tbuckley/cabot-search huggingface dataset:
HETEROGENEITY OF RABBIT I<scp>G</scp>M ANTIBODY AS DETECTED BY C'1a FIXATION
Authors: Leon W. Hoyer, Tibor Borsos, Herbert J. Rapp, Wilton E. Vannier
Journal: The Journal of Experimental Medicine (1968)

The C'1a-fixing properties of purified rabbit IgM anti-benzenearsonate antibody were determined. When tested with sheep erythrocytes to which hapten had been coupled by diazo linkage, the number of C'1a molecules fixed was 21% of the number of IgM antibody molecules bound to the erythrocyte surface. This was not due to loss of C'1a-fixing capacity during the purification procedure. Preparative electrophoresis of the antibody concentrated C'1a-fixing molecules in the anodal region so that antibody fractions with greater C'1a-fixing capacity were obtained. The demonstration that C'1a fixation is a property of a subpopulation of IgM molecules provides evidence for previously unrecognized µ-chain heterogeneity.
Establishing a Framework for Improving the Quality of Clinical and Translational Research
Authors: Robert M. Califf, Sally Kornbluth
Journal: Journal of Clinical Oncology (2012)

TO THEEDITOR: The discovery of serious problems with research conducted in a laboratory at Duke University 1 has had a profound effect on our approach to translational research. We believe that this experience provides a number of salient, broadly applicable lessons— not just for the field of cancer genomics, but for scientific endeavors and institutions across the spectrum of biomedical research. As part of our initial response, we have developed a set of principles for translational research. 2 This Translational Medicine Quality Framework (TMQF) Principles document reflects the work of a multidisciplinary faculty leadership group and a panel of external experts who represent clinical, laboratory, and genomic research, including quantitative sciences. These principles have been formulated to ensure that research efforts at Duke University are guided by clear and consistent standards for quality. In particular, this framework will enhance the degree to which both the public and the scientific community can be confident that basic and translational research resulting in human applications has been conducted and validated in a manner consistent with current knowledge of the issues, the necessary scope of expertise, an awareness of the potential pitfalls of translational genomic research, and the relevant regulatory requirements. Key points of the TMQF document include creating accountability for research quality and fostering a culture of open discussion and challenge of research beyond the individual laboratory and investigator; guaranteeing robust data provenance and reproducible data management; ensuring adequate quantitative collaboration as a standard in the research environment; and enacting heightened scrutiny of human research that involves conflicts of interest, whether individual or institutional. We are currently finalizing a document that will detail our specific plans for implementing improvements to research quality throughout the institution. As part of the corrective actions taken, we have conducted an intensive review of all publications that resulted from Anil Potti’s work at Duke University (including five that appeared inJournal of Clinical Oncology) 3-7 and for which Potti appears as an author or coauthor. After we excluded opinion pieces and reviews without original data, we were left with 32 articles that included more than 150 coauthors. In each case, we asked the coauthors to attest once again to the conditions of authorship and to collaborate to determine whether they could vouch for the reproducibility of the results. This effort led to the full retraction of 10 articles (nine published;
The Membrane-Anchored Matrix Metalloproteinase (MMP) Regulator RECK in Combination with MMP-9 Serves as an Informative Prognostic Indicator for Colorectal Cancer
Authors: Taku Takeuchi, Michiyoshi Hisanaga, Mitsuo Nagao, Naoya Ikeda, Hisao Fujii, Fumikazu Koyama, Tomohide Mukogawa, Hiroshi Matsumoto, Shunya Kondo, Chiaki Takahashi, Makoto Noda, Yoshiyuki Nakajima
Journal: Clinical Cancer Research (2004)

