tbuckley/cabot-search huggingface dataset:
Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8<b>+</b> T cells
Authors: Luca Gattinoni, Steven E. Finkelstein, Christopher A. Klebanoff, Paul A. Antony, Douglas C. Palmer, Paul J. Spiess, Leroy N. Hwang, Zhiya Yu, Claudia Wrzesinski, David M. Heimann, Charles D. Surh, Steven A. Rosenberg, Nicholas P. Restifo
Journal: The Journal of Experimental Medicine (2005)

Depletion of immune elements before adoptive cell transfer (ACT) can dramatically improve the antitumor efficacy of transferred CD8+ T cells, but the specific mechanisms that contribute to this enhanced immunity remain poorly defined. Elimination of CD4+CD25+ regulatory T (T reg) cells has been proposed as a key mechanism by which lymphodepletion augments ACT-based immunotherapy. We found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8+ T cell reactivity to self-tissue and tumor. Surprisingly, enhanced antitumor efficacy and autoimmunity was caused by increased function rather than increased numbers of tumor-reactive T cells, as would be expected by homeostatic mechanisms. The γC cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of γC cytokine–responsive endogenous cells using antibody or genetic means resulted in the enhanced antitumor responses similar to those seen after nonmyeloablative conditioning. These data indicate that lymphodepletion removes endogenous cellular elements that act as sinks for cytokines that are capable of augmenting the activity of self/tumor-reactive CD8+ T cells. Thus, the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells.
Sialophorin, a surface sialoglycoprotein defective in the Wiskott-Aldrich syndrome, is involved in human T lymphocyte proliferation.
Authors: S J Mentzer, E Remold-O'Donnell, M A Crimmins, B E Bierer, F S Rosen, S J Burakoff
Journal: The Journal of Experimental Medicine (1987)

The mAb L10 was used to determine the distribution and the function of sialophorin, the heavily glycosylated surface molecule that is deficient/defective in lymphocytes of patients with the X-linked immunodeficiency Wiskott-Aldrich syndrome. Dual-parameter FACS analysis indicated that sialophorin is expressed on CD4+ and CD8+ lymphocytes, on a subpopulation of peripheral blood B lymphocytes, on all thymocytes, and on a subpopulation of bone marrow cells. Functional studies demonstrated that L10 mAb stimulates the proliferation of peripheral blood T lymphocytes as measured by stimulation of [3H]thymidine incorporation. The time course and magnitude of increased [3H]thymidine incorporation by T lymphocytes in response to L10 mAb paralleled that induced by anti-CD3 mAb. Effective stimulation was dependent on the presence of monocytes and the Fc portion of L10 mAb. Stimulation of lymphocytes by L10, like stimulation by anti-CD3 mAb, involves increased expression of 4F2, HLA-DR, and IL-2-R. These observations suggest that sialophorin functions in T cell activation.
Lack of managers is hampering efforts to make NHS efficiency savings, MPs hear
Authors: A. O'Dowd
Journal: BMJ (2014)

A lack of good managers is making it harder for the NHS to make efficiency savings, the head of the sector regulator for health services in England has said.

David Bennett, chief executive of Monitor, told MPs on the parliamentary health committee that he had concerns about a lack of managers available to help in ongoing efforts to achieve the significant potential savings if trusts all perform as well as possible.

During an evidence session on 2 December for its annual accountability hearing with Monitor, MPs asked whether foundation trusts had enough managers to carry out the kind of transformational change set out in the Five Year Forward View published in October by NHS England and other national bodies.1 2

Bennett …
From Discovery to Function: The Expanding Roles of Long NonCoding RNAs in Physiology and Disease
Authors: Miao Sun, W. Lee Kraus
Journal: Endocrine Reviews (2014)

