raffi Bekeredjian, Peter Boekstegers, Rabea Hinkel, Stefanie Schinkel, Barbara Leuchs, Jochen Ludwig, Gang Qiu, Christophe Weber, Philip Raake, Walter J. Koch, Hugo A. Katus, Oliver J. Müller, Patrick Most
Journal: Science Translational Medicine (2011)

As a prerequisite for clinical application, we determined the long-term therapeutic effectiveness and safety of adeno-associated virus (AAV)-S100A1 gene therapy in a preclinical large animal model of heart failure. S100A1, a positive inotropic regulator of myocardial contractility, becomes depleted in failing cardiomyocytes in humans and animals, and myocardial-targeted S100A1 gene transfer rescues cardiac contractile function by restoring sarcoplasmic reticulum calcium (Ca(2+)) handling in acutely and chronically failing hearts in small animal models. We induced heart failure in domestic pigs by balloon occlusion of the left circumflex coronary artery, resulting in myocardial infarction. After 2 weeks, when the pigs displayed significant left ventricular contractile dysfunction, we administered, by retrograde coronary venous delivery, AAV serotype 9 (AAV9)-S100A1 to the left ventricular, non-infarcted myocardium. AAV9-luciferase and saline treatment served as control. At 14 weeks, both control groups showed significantly decreased myocardial S100A1 protein expression along with progressive deterioration of cardiac performance and left ventricular remodeling. AAV9-S100A1 treatment prevented and reversed these functional and structural changes by restoring cardiac S100A1 protein levels. S100A1 treatment normalized cardiomyocyte Ca(2+) cycling, sarcoplasmic reticulum calcium handling, and energy homeostasis. Transgene expression was restricted to cardiac tissue, and extracardiac organ function was uncompromised. This translational study shows the preclinical feasibility of long-term therapeutic effectiveness of and a favorable safety profile for cardiac AAV9-S100A1 gene therapy in a preclinical model of heart failure. Our results present a strong rationale for a clinical trial of S100A1 gene therapy for human heart failure that could potentially complement current strategies to treat end-stage heart failure.
Cyclist's iliac syndrome: temporary relief by balloon angioplasty
Authors: L D Wijesinghe, P A Coughlin, I Robertson, D Kessel, P J Kent, R C Kester
Journal: British Journal of Sports Medicine (2001)

External iliac stenosis due to endofibrosis is a rare condition that predominantly affects top level cyclists. Short term symptomatic relief is reported in an Olympian after percutaneous transluminal angioplasty, which was performed to allow the patient to return to training without delay.
Maximal inspiratory pressures and dimensions of the diaphragm.
Authors: F D McCool, P Conomos, J O Benditt, D Cohn, C B Sherman, F G Hoppin
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

We postulated that the variation of maximal voluntary inspiratory pressures (PI,max and Pdi,max) among individuals largely reflects the variation of the structural attributes of the inspiratory muscles, in particular the muscular cross-sectional area of the diaphragm (CSAdi) and its axially projected area (A(thor)). To test this postulate, we measured PI,max in 36 healthy subjects, including 3 children and 15 weight-lifters, and Pdi,max in 11 subjects. Structural measurements by ultrasonography and anthropometric calipers were available as reported in the companion manuscript. We found a high degree of correlation of Pdi,max with diaphragm thickness (tdi), CSAdi, and CSAdi/A(thor) (r2 = 0.89, 0.89, and 0.77, respectively). PI,max was also correlated with diaphragm structural measurements, although less well. The weight-lifters had greater pressures, thicker diaphragms, and greater diaphragm maximal stress (sigma(max)) than adults of similar stature who had not trained with weights. We conclude (1) that both Pdi,max and PI,max reflect in part structural attributes of the respiratory muscles; (2) that the variation of maximal transdiaphragmatic pressures is largely attributable to the normal variation of diaphragm structure; (3) weight lifting increases diaphragm structure and pressures.
Race and socioeconomic factors influencing early placement on the kidney transplant waiting list.
Authors: B L Kasiske, W London, M D Ellison
Journal: Journal of the American Society of Nephrology (1998)

