tbuckley/cabot-search huggingface dataset:
CD47 Enhances <i>In Vivo</i> Functionality of Artificial Antigen-Presenting Cells
Authors: Heiko Bruns, Catherine Bessell, Juan Carlos Varela, Carl Haupt, Jerry Fang, Shirin Pasemann, Andreas Mackensen, Mathias Oelke, Jonathan P. Schneck, Christian Schütz
Journal: Clinical Cancer Research (2015)

Artificial antigen-presenting cells, aAPC, have successfully been used to stimulate antigen-specific T-cell responses in vitro as well as in vivo. Although aAPC compare favorably with autologous dendritic cells in vitro, their effect in vivo might be diminished through rapid clearance by macrophages. Therefore, to prevent uptake and minimize clearance of aAPC by macrophages, thereby increasing in vivo functionality, we investigated the efficiency of "don't eat me" three-signal aAPC compared with classical two-signal aAPC.To generate "don't eat me" aAPC, CD47 was additionally immobilized onto classical aAPC (aAPC(CD47+)). aAPC and aAPC(CD47+) were analyzed in in vitro human primary T-cell and macrophage cocultures. In vivo efficiency was compared in a NOD/SCID T-cell proliferation and a B16-SIY melanoma model.This study demonstrates that aAPC(CD47+) in coculture with human macrophages show a CD47 concentration-dependent inhibition of phagocytosis, whereas their ability to generate and expand antigen-specific T cells was not affected. Furthermore, aAPC(CD47+)-generated T cells displayed equivalent killing abilities and polyfunctionality when compared with aAPC-generated T cells. In addition, in vivo studies demonstrated an enhanced stimulatory capacity and tumor inhibition of aAPC(CD47+) over normal aAPC in conjunction with diverging biodistribution in different organs.Our data for the first time show that aAPC functionalized with CD47 maintain their stimulatory capacity in vitro and demonstrate enhanced in vivo efficiency. Thus, these next-generation aAPC(CD47+) have a unique potential to enhance the application of the aAPC technology for future immunotherapy approaches.
Differences in survivin location and Bcl-2 expression in CD30+ lymphoproliferative disorders of the skin compared with systemic anaplastic large cell lymphomas: an immunohistochemical study
Authors: G. Goteri, O. Simonetti, S. Rupoli, G. Piccinini, C. Rubini, D. Stramazzotti, F. Fazioli, C. Capomagi, P. Leoni, A.M. Offidani, L. Lomuzio
Journal: British Journal of Dermatology (2007)

Cutaneous CD30+ lymphoproliferative disorders (LPDs) are a spectrum of disease associated with a favourable prognosis. Systemic anaplastic large cell lymphoma (ALCL), although morphologically and phenotypically similar, differs in clinical presentation and has a less favourable biological behaviour. Dysregulation of apoptosis, the process regulating cell population by programmed death, can explain the differences among these disorders.We investigated the expression of two inhibitors of apoptosis, survivin and Bcl-2 protein, in serial skin lesion samples from CD30+ LPDs compared with systemic ALCL.Immunohistochemical analysis with antibodies against anaplastic lymphoma kinase (ALK)-1 protein, survivin and Bcl-2 protein was performed in 10 cutaneous CD30+ LPDs (five lymphomatoid papulosis, five ALCL) and 18 systemic ALCLs. Reverse transcription-polymerase chain reaction studies for ALK and ALK/nucleophosmin were also performed.Cutaneous CD30+ LPDs shared a heterogeneous expression of cytoplasmic survivin with all systemic ALCLs, and of Bcl-2 with systemic ALK- ALCLs; however, they differ from systemic ALK- ALCLs because they lack nuclear survivin (P = 0.045), and from systemic ALK+ ALCLs by a higher expression of Bcl-2 (P = 0.045) and a lack of ALK-1. Overall, coexpression of Bcl-2 and nuclear survivin in CD30+ LPDs was associated with a less favourable disease survival.The different patterns of expression of Bcl-2 and survivin in CD30+ LPDs might have an impact on their different biological and clinical behaviour. Moreover, nuclear localization of survivin, similarly to ALK, may be a useful marker for predicting a systemic form of ALCL with cutaneous presentation.
Recent Resurgence of Mumps in the United States
Authors: Gustavo H. Dayan, M. Patricia Quinlisk, Amy A. Parker, Albert E. Barskey, Meghan L. Harris, Jennifer M. Hill Schwartz, Kae Hunt, Carol G. Finley, Dennis P. Leschinsky, Anne L. O'Keefe, Joshua Clayton, Lon K. Kightlinger, Eden G. Dietle, Jeffrey Berg, Cynthia L. Kenyon, Susan T. Goldstein, Shannon K. Stokley, Susan B. Redd, Paul A. Rota, Jennifer Rota, Daoling Bi, Sandra W. Roush, Carolyn B. Bridges, Tammy A. Santibanez, Umesh Parashar, William J. Bellini, Jane F. Seward
Journal: New England Journal of Medicine (2008)

