tbuckley/cabot-search huggingface dataset:
Avirulent <i>Toxoplasma gondii</i> Generates Therapeutic Antitumor Immunity by Reversing Immunosuppression in the Ovarian Cancer Microenvironment
Authors: Jason R. Baird, Barbara A. Fox, Kiah L. Sanders, Patrick H. Lizotte, Juan R. Cubillos-Ruiz, Uciane K. Scarlett, Melanie R. Rutkowski, Jose R. Conejo-Garcia, Steven Fiering, David J. Bzik
Journal: Cancer Research (2013)

Abstract Reversing tumor-associated immunosuppression seems necessary to stimulate effective therapeutic immunity against lethal epithelial tumors. Here, we show this goal can be addressed using cps, an avirulent, nonreplicating uracil auxotroph strain of the parasite Toxoplasma gondii (T. gondii), which preferentially invades immunosuppressive CD11c+ antigen-presenting cells in the ovarian carcinoma microenvironment. Tumor-associated CD11c+ cells invaded by cps were converted to immunostimulatory phenotypes, which expressed increased levels of the T-cell receptor costimulatory molecules CD80 and CD86. In response to cps treatment of the immunosuppressive ovarian tumor environment, CD11c+ cells regained the ability to efficiently cross-present antigen and prime CD8+ T-cell responses. Correspondingly, cps treatment markedly increased tumor antigen-specific responses by CD8+ T cells. Adoptive transfer experiments showed that these antitumor T-cell responses were effective in suppressing solid tumor development. Indeed, intraperitoneal cps treatment triggered rejection of established ID8-VegfA tumors, an aggressive xenograft model of ovarian carcinoma, also conferring a survival benefit in a related aggressive model (ID8-Defb29/Vegf-A). The therapeutic benefit of cps treatment relied on expression of IL-12, but it was unexpectedly independent of MyD88 signaling as well as immune experience with T. gondii. Taken together, our results establish that cps preferentially invades tumor-associated antigen-presenting cells and restores their ability to trigger potent antitumor CD8+ T-cell responses. Immunochemotherapeutic applications of cps might be broadly useful to reawaken natural immunity in the highly immunosuppressive microenvironment of most solid tumors. Cancer Res; 73(13); 3842–51. ©2013 AACR.
THE STRANGE CROSS-REACTION OF MENADIONE (VITAMIN K3) AND 2,4-DINITROPHENYL LIGANDS WITH A MYELOMA PROTEIN AND SOME CONVENTIONAL ANTIBODIES
Authors: Maria C. Michaelides, Herman N. Eisen
Journal: The Journal of Experimental Medicine (1974)

To explore the possibility that the affinity of some myeloma proteins for 2,4-dinitrophenyl (DNP) ligands is the consequence of a "strange" (i.e., unexpected) cross-reaction for more natural ligands, a variety of substances (primarily derivatives of purines, pyrimidines, naphthaquinone) were tested for ability to block the binding of [(3)H]-epsilon-DNP-L-lysine by protein 315, an IgA mouse myeloma protein with high affinity for DNP ligands. The most impressive inhibiting activity was observed with 2-methyl-1,4-napthaquinone (menadione, vitamin K(3)). The affinity (intrinsic association constant) of protein 315 for menadione was 5 x 10(5) L/M (at 4 degrees C). Because the same affinity was measured in direct-binding assays (e.g., equilibrium dialysis) and in an indirect one based on the assumption of competitive binding with DNP-lysine, it is likely that menadione and DNP bind at overlapping sites in the protein's combining region. This conclusion is supported by molecular models which reveal some common structural features in these ligands. Hence it is not surprising that antinitrophenyl antibody preparations, raised by conventional immunization procedures (anti-2,4-DNP; anti-2,6-DNP; anti-2,4,6-TNP) also bind menadione with considerable affinity. As with DNP ligands, when menadione binds to protein 315 or to conventional antinitrophenyl antibodies, some of the protein's tryptophan fluorescence is quenched, there is a change in the ligand's absorption spectrum (hypochromia and/or red shift), and the binding is temperature-dependent (exothermal).
History and implications of the neutrophil glycoprotein deficiencies
Authors: Barbara Styrt
Journal: American Journal of Hematology (1989)