This cohort study investigates whether there are inequities in the current system for listing patients for cadaveric renal transplantation, using univariate and multivariate analyses to identify factors associated with early registration before initiation of dialysis. It includes patient registrations for the kidney and kidney-pancreas waiting lists between April 1, 1994, and June 30, 1996 (n = 41,596) from all 238 United Network for Organ Sharing renal transplant centers. Patient and center factors predicting dialysis status (pre- or postdialysis initiation) at the time of registration were examined. Independent predictors of listing before dialysis (P < 0.001) included: female (odds ratio [OR] = 1.14, reference: male, i.e., listing before dialysis was 14% more likely in females than in males); age < or =17 and age 18 to 55 (OR = 1.91 and 1.14, respectively, reference: age >55); prior transplant (OR = 1.80, reference: no prior transplant); 0 to 8 yr education, attended college, and received a college degree (OR = 0.78, 1.18, and 1.37, respectively, reference: high school degree); black race, Hispanic, and Asian/other (OR = 0.47, 0.59, and 0.55, reference: white); full-time employment (OR = 1.98, reference: less than full time); payment with Medicare and private insurance (OR = 0.35 and 1.24, respectively, reference: other pay); receiving insulin (OR = 1.29, reference; not on insulin); listed for kidney-pancreas (OR = 1.43, reference: listed for kidney only); listed at a center with volume >400 (OR = 1.22, reference: volume <400). To remove possible bias for general access to health care and referral for transplantation, the analysis was limited to patients who had a previous transplant and found similar results. It is concluded that racial and ethnic minorities, those less well educated, and those with fewer financial resources are less likely than their counterparts to be listed for renal transplantation before dialysis. These results suggest there may be remediable inequities in the current system for registration for renal transplantation in the United States. Education efforts directed at patients and providers, as well as recently mandated uniform listing criteria for cadaveric organ transplantation, may help to reduce these inequities.
New targets for disease modifying osteoarthritis drugs: chondrogenesis and Runx1
Authors: Francisco J Blanco, Cristina Ruiz-Romero
Journal: Annals of the Rheumatic Diseases (2013)

Osteoarthritis (OA) has recently been defined as a ‘whole joint’ disease with pathological changes in all tissues, including articular cartilage degradation, subchondral bone thickening, osteophyte formation, synovial inflammation and degeneration of ligaments, and, in the knee, the menisci.1 OA is a chronic musculoskeletal disease that leads to pain and severe impairment of mobility. OA is the main cause of work incapacity and one of the most common reasons for visiting primary care physicians; its prevalence reaches up to 40% of people over the age of 70.2 In later stages of OA, patients experience limited mobility and persistent pain, often requiring reconstructive surgery at that time. Although OA is the most prevalent rheumatic disease, affecting 40 million patients in Europe, existing therapies are symptomatic and pursue only pain alleviation with no effect on slowing disease progression.3 ,4

While affecting all structures within a joint, OA has generally been defined as a disease characterised by loss of hyaline articular cartilage. Adult articular cartilage exists as four distinct cellular zones. The superficial zone consists of one to two layers of flattened chondrocytes expressing proteoglycan 4 or lubricin, SRY-box 9 (Sox9), type II collagen, aggrecan, tenascin C and low levels of cartilage intermediate layer protein. Chondrocytes of the intermediate zone are round in appearance, do not express lubricin, but do express higher levels of cartilage intermediate layer protein. The chondrocytes of the radial and calcified zones express markers of chondrocyte differentiation and hypertrophy, such as type X collagen and alkaline phosphatase. Each of the articular cartilage regions is normally maintained throughout adulthood unless stress-related injury, inflammation or a genetic defect leads to the loss of either the signals required to maintain these cells or the signals required to inhibit excessive differentiation of these cells. Disruption or impairment of the signals …
HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity
Authors: S. G Deeks, A. N Phillips
Journal: BMJ (2009)