RECK, a membrane-anchored regulator of matrix metalloproteinases (MMPs), is widely expressed in healthy tissue, whereas it is expressed at lower levels in many tumor-derived cell lines. Studies in mice and cultured cells have shown that restoration of RECK expression inhibits tumor invasion, metastasis, and angiogenesis. However, the clinical relevance of these findings remains to be fully documented. Here we examined the expression of RECK and one of its targets, MMP-9, in colorectal cancer tissue.The RECK and MMP-9 expression levels in colorectal cancer samples from 53 patients were determined by immunohistochemical techniques. The expression level of each protein was scored, and the patients were divided into two groups based on these scores. In 33 cases, we performed gelatin zymography to estimate the degree of MMP-2 and MMP-9 activation. Microvessel density and vascular endothelial growth factor (VEGF) expression were also evaluated histologically.RECK protein was detected in 30 of 53 (56.6%) specimens. Importantly, patients with tumors expressing relatively high levels of RECK (high-RECK group) had a significantly lower risk of recurrence than did patients with tumors expressing relatively low levels of RECK (low-RECK group; P = 0.011). Moreover, RECK-dominant (RECK score > or = MMP-9 score) patients showed a significantly lower incidence of recurrence than did MMP-9-dominant patients (P = 0.0003). Multivariate analysis revealed that the RECK/MMP-9 balance was an independent prognostic factor (P = 0.0122). The expression of VEGF and microvessel density were inversely correlated with the level of RECK expression.RECK/MMP-9-balance is an informative prognostic indicator for colorectal cancer. Our data also suggest that RECK suppresses tumor angiogenesis, probably by limiting the availability of VEGF in tumor tissues.
The relation of megakaryocyte ploidy to platelet volume
Authors: J. David Bessman
Journal: American Journal of Hematology (1984)

Abstract To determine how alterations of megakaryocyte proliferation will affect platelet production, we measured mean platelet volume (MPV), platelet volume heterogeneity, platelet count, and mean megakaryocyte ploidy in 42 patients. In normal subjects, mean platelet volume and megakaryocyte ploidy were related inversely but nonlin‐early to platelet count, whereas mean platelet volume and platelet volume heterogeneity were related directly. In patients with immune thrombocytopenic purpura (low platelet count, MPV above normal, and increased megakaryocyte ploidy), and in those with reactive thrombocytosis (high platelet count, low MPV and megakaryocyte ploidy), the relation of MPV to megakaryocyte ploidy, platelet volume heterogeneity, and platelet count resembled or extended the relations found in normal subjects. By contrast, in patients with aplastic anemia or megaloblastic anemia, or in patients who were undergoing chemotherapy for leukemia, heterogeneity was increased abnormally at any MPV, and both MPV and megakaryocyte ploidy were substantially lower, at any platelet volume, than in normals or the above other groups. The most common ploidy class was 8N in all patients, and the mean megakaryocyte ploidy correlated directly and linearly with mean platelet volume. The data show that bone marrow with megakaryocytes of higher ploidy produces platelets that are both larger and more heterogeneous.
PRECEDENT: A Randomized Phase II Trial Comparing Vintafolide (EC145) and Pegylated Liposomal Doxorubicin (PLD) in Combination Versus PLD Alone in Patients With Platinum-Resistant Ovarian Cancer
Authors: R. Wendel Naumann, Robert L. Coleman, Robert A. Burger, Edward A. Sausville, Elzbieta Kutarska, Sharad A. Ghamande, Nashat Y. Gabrail, Stephen E. DePasquale, Elzbieta Nowara, Lucy Gilbert, Robert H. Gersh, Michael G. Teneriello, Wael A. Harb, Panagiotis A. Konstantinopoulos, Richard T. Penson, James T. Symanowski, Chandra D. Lovejoy, Christopher P. Leamon, David E. Morgenstern, Richard A. Messmann
Journal: Journal of Clinical Oncology (2013)

Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. This randomized phase II trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined.Women with recurrent platinum-resistant ovarian cancer who had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1 ratio to PLD (50 mg/m(2) intravenously [IV] once every 28 days) with or without vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide scanning was optional. The primary objective was to compare progression-free survival (PFS) between the groups.The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio [HR], 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806).Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to benefit from vintafolide.
Electron Microscopic Studies on the Localization of Antibodies in Rat Lymph Node Cells Producing Moloney Virus&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Lyndon S. Oshiro, Natalie E. Cremer, Dee O. N. Taylor, Edwin H. Lennette
Journal: JNCI Journal of the National Cancer Institute (1969)