Long noncoding RNAs (lncRNAs) are a relatively poorly understood class of RNAs with little or no coding capacity transcribed from a set of incompletely annotated genes. They have received considerable attention in the past few years and are emerging as potentially important players in biological regulation. Here we discuss the evolving understanding of this new class of molecular regulators that has emerged from ongoing research, which continues to expand our databases of annotated lncRNAs and provide new insights into their physical properties, molecular mechanisms of action, and biological functions. We outline the current strategies and approaches that have been employed to identify and characterize lncRNAs, which have been instrumental in revealing their multifaceted roles ranging from cis- to trans-regulation of gene expression and from epigenetic modulation in the nucleus to posttranscriptional control in the cytoplasm. In addition, we highlight the molecular and biological functions of some of the best characterized lncRNAs in physiology and disease, especially those relevant to endocrinology, reproduction, metabolism, immunology, neurobiology, muscle biology, and cancer. Finally, we discuss the tremendous diagnostic and therapeutic potential of lncRNAs in cancer and other diseases.
IMMUNOHISTOCHEMICAL ANALYSIS OF AMYLOID BY THE FLUORESCENCE TECHNIQUE
Authors: Jacinto J. Vazquez, Frank J. Dixon
Journal: The Journal of Experimental Medicine (1956)

The immunohistochemical composition of amyloid deposits in secondary human amyloidosis and experimental amyloidosis in rabbits was studied by means of the "fluorescent antibody" technique of Coons et al. Quantitative studies of the relative amounts of gamma globulin present in the amyloid deposits by the use of radioiodinated fluorescent antibody are reported. It is concluded that amyloid deposits in several organs from cases of secondary human amyloidosis and experimental amyloidosis in rabbits contain considerable concentrations of gamma globulin. The presence of gamma globulin in amyloid might be interpreted as either a metabolic deposition of circulating globulin present in high concentrations in the plasma or as a result of an immunologic reaction involving antigen and antibody.
STUDY OF THE PARADOXICAL EFFECTS OF SALICYLATE IN LOW, INTERMEDIATE AND HIGH DOSAGE ON THE RENAL MECHANISMS FOR EXCRETION OF URATE IN MAN *
Authors: T'Sai Fan Yü, Alexander B. Gutman
Journal: Journal of Clinical Investigation (1959)

of a salicylate metabolite, gentisic acid. The re- lationships between the renal excretion of salicyl- ate and of urate are then examined by means of simultaneous clearance techniques, including studies under conditions of urine pH made to vary from markedly acid to markedly alkaline. Clearance data on the antagonistic effect of small doses of salicylate on probenecid uricosuria, and vice versa, also are presented. Finally, the im- plications of the results as a whole are considered in relation to current concepts of renal mecha- nisms for the excretion of salicylate and of urate, with special reference to inferences regarding the possibility of tubular excretion of urate in man.
Mechanisms of cigarette smoke induced increased airspace permeability.
Authors: X. Y. Li, I. Rahman, K. Donaldson, W. MacNee
Journal: Thorax (1996)

Increased epithelial permeability of the airspaces occurs commonly in the lungs of cigarette smokers. It is likely to be important in augmenting the inflammatory response in the airspaces and hence may have a role in the pathogenesis of emphysema. It has previously been shown that intratracheal instillation of cigarette smoke condensate induces increased epithelial permeability in vivo in rats and in vitro in epithelial cell monolayers, associated with a disturbance in the lung antioxidant, glutathione (GSH). The aim of this study was to assess the role of neutrophils, GSH, and tumour necrosis factor (TNF) in the increased epithelial permeability following intratracheal instillation of cigarette smoke condensate.Epithelial permeability of the airspaces was measured in rat lungs as the passage of intratracheally instilled 125-iodine labelled bovine serum albumin (BSA) into the blood. The permeability of a monolayer of human type II alveolar epithelial cells to 125I-BSA was also measured.Cigarette smoke condensate produced a 59.7% increase in epithelial permeability over control values peaking six hours after instillation and returning to control values by 24 hours. Depletion of neutrophils and, to a lesser extent, macrophages by an intraperitoneal injection of antineutrophil antibody did not influence the increased epithelial permeability induced by cigarette smoke condensate. Although instillation of human recombinant TNF alpha produced an increase in epithelial permeability in the rat lung from 0.62 (0.61)% to 1.27 (0.08)%, only a trivial amount of TNF alpha was detected in bronchoalveolar lavage (BAL) fluid in vivo or in culture medium from BAL leucocytes obtained from animals treated with cigarette smoke condensate (94.9 (28.8) units/ml). Furthermore, antiTNF antibody did not abolish the increased epithelial permeability produced by cigarette smoke condensate. The role of GSH was assessed by measuring the changes in both the reduced (GSH) and oxidised form (GSSG) in lung tissue and in BAL fluid. One hour after instillation of cigarette smoke condensate there was a marked fall in the GSH content in the lung (from 809.8 (31.8) to 501.7 (40.5) nmol/g) in association with increased GSSG levels (from 89.8 (2.7) to 148.7 (48.8) nmol/g). This was followed by a return of GSH levels to control values, with a concomitant decrease in GSSG levels six hours after instillation. GSH levels in BAL fluid fell dramatically following cigarette smoke condensate (from 2.56 (0.30) to 0.31 (0.21) nmol/ml) and this fall was sustained up to six hours after instillation of cigarette smoke condensate.These studies suggest that neutrophils and TNF do not have a major role in the increased epithelial permeability induced by cigarette smoke condensate. However, the data support a role for the depletion of the antioxidant glutathione in the increased epithelial permeability caused by cigarette smoke condensate.
Non-nuclear estrogen receptor α signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice
Authors: Ken L. Chambliss, Qian Wu, Sarah Oltmann, Eddy S. Konaniah, Michihisa Umetani, Kenneth S. Korach, Gail D. Thomas, Chieko Mineo, Ivan S. Yuhanna, Sung Hoon Kim, Zeynep Madak-Erdogan, Adriana Maggi, Sean P. Dineen, Christina L. Roland, David Y. Hui, Rolf A. Brekken, John A. Katzenellenbogen, Benita S. Katzenellenbogen, Philip W. Shaul
Journal: Journal of Clinical Investigation (2010)