The widespread use of a second dose of mumps vaccine among U.S. schoolchildren beginning in 1990 was followed by historically low reports of mumps cases. A 2010 elimination goal was established, but in 2006 the largest mumps outbreak in two decades occurred in the United States.We examined national data on mumps cases reported during 2006, detailed case data from the most highly affected states, and vaccination-coverage data from three nationwide surveys.A total of 6584 cases of mumps were reported in 2006, with 76% occurring between March and May. There were 85 hospitalizations, but no deaths were reported; 85% of patients lived in eight contiguous midwestern states. The national incidence of mumps was 2.2 per 100,000, with the highest incidence among persons 18 to 24 years of age (an incidence 3.7 times that of all other age groups combined). In a subgroup analysis, 83% of these patients reported current college attendance. Among patients in eight highly affected states with known vaccination status, 63% overall and 84% between the ages of 18 and 24 years had received two doses of mumps vaccine. For the 12 years preceding the outbreak, national coverage of one-dose mumps vaccination among preschoolers was 89% or more nationwide and 86% or more in highly affected states. In 2006, the national two-dose coverage among adolescents was 87%, the highest in U.S. history.Despite a high coverage rate with two doses of mumps-containing vaccine, a large mumps outbreak occurred, characterized by two-dose vaccine failure, particularly among midwestern college-age adults who probably received the second dose as schoolchildren. A more effective mumps vaccine or changes in vaccine policy may be needed to avert future outbreaks and achieve the elimination of mumps.
PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice
Authors: Taku Okazaki, Il-mi Okazaki, Jian Wang, Daisuke Sugiura, Fumio Nakaki, Taku Yoshida, Yu Kato, Sidonia Fagarasan, Masamichi Muramatsu, Tomoo Eto, Kyoji Hioki, Tasuku Honjo
Journal: The Journal of Experimental Medicine (2011)

Stimulatory and inhibitory co-receptors play fundamental roles in the regulation of the immune system. We describe a new mouse model of spontaneous autoimmune disease. Activation-induced cytidine deaminase–linked autoimmunity (aida) mice harbor a loss-of-function mutation in the gene encoding lymphocyte activation gene 3 (LAG-3), an inhibitory co-receptor. Although LAG-3 deficiency alone did not induce autoimmunity in nonautoimmune-prone mouse strains, it induced lethal myocarditis in BALB/c mice deficient for the gene encoding the inhibitory co-receptor programmed cell death 1 (PD-1). In addition, LAG-3 deficiency alone accelerated type 1 diabetes mellitus in nonobese diabetic mice. These results demonstrate that LAG-3 acts synergistically with PD-1 and/or other immunoregulatory genes to prevent autoimmunity in mice.
What is Appropriate Care?
Authors: C. David Naylor
Journal: New England Journal of Medicine (1998)

In virtually all industrialized nations, the past decade has brought unprecedented scrutiny of the processes and outcomes of medical care, even as private and public payers press for further cost containment. An old management-consulting adage reads: “Good, fast, cheap: pick any two.” In health care, the contemporary equivalent seems to be: “Quality, accessibility, affordability: have all three.”This management revolution in medicine has gained legitimacy from countless studies showing inexplicable variations in what physicians do and how effectively or efficiently they do it. However, the Achilles' heel of managed care is mounting public and professional concern that quality has been . . .
Caspase-8 Association with the Focal Adhesion Complex Promotes Tumor Cell Migration and Metastasis
Authors: Simone Barbero, Ainhoa Mielgo, Vicente Torres, Tal Teitz, David J. Shields, David Mikolon, Matthew Bogyo, Daniela Barilà, Jill M. Lahti, David Schlaepfer, Dwayne G. Stupack
Journal: Cancer Research (2009)