#### Summary points

More than 25 antiretroviral drugs from six therapeutic classes are now available for the management of HIV infection (box 1). Most patients who take medication achieve durable and perhaps lifelong viral suppression, so the classic AIDS related conditions are becoming less common. However, treated patients do not have completely restored health. Compared with people without HIV infection, patients with the infection who are treated with antiretrovirals have increased risk for several “non-AIDS” complications, many of which are commonly associated with ageing (box 2). This risk is particularly evident in patients whose CD4+ T cell counts are below normal during long term treatment, but it is also seen to some extent in those with higher CD4+ T cell counts. As a consequence of the changing spectrum of HIV associated disease, the medical management of HIV infection is evolving—a lower proportion of time is now spent managing drug resistance and short term toxicities and a higher proportion is spent managing these premature age associated complications. This review discusses the evidence that the major complications of “treated” HIV disease—including cardiovascular disease, malignancy, renal disease, …
Barrett's Esophagus and Esophageal Adenocarcinoma
Authors: Robert S. Bresalier
Journal: Annual Review of Medicine (2008)

The incidence of esophageal adenocarcinoma (EAC) has risen dramatically over the past three decades in western countries. The importance of Barrett's esophagus (BE) derives from its potential to transform to adenocarcinoma. BE is characterized by endoscopically recognized displacement of the squamocolumnar junction proximal to the gastroesophageal junction, with replacement of squamous mucosa with columnar lined mucosa. Adenocarcinomas of the esophagus appear to arise from Barrett's mucosa through progressive degrees of dysplasia, but the pathogenesis and natural history of this process are still unclear. Much of our knowledge regarding BE and the risk of EAC is based on observational and cross-sectional analyses, and recommendations regarding management have traditionally represented “expert opinion.” The past few years have seen an explosion in new information and the initiation of longitudinal studies to define the risk of adenocarcinoma in BE, the identification of predictive and prognostic markers of cancer risk, sensitive and cost-effective methods of surveillance, and methods of management of dysplasia and early neoplasia including disease prevention.
Expression and Functional Role of CCR9 in Prostate Cancer Cell Migration and Invasion
Authors: Shailesh Singh, Udai P. Singh, Jonathan K. Stiles, William E. Grizzle, James W. Lillard
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Metastasis is responsible for most cancer-related deaths; hence, therapies designed to minimize metastasis are greatly needed. The precise cellular and molecular mechanisms used by cancer cells for metastasis are not fully understood; however, the metastatic spread of neoplastic cells is probably related to the ability of these cells to migrate, invade, home, and survive locally. The migration of tumor cells shares many similarities with leukocyte trafficking, which is regulated by chemokine receptor–ligand interactions. The current study evaluates the molecular mechanisms of CCL25 and CCR9 in prostate cancer cell migration and invasion. Experimental Design: In the current study, real-time quantitative polymerase chain reaction, flow cytometry analysis, and in vitro migration as well as invasion chamber analysis (with and without antibody-mediated inhibition) were used to ascertain the biological and functional significance of CCR9 expression by normal prostatic epithelial cells (PrEC) or prostate cancer cell lines (LNCaP-10995 and PC3). Results: We report that functional CCR9 is highly expressed by LNCaP cells and modestly, yet significantly, expressed by PC3 cells when compared with PrEC cells. Neutralization of CCL25–CCR9 interactions impaired the migration and invasion potential of the LNCaP and PC3 cell lines. CCL25 differentially modulated the expression of collagenase-1 or matrix metalloproteinase (MMP)-1, collagenase-3 (MMP-13), stromalysin-2 (MMP-10), stromalysin-3 (MMP-11), and gelatinase-A (MMP-2), but not MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, or MMP-14 in prostate cancer cells. Conclusions: These studies suggest that the expression and activation of CCR9 affect cancer cell migration, invasion, and MMP expression, which together may affect prostate cancer metastasis.
GLIPR1 Suppresses Prostate Cancer Development through Targeted Oncoprotein Destruction
Authors: Likun Li, Chengzhen Ren, Guang Yang, Elmoataz Abdel Fattah, Alexei A. Goltsov, Soo Mi Kim, Ju-Seog Lee, Sanghee Park, Francesco J. Demayo, Michael M. Ittmann, Patricia Troncoso, Timothy C. Thompson
Journal: Cancer Research (2011)