Electron microscopic studies were done on the localization of antibodies in lymph node cells from rats infected with Moloney virus and immunized with apoferritin. Frozen sections of lymph nodes were treated with ferritin and processed for electron microscopy. Examination of thin sections revealed infected cells without ferritin, infected cells containing ferritin, uninfected cells containing ferritin, and uninfected cells without ferritin. Ferritin within cells indicated the presence of antiapoferritin antibodies. Ferritin was located in the cisternae of the endoplasmic reticulum, in the perinuclear spaces, and in the Golgi region. The presence of budding C-type particles and ferritin within the same cell indicated that Moloney leukemia virus was being produced in a cell that was or had been producing antibody.
Gemfibrozil enhances the listeriacidal effects of fluoroquinolone antibiotics in J774 macrophages.
Authors: D E Rudin, P X Gao, C X Cao, H C Neu, S C Silverstein
Journal: The Journal of Experimental Medicine (1992)

J774 macrophage-like cells express organic anion transporters that promote the efflux of fluoroquinolone antibiotics such as norfloxacin (NFX) from these cells. Gemfibrozil (GFZ) blocks organic anion transport in J774 cells, thereby facilitating the intracellular accumulation of NFX (Cao, C., H.C. Neu, and S.C. Silverstein. 1991. J. Cell Biol. 115:467a [Abstr.]). To determine whether GFZ enhances the efficacy of fluoroquinolone antibiotics against intracellular bacterial pathogens, J774 cells were infected with Listeria monocytogenes and incubated in medium containing a fluoroquinolone antibiotic in the presence or absence of GFZ. Intracellular growth of L. monocytogenes was evaluated by lysing J774 cells and assaying for colony-forming units of Listeria. GFZ intensified the bacteriostatic effect of 4 micrograms/ml NFX and rendered 8 micrograms/ml bactericidal for L. monocytogenes. GFZ had a similar potentiating effect when used in combination with 2 micrograms/ml ciprofloxacin (CFX). CFX plus GFZ was bactericidal for intracellular L. monocytogenes. Treatment of J774 cells with NFX plus GFZ markedly reduced the cytotoxic effect of the bacteria on these cells. Over 55% of cells treated with 8 micrograms/ml NFX alone were dead 16 h after infection, whereas only 5% of cells treated with 8 micrograms/ml NFX plus GFZ were dead at 16 h. Similarly, GFZ potentiated the ability of 2 micrograms/ml to protect J774 cells against the cytocidal effect of Listeria. NFX in combination with GFZ limited cell-to-cell spread of L. monocytogenes. In antibiotic-free medium, &amp;gt; 99% of J774 cells contained intracellular L. monocytogenes at 14 h after infection. NFX alone in the medium did not change this outcome. However, 4 micrograms/ml NFX plus GFZ decreased bacterial spread by approximately 40% at 24 h postinfection, and 8 micrograms/ml NFX plus GFZ prevented all spread beyond the initially infected cell population. These results suggest that GFZ could be used clinically to enhance the efficacy of fluoroquinolone and of other anionic antibiotics against bacteria that grow and/or reside within macrophages and/or other cells.
A Positive Diagnostic Strategy Is Noninferior to a Strategy of Exclusion for Patients With Irritable Bowel Syndrome
Authors: Luise M. Begtrup, Anne Line Engsbro, Jens Kjeldsen, Pia V. Larsen, Ove Schaffalitzky de Muckadell, Peter Bytzer, Dorte E. Jarbøl
Journal: Clinical Gastroenterology and Hepatology (2013)
Lipid emulsions in parenteral nutrition of intensive care patients: current thinking and future directions
Authors: Philip C. Calder, Gordon L. Jensen, Berthold V. Koletzko, Pierre Singer, Geert J. A. Wanten
Journal: Intensive Care Medicine (2010)