Caspase-8 is a proapoptotic protease that suppresses neuroblastoma metastasis by inducing programmed cell death. Paradoxically, caspase-8 can also promote cell migration among nonapoptotic cells; here, we show that caspase-8 can promote metastasis when apoptosis is compromised. Migration is enhanced by caspase-8 recruitment to the cellular migration machinery following integrin ligation. Caspase-8 catalytic activity is not required for caspase-8-enhanced cell migration; rather, caspase-8 interacts with a multiprotein complex that can include focal adhesion kinase and calpain 2 (CPN2), enhancing cleavage of focal adhesion substrates and cell migration. Caspase-8 association with CPN2/calpastatin disrupts calpastatin-mediated inhibition of CPN2. In vivo, knockdown of either caspase-8 or CPN2 disrupts metastasis among apoptosis-resistant tumors. This unexpected molecular collaboration provides an explanation for the continued or elevated expression of caspase-8 observed in many tumors.
Identification of Biomarkers for Breast Cancer in Nipple Aspiration and Ductal Lavage Fluid
Authors: Jinong Li, Jing Zhao, Xiaodong Yu, Julie Lange, Henry Kuerer, Savitri Krishnamurthy, Eric Schilling, Seema A. Khan, Saraswati Sukumar, Daniel W. Chan
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To establish a comprehensive proteomic approach for biomarker discovery and validation in breast fluid. Experimental Design: A total of 95 specimens from three institutions were used including 10 nipple aspiration fluid (5 stage I/II cancerous breasts and 5 age-matched healthy controls), 42 ductal lavage fluid from 14 patients with unilateral stage I/II cancer (25 from 9 cancerous breasts and 17 from 7 contralateral breasts), and 42 ductal lavage fluid from 14 high-risk women (multiple ducts repeated lavage). Differentially expressed protein/peptides were discovered by proteomic analysis of training sample, using ProteinChip arrays and surface-enhanced laser desorption ionization (SELDI) time-of-flight mass spectrometry, and validated on independently collected testing samples. After protein identification, ELISA was done to confirm the SELDI findings. Results: We were able to obtain reproducible protein profiles using minimal amount of protein (1 μg) by applying an optimized chip protocol and SELDI. We were able to select cancer-associated biomarkers despite large individual variability by applying both unsupervised and supervised cluster analysis. Furthermore, we were able to train and test candidate biomarkers on independently collected samples and identified one component of a multimarker panel as human neutrophil peptides 1 to 3. Conclusions: Breast fluid is a rich source of breast cancer biomarkers. In combination with high-throughput novel proteomic profiling technology and multicenter study design, markers that are highly specific to breast cancer can be discovered and validated. Our observations also suggest that persistent elevation of human neutrophil peptide in high-risk women may imply early onset of cancer not yet detectable by current detection method. Proof of this hypothesis requires follow-up on a larger study population.
ELECTROPHORESIS OF ANTERIOR PITUITARY PROTEINS
Authors: Reginald A. Shipley, Kurt G. Stern, Abraham White
Journal: The Journal of Experimental Medicine (1939)

The moving boundary method of electrophoresis has been applied to a study of pituitary extracts and purified protein fractions derived from these extracts. The technique employed was that developed by Tiselius and involved the optical observation of the protein boundaries by Toepler's schlieren method. The present experiments were designed primarily to determine the number of proteins present, the degree of homogeneity of the various fractions, and the electrophoretic mobility of the individual components under standard conditions. The preparations studied included crude gland extracts obtained with dilute alkali, glycerol, and saline; purified pituitary fractions prepared by isoelectric and precipitation procedures; and freshly prepared and aged solutions of crystalline prolactin. The bulk of the crude gland extracts is composed of physiologically inert proteins, the gradual removal of which in the course of the chemical purification procedures could be controlled by electrophoretic analysis. Freshly prepared solutions of crystalline prolactin exhibit a high degree of electrochemical homogeneity. Upon storage, however, a second component, presumably denatured prolactin, is formed.
Adenoviral transfer of HSP-70 into pulmonary epithelium ameliorates experimental acute respiratory distress syndrome
Authors: Yoram G. Weiss, Alina Maloyan, John Tazelaar, Nichelle Raj, Clifford S. Deutschman
Journal: Journal of Clinical Investigation (2002)