Abstract This review focuses on the initial clinical descriptions and subsequent investigation of the syndrome of recurrent infections associated with neutrophil membrane glycoprotein deficiencies. Characterization of the missing group of three glycoprotein heterodimers and their role in adhesion‐related neutrophil function is summarized. Study of the clinical consequences of these genetically determined membrane glycoprotein defects has also contributed to the understanding of the role of normal neutrophils in both host defense and host tissue damage.
DNA Vaccination: Transfection and Activation of Dendritic Cells as Key Events for Immunity
Authors: Omid Akbari, Naveed Panjwani, Sylvie Garcia, Ricardo Tascon, Doug Lowrie, Brigitta Stockinger
Journal: The Journal of Experimental Medicine (1999)

The mechanisms underlying initiation and maintenance of CD4 T cell responses after DNA vaccination were studied using a construct coding for nonsecreted fifth component of complement (C5) protein, thus restricting the availability of antigen. The only cell types to express C5 were keratinocytes at the site of DNA application and a small number of dendritic cells present in the draining lymph nodes. Antigen expression persisted for up to 12 wk in keratinocytes, but dendritic cells did not express C5 beyond 2 wk after vaccination. Cross-priming of dendritic cells by C5 expressed in keratinocytes did not occur unless keratinocyte death was induced by irradiation in vitro. CD4 T cells were activated in the draining lymph nodes only and subsequently migrated to the spleen, where memory T cells persisted for longer than 40 wk despite the absence of a source of persistent antigen. While DNA vaccination resulted in transfection of a small proportion of dendritic cells only, it led to general activation of all dendritic cells, thus providing optimal conditions for effective T cell activation and maintenance of memory.
Risk of traffic accidents in patients with sleep-disordered breathing: reduction with nasal CPAP
Authors: W Cassel, T Ploch, C Becker, D Dugnus, JH Peter, P von Wichert
Journal: European Respiratory Journal (1996)

Sleepiness whilst driving constitutes a road safety risk. Sleep-related breathing disorders are the most frequent medical cause of daytime sleepiness, and untreated patients with this condition have been shown to be at a higher risk of having accidents while driving. This study addressed the question of the extent to which treatment of sleep-disordered breathing by nasal continuous positive airway pressure (nCPAP) is related to changes in patient's accident risk. Seventy eight male patients requiring treatment of sleep-related breathing disorders with nCPAP were enrolled in the study. The protocol included a questionnaire dealing with alertness-related problems while driving, an 80 min vigilance test, and the Multiple Sleep Latency Test. These baseline evaluations were repeated after 1 year of treatment with nCPAP. Fifty nine patients completed the study. The accident rate was significantly decreased from 0.8 per 100,000 km (untreated) to 0.15 per 100,000 km with nCPAP treatment. Variables that were considered to be likely to increase accident risk (sleeping spells, fatigue, vigilance test reaction time, daytime sleep latency) also improved with treatment. We conclude that treatment of sleep-disordered breathing by nasal continuous positive airway pressure is related to reduction in patient motor vehicle accident rates, probably due to the reversal of excessive daytime sleepiness.
The role of long chain fatty acids in regulating food intake and cholecystokinin release in humans
Authors: D Matzinger
Journal: Gut (2000)