Steroid hormone receptors function classically in the nucleus as transcription factors. However, recent data indicate that there are also non-nuclear subpopulations of steroid hormone receptors, including estrogen receptors (ERs), that mediate membrane-initiated signaling of unclear basis and significance. Here we have shown that an estrogen-dendrimer conjugate (EDC) that is excluded from the nucleus stimulates endothelial cell proliferation and migration via ERα, direct ERα-Gαi interaction, and endothelial NOS (eNOS) activation. Analysis of mice carrying an estrogen response element luciferase reporter, ER-regulated genes in the mouse uterus, and eNOS enzyme activation further indicated that EDC specifically targets non-nuclear processes in vivo. In mice, estradiol and EDC equally stimulated carotid artery reendothelialization in an ERα- and G protein–dependent manner, and both agents attenuated the development of neointimal hyperplasia following endothelial injury. In contrast, endometrial carcinoma cell growth in vitro and uterine enlargement and MCF-7 cell breast cancer xenograft growth in vivo were stimulated by estradiol but not EDC. Thus, EDC is a non-nuclear selective ER modulator (SERM) in vivo, and in mice, non-nuclear ER signaling promotes cardiovascular protection. These processes potentially could be harnessed to provide vascular benefit without increasing the risk of uterine or breast cancer.
1364. Adenoviral Gene Therapy for Renal Cancer Requires Retargeting to Alternative Cellular Receptors
Authors: Yosef S. Haviv, Jerry L. Blackwell, Anna Kanerva, Peter Nagi, Victor Krasnykh, Igor Dmitriev, Minghui Wang, Seiji Naito, Xiaosheng Lei, Akseli Hemminki, Delicia Carey, David T. Curiel
Journal: Molecular Therapy (2002)