Downregulation of the proapoptotic p53 target gene glioma pathogenesis-related protein 1 (GLIPR1) occurs frequently in prostate cancer, but the functional meaning of this event is obscure. Here, we report the discovery of functional relationship between GLIPR1 and c-Myc in prostate cancer where c-Myc is often upregulated. We found that the expression of GLIPR1 and c-Myc were inversely correlated in human prostate cancer. Restoration of GLIPR1 expression in prostate cancer cells downregulated c-myc levels, inhibiting cell-cycle progression. Downregulation was linked to a reduction in β-catenin/TCF4-mediated transcription of the c-myc gene, which was caused by GLIPR1-mediated redistribution of casein kinase 1α (CK1α) from the Golgi apparatus to the cytoplasm where CK1α could phosphorylate β-catenin and mediate its destruction. In parallel, GLIPR1 also promoted c-Myc protein ubiquitination and degradation by glycogen synthase kinase-3α- and/or CK1α-mediated c-Myc phosphorylation. Notably, genetic ablation of the mouse homolog of Glipr1 cooperated with c-myc overexpression to induce prostatic intraepithelial neoplasia and prostate cancer. Together, our findings provide evidence for CK1α-mediated destruction of c-Myc and identify c-Myc S252 as a crucial CK1α phosphorylation site for c-Myc degradation. Furthermore, they reveal parallel mechanisms of c-myc downregulation by GLIPR1 that when ablated in the prostate are sufficient to drive c-Myc expression and malignant development.
A Phase I-II Study of Docetaxel and Atrasentan in Men with Castration-Resistant Metastatic Prostate Cancer
Authors: Andrew J. Armstrong, Patricia Creel, James Turnbull, Cassandra Moore, Tracy A. Jaffe, Sherri Haley, William Petros, Sarah Yenser, Jon P. Gockerman, Darryl Sleep, Herbert Hurwitz, Daniel J. George
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The primary aims of this phase I-II study were to determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary efficacy of the combination of docetaxel and the endothelin A receptor antagonist atrasentan as first-line treatment for men with metastatic castration-resistant prostate cancer. Experimental Design: Patients were treated with docetaxel at doses ranging from 60 to 75 mg/m2 every 21 days, with daily oral atrasentan 10 mg starting on day 3. Patients were treated until evidence of disease progression or unacceptable toxicity. Results: Thirty-one patients were enrolled over three docetaxel dose levels (8 at 60 mg/m2, 19 at 70 mg/m2, and 4 at 75 mg/m2) including dose expansion at 70 mg/m2. The maximum tolerated dose of docetaxel was 70 to 75 mg/m2. Drug-related grade 3-4 toxicities included neutropenia (50-63%) and febrile neutropenia (16-25%); other grade 1-2 toxicities included fatigue, peripheral edema, diarrhea, headache, rhinitis, anorexia, and nausea. Confirmed prostate-specific antigen (PSA) responses were observed in 23% [95% confidence interval (95% CI), 10-41%]; the rate of &amp;gt;30% declines in PSA was 35% (95% CI, 19-55%). Median overall survival was 17.6 months (95% CI, 13.0-23.2) and median progression-free survival was 4.2 months (95% CI, 2.3-5.8). Significant declines in bone alkaline phosphatase and serum N-telopeptides were observed with therapy. Conclusions: The maximum tolerated dose of every-3-week docetaxel with 10 mg atrasentan is 70 to 75 mg/m2. Overall survival and progression-free survival are comparable to that seen with docetaxel and prednisone, whereas the rates of PSA decline are slightly lower than expected. A phase III study of this combination with prednisone has been initiated and is ongoing.
Proceedings of the Oxygen Homeostasis/Hypoxia Meeting
Authors: Bennett Kaufman, Orit Scharf, Jeffrey Arbeit, Margaret Ashcroft, J. Martin Brown, Richard K. Bruick, J. Donald Chapman, Sydney M. Evans, Amato J. Giaccia, Adrian L. Harris, Eric Huang, Randall Johnson, William Kaelin, Cameron J. Koch, Patrick Maxwell, James Mitchell, Len Neckers, Garth Powis, Joseph Rajendran, Gregg L. Semenza, Jonathan Simons, Erik Storkebaum, Michael J. Welch, Murray Whitelaw, Giovanni Melillo, S. Percy Ivy
Journal: Cancer Research (2004)