Energy deficit is a common and serious problem in intensive care units and is associated with increased rates of complications, length of stay, and mortality. Parenteral nutrition (PN), either alone or in combination with enteral nutrition, can improve nutrient delivery to critically ill patients. Lipids provide a key source of calories within PN formulations, preventing or correcting energy deficits and improving outcomes.In this article, we review the role of parenteral lipid emulsions (LEs) in the management of critically ill patients and highlight important biologic activities associated with lipids. Soybean-oil-based LEs with high contents of polyunsaturated fatty acids (PUFA) were the first widely used formulations in the intensive care setting. However, they may be associated with increased rates of infection and lipid peroxidation, which can exacerbate oxidative stress. More recently developed parenteral LEs employ partial substitution of soybean oil with oils providing medium-chain triglycerides, omega-9 monounsaturated fatty acids or omega-3 PUFA. Many of these LEs have demonstrated reduced effects on oxidative stress, immune responses, and inflammation. However, the effects of these LEs on clinical outcomes have not been extensively evaluated.Ongoing research using adequately designed and well-controlled studies that characterize the biologic properties of LEs should assist clinicians in selecting LEs within the critical care setting. Prescription of PN containing LEs should be based on available clinical data, while considering the individual patient's physiologic profile and therapeutic requirements.
APPLICATION OF AN OBJECTIVE METHOD FOR MEASURING THE ACTION OF "ANTIDEPRESSANT" MEDICATIONS
Authors: GORDON W. OLSON
Journal: American Journal of Psychiatry (1962)

Most investigations of "antidepressant" medications have depended on clinical assessment of the symptom. This study undertook to apply an objective measure of depression to determine the effectiveness of nialamide, as representative of monoamine oxidase inhibitors, in a state hospital population. The results showed that both ward behaviour and depression improved significantly more in a high dosage group than for the low dosage and control groups but at the risk of additional behavioral and physical side effects. It was concluded that the measure of depression employed has merit and that nialamide used watchfully in high doses represents a worthwhile contribution for the treatment of the depressed or apathetic patient.
Abstract C65: Mechanisms to maintain extra centrosomes in cancer cells
Authors: Susana A. Godinho, Mijung Kwon, Neil J. Ganem, David Pellman
Journal: Cancer Research (2009)

Abstract Multiple centrosomes in tumor cells create the potential for multipolar divisions that can lead to aneuploidy and cell death. Nevertheless, many cancer cells successfully divide because of mechanisms that suppress multipolar mitoses. Using a genome-wide RNAi screen in Drosophila S2 cells, we defined several mechanisms that suppress multipolar mitoses. We also found that HSET, a normally non-essential kinesin motor was essential for the viability of cancer cells containing extra centrosomes. Interestingly, using fibronectin micropatterns, we found that interphase cell shape and adhesion pattern can determine the success of the subsequent mitosis in cells with extra centrosomes. Thus, cell adhesion is an important morphological feature that contributes to centrosome clustering. Importantly, during tumor progression, changes in cell architecture and adhesion patterns, such as loss of E-cadherin and acquisition of an elongated cell shape, are often observed. This is referred to as the epithelial-to-mesenchymal transition (EMT). The presence of extra centrosomes is often correlated with more malignant tumors, which lost their epithelial phenotype most likely through EMT. Thus, we hypothesized that the ability of cells to cluster extra centrosomes varies between epithelial cells and non-epithelial cells. To test this idea we used a panel of non-transformed mammalian epithelial and non-epithelial cell lines and quantified their ability to cluster extra centrosomes. We treated cells with DCB to generate tetraploid cells containing extra centrosomes and followed them by live-cell imaging. We found that non-epithelial cells cluster their extra centrosomes much more efficiently than epithelial cells. This finding suggests that loss of cell-cell adhesion might facilitate centrosome clustering. Consistent with this idea, our preliminary data indicate that induction of EMT in the epithelial cell lines MCF10A and MDCK increases the number of tetraploid cells that undergo a bipolar mitosis. We propose that changes that take place during tumor progression, such as loss of cell-cell adhesion, might facilitate centrosome clustering and therefore increase the ability of cancer cells to maintain extra centrosomes. We are currently investigating the nature of the changes that occur during EMT that facilitate centrosome clustering. Citation Information: Cancer Res 2009;69(23 Suppl):C65.
Downregulation of Rap1GAP through Epigenetic Silencing and Loss of Heterozygosity Promotes Invasion and Progression of Thyroid Tumors
Authors: Hui Zuo, Manoj Gandhi, Martin M. Edreira, Daniel Hochbaum, Vishwajit L. Nimgaonkar, Ping Zhang, James DiPaola, Viktoria Evdokimova, Daniel L. Altschuler, Yuri E. Nikiforov
Journal: Cancer Research (2010)