Metastatic renal cell carcinoma (RCC) is one of the most treatment-resistant malignancies in humans. Therefore, the identification of new agents with better antitumor activity merits a high priority in the treatment of advanced RCC. In this regard, gene therapy with adenoviral (Ad) vectors is a promising new modality for cancer. However, a primary limiting factor for the use of Ad vectors for cancer gene therapy is their critical dependence on cellular expression of the primary Ad receptor, the coxsackie and adenovirus receptor (CAR), known to be down-regulated in many cancer types. Following the identification of CAR deficiency in RCC lines, we have found abundant membrane expression of alpha(v)beta 3 and alpha(v)beta 5 integrins and of the putative receptor to Ad serotype 3 (Ad3). As an alternative gene therapy approach for RCC that would circumvent CAR deficiency, we employed retargeting of replication-incompetent Ad vectors and replication-competent Ad viruses to alpha(v)beta 3 and alpha(v)beta 5 integrins and to the putative Ad3 receptor. These strategies to genetically alter Ad tropism were based on either the insertion of a cysteine-aspartate-cysteine-arginine-glycine-aspartate-cysteine-phenylalanine-cysteine (RGD) motif into the HI loop of the Ad fiber knob domain or on generation of a chimeric Ad fiber composed of adenovirus serotype 5 shaft/Ad3 knob. Both strategies proved highly efficient to circumvent CAR deficiency and enhance gene delivery into RCC cells. Furthermore, in the context of replication-competent Ad, tropism alteration resulted in distinct capacity of the retargeted viruses to infect, replicate, and lyse RCC models in vitro and in vivo. The retargeting strategies were particularly beneficial in the context of replication-competent Ad. These findings underscore the importance of CAR-independent cellular entry mechanisms in RCC and are highly consequential for the development of viral antitumor agents for RCC and other CAR-negative tumors.
Monocyte trafficking across the vessel wall
Authors: Teresa Gerhardt, Klaus Ley
Journal: Cardiovascular Research (2015)

Monocytes fundamentally contribute to immune surveillance and the inflammatory response in immunoinflammatory diseases like atherosclerosis. Recruitment of these cells to the site of injury requires their trafficking across the blood vessel wall. A series of events, including capture, rolling, slow rolling, arrest, adhesion strengthening, and lateral locomotion, precede monocyte transmigration. Recent investigations have revealed new aspects of this cascade. This article revisits some conventional paradigms and selectively highlights new findings, including novel insights into monocyte differentiation and recently identified functional mediators, signalling pathways, and new structural aspects of monocyte extravasation. The emerging roles of endothelial junctional molecules like vascular endothelial-cadherin and the junctional adhesion molecule family, adhesion molecules such as intercellular adhesion molecule-1, molecules localized to the lateral border recycling compartment like cluster of differentiation 99, platelet/endothelial cell adhesion molecule-1, and poliovirus receptor (CD155), as well as other cell surface molecules such as cluster of differentiation 146 and ephrins in transendothelial migration are discussed.
Diagnosis of Pulmonary Tuberculosis Using PCR Assays on Sputum Collected within 24 Hours of Hospital Admission
Authors: ROBERT A. COHEN, SHIRIN MUZAFFAR, DAVID SCHWARTZ, SHAHID BASHIR, SCOTT LUKE, LAURA P. McGARTLAND, KAREN KAUL
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

There have been few studies evaluating the efficacy of polymerase chain reaction (PCR) testing in front-line clinical practice. We assessed the diagnostic yield of PCR prospectively in a blinded study of patients admitted to rule out tuberculosis and compared PCR results to a culture and clinical diagnosis of tuberculosis. Specimens were sent for routine smear, culture, and PCR analysis. Sputum sediments were submitted for PCR amplification of IS6110 sequences by an in-house assay and also the Roche Amplicor PCR assay targeting 16s ribosomal RNA genes. Eighty-five patients were enrolled: 27 patients had cultures positive for tuberculosis; 12 were smear-positive. PCR by both assays on the first specimen picked up all patients smear-positive on any specimen. A positive PCR on at least one of two specimens collected in the first 24 h was 85 and 74% sensitive and 88 and 93% specific for tuberculosis by the in-house and Roche techniques, respectively. Sensitivity in smear-negative patients was 73 and 53%, respectively. The in-house PCR detected 100% and Roche detected 95% of patients with more than paucibacillary (greater than 20 colonies) tuberculosis. We conclude that PCR may be a useful tool to evaluate patients for tuberculosis within the first hospital day.
Cardiac arrhythmias: theory and practice
Authors: J P Saunders
Journal: BMJ (1985)

paring different drugs for the treatment of serious arrhythmias.It does not follow, however, that the data obtained from such "single drug" studies are of no value.For example, in many studies using intracardiac techniques, tape monitoring, or exercise testing the patient acts as his own control and drug effect (or lack of it) can be accurately documented.There is now very good evidence that the acute effect of a drug on a ventricular tachycardia correlates well with long term suppression of the arrhythmia and prolonged survival.9Rigorously controlled comparisons of drugs in this patient group would be clinic- ally inappropriate and beset with ethical difficulties.We believe there is no place for an empirical approach to the treatment of tachycardias.Careful analysis of spontaneous recordings should allow correct diagnosis in most cases.Armed with this information and the clinical pattern of the arrhythmia, the physician should be able rationally to select a drug with known effects with a high chance of therapeutic success.
Proliferating dendritic cell progenitors in human blood.
Authors: N Romani, S Gruner, D Brang, E Kämpgen, A Lenz, B Trockenbacher, G Konwalinka, P O Fritsch, R M Steinman, G Schuler
Journal: The Journal of Experimental Medicine (1994)