Abstract The first Oxygen Homeostasis/Hypoxia Meeting was held on February 12, 2003, at the Sheraton National Hotel, Washington, D.C. The meeting was hosted by Drs. S. Percy Ivy and Giovanni Melillo of the National Cancer Institute, NIH. The purpose of the meeting was to stimulate collaborations among the participants who are engaged in different areas of hypoxia research and application, including basic research on hypoxia, and its induction and consequences; the development of drugs targeting hypoxia and factors involved in pathways leading to (or controlled by) hypoxia; and the development and application of hypoxia imaging techniques and reagents.
The Wilms’ tumor gene (WT1) regulates E-cadherin expression and migration of prostate cancer cells
Authors: Adina Brett, Sony Pandey, Gail Fraizer
Journal: Molecular Cancer (2013)

Abstract Background One key step in the development of prostate cancer (PCa) metastasis is the loss of E-cadherin expression associated with increased cellular motility and tumor invasion. This loss of E-cadherin expression is also required during normal embryogenesis and similar transcriptional repressors have been identified in both processes. We have previously reported the presence of one such transcription factor, WT1 in high Gleason grade prostate tumor tissues, and its absence in non-neoplastic or benign prostatic hyperplasia tissues. Results To better understand the effect of WT1 on E-cadherin expression and migration of PCa cells we quantified WT1 and E-cadherin mRNA levels in normal prostate epithelial and PCa cell lines with varying migratory potential. In WT1 transfected cells E-cadherin transcript levels were decreased, while they were increased in siWT1-RNA transfected PCa cells, suggesting that elevated WT1 expression was sufficient to dampen E-cadherin levels and potentially enhance migratory ability. To delineate the mechanism of WT1-mediated repression of E-cadherin, potential WT1 binding sites were tested in vitro and in vivo binding of WT1 to the E-cadherin promoter in the chromatin of LNCaP and PC3 cells was assessed by Chromatin Immunoprecipitation. The effect of WT1 binding was measured in reporter assays; in PC3 and DU145 cells WT1 decreased the activity of the proximal E-cadherin promoter. Using site-directed mutagenesis, a newly identified WT1 binding site located 146 bp from the transcription start site was shown to be required for this repression by WT1. Transwell migration and wound healing assays revealed that in LNCaP cells with low migratory potential, over-expression of WT1 was sufficient to enhance migration, conversely, in the highly migratory PC3 cells silencing of WT1 decreased migration. Conclusions These findings suggested that WT1 expression in high grade prostate cancer may contribute to migration and metastasis. Thus, in prostate cancer WT1 may function as a novel oncogene facilitating development of the lethal metastatic phenotype.
A patient with respiratory obstruction in glandular fever
Authors: A. D. Simcock, B. J. Prout
Journal: Thorax (1974)

<b>Simcock, A. D., and Prout, B. J. (1974).</b><i>Thorax</i>, <b>29</b>, 145-146. <b>A patient with respiratory obstruction in glandular fever.</b> Glandular fever is a common disease, and one of the most consistent features is enlargement of tonsillar and nasopharyngeal lymph nodes. This is usually of little serious consequence and, if difficulty in swallowing or breathing occurs, responds rapidly to treatment. We report a case of glandular fever where lymph node enlargement caused respiratory obstruction which required urgent tracheostomy. Some other uncommon features are discussed.