The acute respiratory distress syndrome (ARDS) provokes three pathologic processes: unchecked inflammation, interstitial/alveolar protein accumulation, and destruction of pulmonary epithelial cells. The highly conserved heat shock protein HSP-70 can limit all three responses but is not appropriately expressed in the lungs after cecal ligation and double puncture (2CLP), a clinically relevant model of ARDS. We hypothesize that restoring expression of HSP-70 using adenovirus-mediated gene therapy will limit pulmonary pathology following 2CLP. We administered a vector containing the porcine HSP-70 cDNA driven by a CMV promoter (AdHSP) into the lungs of rats subjected to 2CLP or sham operation. Administration of AdHSP after either sham operation or 2CLP increased HSP-70 protein expression in lung tissue, as determined by immunohistochemistry and Western blot hybridization. Administration of AdHSP significantly attenuated interstitial and alveolar edema and protein exudation and dramatically decreased neutrophil accumulation, relative to a control adenovirus. CLP-associated mortality at 48 hours was reduced by half. Modulation of HSP-70 production reduces pathologic changes and may improve outcome in experimental ARDS.
Spermatomania--the English response to Lallemand's disease
Authors: D. Hodgson
Journal: Journal of the Royal Society of Medicine (2005)

Spermatorrhoea, the involuntary loss of semen, is in Western medicine a complaint peculiar to the 19th century.The disease was championed by Professor Claude-Francois Lallemand, from Montpellier.In 1835, citing masturbation as a major cause, he wrote that the condition 'degrades man, poisons the happiness of his best days, and ravages society'.In England, for fifty years, doctors, patients and social commentators alike took a frenzied interest in the condition.It was only at the end of the century, when the likes of Sir James Paget questioned the very existence of spermatorrhoea, that it faded from prominence.
Insulin Resistance and Hyperinsulinemia
Authors: Sun H. Kim, Gerald M. Reaven
Journal: Diabetes Care (2008)

OBJECTIVE—Recently, it has been suggested that insulin resistance and hyperinsulinemia can exist in isolation and have differential impacts on cardiovascular disease (CVD). To evaluate this suggestion, we assessed the degree of discordance between insulin sensitivity and insulin response in a healthy, nondiabetic population. RESEARCH DESIGN AND METHODS—Insulin sensitivity was quantified by determining the steady-state plasma glucose (SSPG) concentration during an insulin suppression test in 446 individuals. The integrated insulin response was calculated after a 75-g oral glucose challenge. We analyzed the correlation between insulin resistance and insulin response in addition to quantifying the proportion in quartiles of insulin response by quartiles of insulin sensitivity. Then we compared CVD risk factors between individuals within the same insulin sensitivity quartile but within different insulin response quartiles to evaluate the differential clinical impact of insulin resistance and hyperinsulinemia. RESULTS—Insulin resistance and insulin response were highly correlated (r = 0.76, P &amp;lt; 0.001). A majority (95%) of the most insulin-resistant individuals (top SSPG quartile) were either in the highest insulin response quartile (71%) or second highest (24%). Similarly, 92% of the most insulin-sensitive individuals (lowest SSPG quartile) were in the lowest two insulin response quartiles. There were minimal differences in CVD risk factors between individuals with different insulin responses but within the same insulin sensitivity quartile. CONCLUSIONS—Although not perfectly related, insulin resistance and hyperinsulinemia rarely exist in isolation in a nondiabetic population. It is difficult to discern an independent impact of hyperinsulinemia on CVD risk factors associated with insulin resistance.
Use of Multiple Endpoints and Approval Paths Depicts a Decade of FDA Oncology Drug Approvals
Authors: Michael B. Shea, Samantha A. Roberts, Jessica C. Walrath, Jeff D. Allen, Ellen V. Sigal
Journal: Clinical Cancer Research (2013)

This study explores the historic use of different endpoints to support regular and accelerated approval of cancer drugs between 2002 and 2012. In the past 10 years, two thirds of oncology regular approvals were based on endpoints other than overall survival. More than three quarters of accelerated approvals were based on response rates. The accelerated approval program has been heavily used over this time period, with one third of all approved oncology indications receiving accelerated approval. At times, critics have characterized the agency as rigid and unpredictable. This research describes the degree of regulatory flexibility that U.S. Food and Drug Administration and drug sponsors have used over the past decade in the development of new treatments for cancer.
Age-Related Changes in Vascular Endothelial Growth Factor Dependency and Angiopoietin-1-Induced Plasticity of Adult Blood Vessels
Authors: Fabienne Baffert, Gavin Thurston, Michael Rochon-Duck, Tom Le, Rolf Brekken, Donald M. McDonald
Journal: Circulation Research (2004)

Vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) are essential for vascular development, but this dependency has been assumed not to persist into adult life. In this study, we report that after 10 days of systemic treatment of 4-, 8-, and 16-week-old mice with VEGF-Trap, an inhibitor of VEGF, the number of capillaries in the tracheal mucosa was reduced by 39%, 28%, and 14%, respectively. The magnitude of the reduction decreased with age ( r 2 =0.6, P &lt;0.001), but was still significant at 16 weeks. A corresponding age-related decrease in vascular endothelial growth factor receptor-2 (VEGFR-2) immunoreactivity suggests that diminished VEGFR-2 expression may contribute to resistance to VEGF signaling inhibition. VEGF-Trap further reduced VEGFR-2 expression in tracheal capillaries. By comparison, systemic treatment with adenovirus encoding Ang1 led to a significant enlargement of tracheal venules with little age effect (64%, 56%, and 49% increase in diameter at 10 days). When Ang1 was given in combination with VEGF-Trap, tracheal vessels presented the typical response to each factor, showing that the Ang1 effect was not VEGF-mediated, yet Ang1 seems to have a protective effect, as judged by prevention of VEGF-Trap-induced reduction in tracheal capillaries in the oldest group. Together, these findings indicate that VEGF and Ang1 participate in blood vessel survival and plasticity in adult life.
Abstract 3778: Protein targets for prostate cancer prevention by α-keto acid metabolites of organoselenium compounds
Authors: Raghu Sinha, Indu Sinha, John Pinto
Journal: Cancer Research (2010)

Abstract Our previous studies show that human glutamine transaminase K (GTK) and L-amino acid oxidase convert Se-methylselenocysteine (MSC) and selenomethionine (SM) to methylselenopyruvate (MSP) and α-keto-γ-methylselenobutyrate (KMSB), respectively. Further more, both of these α-seleno keto acids inhibit histone deacetylase (HDAC) activity in cultured human prostate cancer cells in a dose-dependent manner (Cancer Prev. Res. 2:683, 2009). Since human prostate cancer cells have GTK activity and can metabolize MSC to MSP but not SM to KMSB, we studied whether administration of SM and KMSB to human prostate cancer cells each function as direct-acting metabolites of organoselenium compounds and individually can result in differential regulation of protein targets critical for growth regulation. Using a 4-plex-iTRAQ proteomic approach, we examined the potential effects of either SM or KMSB on several protein targets in LNCaP prostate cancer cells. Analyses revealed significant changes (p&amp;lt;0.05) in at least 68 proteins (1-60 peptide residue coverage) following 5 hr incubation of LNCaP cells with SM (200 μM), KMSB (50 μM) and Trichostatin A (TSA) (20 μM), an inhibitor of class I and II mammalian HDACs. The majority of observed protein changes were cytosolic (49%), nuclear (31%), then plasma membrane (4%) and the remainder was extracellular or unknown. Six proteins that included histone 1c, histone 2a, PARP1, and Epoxide hydrolase 1 microsomal (xenobiotic) were up regulated and two proteins, namely, ribosomal protein SA and hematological and neurological expressed-1 protein were down regulated in both KMSB and TSA-treated cells. A total of six proteins (including annexin VI and splicing factor 3a) were significantly altered by KMSB treatment alone while fifteen proteins (among which HSP90, 14-3-3ε, phosphoglycerate kinase 1, and eukaryotic translation initiation factor 4γ) were significantly changed by SM treatment alone. Collectively, our data reveal that several novel protein targets for prostate cancer prevention may be selective for either KMSB or SM alone. Several of these recognized targets will be investigated further to confirm the selectivity of seleno amino acids or seleno keto acids to function as direct-acting metabolites of naturally-occurring organoselenium compounds that can lead to de-repression of silenced tumor suppressor proteins and/or regulation of genes and signal factors. The study was supported by NCI R01CA111842. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3778.
Haemorrhage from peptic ulcer treated by continuous intragastric milk drip and early generous feeding
Authors: D. W. Ashby, J. Anderson, M. J. T. Peaston
Journal: Gut (1963)

Early feeding by means of an intragastric milk drip has been practised in a group of 425 patients admitted to a regional hospital with bleeding peptic ulcers. A low overall mortality of 4·9% was achieved even though more than a quarter of the patients treated were more than 60 years old. The fallacies in comparing mortalities from gastrointestinal bleeding are discussed and the need for adequate blood transfusion, early diagnosis, and medico-surgical collaboration emphasized.