CD34+ cells in human cord blood and marrow are known to give rise to dendritic cells (DC), as well as to other myeloid lineages. CD34+ cells are rare in adult blood, however, making it difficult to use CD34+ cells to ascertain if DC progenitors are present in the circulation and if blood can be a starting point to obtain large numbers of these immunostimulatory antigen-presenting cells for clinical studies. A systematic search for DC progenitors was therefore carried out in several contexts. In each case, we looked initially for the distinctive proliferating aggregates that were described previously in mice. In cord blood, it was only necessary to deplete erythroid progenitors, and add granulocyte/macrophage colony-stimulating factor (GM-CSF) together with tumor necrosis factor (TNF), to observe many aggregates and the production of typical DC progeny. In adult blood from patients receiving CSFs after chemotherapy for malignancy, GM-CSF and TNF likewise generated characteristic DCs from HLA-DR negative precursors. However, in adult blood from healthy donors, the above approaches only generated small DC aggregates which then seemed to become monocytes. When interleukin 4 was used to suppress monocyte development (Jansen, J. H., G.-J. H. M. Wientjens, W. E. Fibbe, R. Willemze, and H. C. Kluin-Nelemans. 1989. J. Exp. Med. 170:577.), the addition of GM-CSF led to the formation of large proliferating DC aggregates and within 5-7 d, many nonproliferating progeny, about 3-8 million cells per 40 ml of blood. The progeny had a characteristic morphology and surface composition (e.g., abundant HLA-DR and accessory molecules for cell-mediated immunity) and were potent stimulators of quiescent T cells. Therefore, large numbers of DCs can be mobilized by specific cytokines from progenitors in the blood stream. These relatively large numbers of DC progeny should facilitate future studies of their Fc epsilon RI and CD4 receptors, and their use in stimulating T cell-mediated resistance to viruses and tumors.
Fluorescence spectroscopy: a rapid, noninvasive method for measurement of skin surface thickness of topical agents
Authors: L.E. RHODES, B.L. DIFFEY
Journal: British Journal of Dermatology (1997)

We report the quantification of skin surface thickness of topical agents by in vivo fluorescence spectroscopy, and demonstrate its potential uses for assessment of application technique and substantivity. A series of studies were performed on forearm skin of eight normal subjects using three creams which have intrinsic fluorescence: a sunscreen (Neutrogena SPF15 waterproof cream), an antiseptic (Hewlett's cream) and a steroid (Trimovate (clobetasone butyrate) cream). Initially, the dose-response relationship was established for each agent by applying a series of five doses (0.5-8 microliters/cm2) and measuring cream fluorescence using appropriate excitation and emission wavelengths. Next, the influence of application technique was examined by comparing light application of cream with firm rubbing. Substantivity of the three creams was assessed on dry skin by taking fluorescence measurements over 8 h. Finally, water resistance of 2 microliters/cm2 of sunscreen and antiseptic cream were compared by measuring fluorescence after each of four water immersions. The fluorescence intensity was strongly correlated with the logarithm of surface density. r = 1.0, 0.92 and 0.98 for sunscreen, antiseptic and steroid creams, respectively, allowing derivation of a simple expression for equivalent thickness. Surface thickness of each cream was lower following firm rubbing compared with light application (P < 0.01). The rate constants for reduction of surface density of the three creams with time on dry skin were not significantly different. However, on washed skin, the rate constant was higher for Hewlett's than Neutrogena cream (0.503 and 0.243 h. respectively, P = 0.02), with a higher rate for each cream on wet compared with dry skin (P < 0.001). Hence, fluorescence spectroscopy is a simple, rapid method for measurement of cream thickness in vivo. The many potential applications in dermatology include quantitative assessment of application technique and substantivity of topical agents.