Thyroid cancer is the most common type of endocrine malignancy, encompassing tumors with various levels of invasive growth and aggressiveness. Rap1GAP, a Rap1 GTPase-activating protein, inhibits the RAS superfamily protein Rap1 by facilitating hydrolysis of GTP to GDP. In this study, we analyzed 197 thyroid tumor samples and showed that Rap1GAP was frequently lost or downregulated in various types of tumors, particularly in the most invasive and aggressive forms of thyroid cancer. The downregulation was due to promoter hypermethylation and/or loss of heterozygosity, found in the majority of thyroid tumors. Treatment with demethylating agent 5-aza-deoxycytidine and/or histone deacetylation inhibitor trichostatin A induced gene reexpression in thyroid cells. A genetic polymorphism, Y609C, was seen in 7% of thyroid tumors but was not related to gene downregulation. Loss of Rap1GAP expression correlated with tumor invasiveness but not with specific mutations activating the mitogen-activated protein kinase pathway. Rap1GAP downregulation was required in vitro for cell migration and Matrigel invasion. Recovery of Rap1GAP expression inhibited thyroid cell proliferation and colony formation. Overall, our findings indicate that epigenetic or genetic loss of Rap1GAP is very common in thyroid cancer, where these events are sufficient to promote cell proliferation and invasion.
Genome-wide approaches for identifying genetic risk factors for osteoporosis
Authors: Shuyan Wu, Yongjun Liu, Lei Zhang, Yingying Han, Yong Lin, Hong-Wen Deng
Journal: Genome Medicine (2013)

Osteoporosis, the most common type of bone disease worldwide, is clinically characterized by low bone mineral density (BMD) and increased susceptibility to fracture. Multiple genetic and environmental factors and gene-environment interactions have been implicated in its pathogenesis. Osteoporosis has strong genetic determination, with the heritability of BMD estimated to be as high as 60%. More than 80 genes or genetic variants have been implicated in risk of osteoporosis by hypothesis-free genome-wide studies. However, these genes or genetic variants can only explain a small portion of BMD variation, suggesting that many other genes or genetic variants underlying osteoporosis risk await discovery. Here, we review recent progress in genome-wide studies of osteoporosis and discuss their implications for medicine and the major challenges in the field.
Missed Opportunities during Family Conferences about End-of-Life Care in the Intensive Care Unit
Authors: J. Randall Curtis, Ruth A. Engelberg, Marjorie D. Wenrich, Sarah E. Shannon, Patsy D. Treece, Gordon D. Rubenfeld
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Improved communication with family members of critically ill patients can decrease the prolongation of dying in the intensive care unit (ICU), but few data exist to guide the conduct of this communication.Our objective was to identify missed opportunities for physicians to provide support for or information to family during family conferences.We identified ICU family conferences in four hospitals that included discussions about withdrawing life support or delivery of bad news. Fifty-one conferences were audiotaped, including 214 family members. Thirty-six physicians led the conferences and some physicians led more than one. We used qualitative methods to identify and categorize missed opportunities, defined as an occurrence when the physician had an opportunity to provide support or information to the family and did not.Fifteen family conferences (29%) had missed opportunities identified. These fell into three categories: opportunities to listen and respond to family; opportunities to acknowledge and address emotions; and opportunities to pursue key principles of medical ethics and palliative care, including exploration of patient preferences, explanation of surrogate decision making, and affirmation of nonabandonment. The most commonly missed opportunities were those to listen and respond, but examples from other categories suggest value in being aware of these opportunities.Identification of missed opportunities during ICU family conferences provides suggestions for improving communication during these conferences. Future studies are needed to demonstrate whether addressing these opportunities will improve quality of care.