<h3>BACKGROUND AND AIMS</h3> The mechanism of intraduodenal fat induced inhibition of food intake is still unclear. Therefore, we tested the ability of duodenal fatty acids to suppress food intake at a lunchtime meal; in addition, we were interested to test if these effects were mediated by cholecystokinin (CCK) A receptors. <h3>SUBJECTS AND METHODS</h3> Three sequential double blind, three period crossover studies were performed in 12 healthy males each: (1) subjects received intraduodenal fat with or without 120 mg of tetrahydrolipstatin, an inhibitor of gastrointestinal lipases, or saline; (2) volunteers received intraduodenal long chain fatty acids, medium chain fatty acids, or saline; (3) subjects received long chain fatty acids or saline together with concomitant intravenous infusions of saline or loxiglumide, a specific CCK-A receptor antagonist. The effect of these treatments on food intake and feelings of hunger was quantified. <h3>RESULTS</h3> Intraduodenal fat perfusion significantly (p&lt;0.05) reduced calorie intake. Inhibition of fat hydrolysis abolished this effect. Only long chain fatty acids significantly (p&lt;0.05) decreased calorie intake, whereas medium chain fatty acids were ineffective. Infusion of loxiglumide abolished the effect of long chain fatty acids. <h3>CONCLUSIONS</h3> Generation of long chain fatty acids through hydrolysis of fat is a critical step for fat induced inhibition of food intake; the signal is mediated via CCK-A receptors.
Menopause and ischaemic stroke: basic, clinical and epidemiological considerations. The role of hormone replacement
Authors: A. Pines
Journal: Human Reproduction Update (2002)

Stroke is a leading cause of disability and death in women, despite progress in its prevention and treatment. As with coronary artery disease, the incidence of stroke rises after the menopause, in parallel with metabolic changes that add up to create an unfavourable risk factor profile for cardiovascular disease. The menopause metabolic syndrome, which includes weight gain and changes in lipids, insulin resistance, endothelial dysfunction, increased levels of homocysteine, lipoprotein (a) and several coagulation factors, may in part be attributable to estrogen deficiency, and may be reversible with hormone replacement therapy (HRT). As for blood pressure, a major detrimental risk factor for stroke, it is probably not affected by either the menopause per se or by HRT. Abundant experimental data exist indicating that estrogens have both anti-atherosclerotic and neuroprotective effects. The width or thickness of the carotid wall is a good indicator of carotid atherosclerosis; it increases after the menopause transition, and decreases with HRT. Estrogens may enhance cerebral blood flow and reduce vascular resistance. In animal models of stroke, estrogen induced anti-ischaemic effects. Several large-scale epidemiological studies have verified the concept of primary protection of stroke by HRT, though others have failed to do so. In light of these contradictory data, several recent reports were highly significant (Nurses' Health Study, HERS Study, Cancer Prevention II Trial, WEST Trial). Despite the known neural and vascular benefits of estrogen, it is uncertain whether HRT is associated with stroke protection. At present, prevention of stroke should involve proven risk reduction strategies.
natural selection of asymmetric traits operates at multiple levels
Authors: michael k. mcbeath, thomas g. sugar
Journal: Behavioral and Brain Sciences (2005)

natural selection of asymmetric traits operates at multiple levels. some asymmetric traits (like having a dominant eye) are tied to more universal aspects of the environment and are coded genetically, while others (like pedestrian turning biases) are tied to more ephemeral patterns and are largely learned. species-wide trends of asymmetry can be better modeled when different levels of natural selection are specified.
Platelet CD36 mediates interactions with endothelial cell–derived microparticles and contributes to thrombosis in mice
Authors: Arunima Ghosh, Wei Li, Maria Febbraio, Ricardo G. Espinola, Keith R. McCrae, Erin Cockrell, Roy L. Silverstein
Journal: Journal of Clinical Investigation (2008)

CD36 is a scavenger receptor that binds multiple ligands, including phosphatidyl serine (PS). Although CD36– mice do not have a bleeding diathesis, we show here that they do have significantly prolonged thrombotic occlusion times in response to FeCl3-induced vascular injury. Because cell-derived microparticles (MPs) are generated in response to vascular injury and circulate in patients with prothrombotic diseases, we hypothesized that PS exposed on their surfaces could be an endogenous CD36 ligand that transmits an activating signal to platelets. We found that MPs prepared from human ECs, monocytes, or platelets or isolated from blood of normal subjects bound to platelets. Binding was not observed with platelets from CD36– donors and was inhibited by an anti-CD36 antibody or by blockade of exposed PS by annexin V or anti-PS IgM. Preincubation of platelets with MPs led to CD36-dependent augmentation of platelet activation in response to low doses of ADP, as assessed by measuring α2bβ3 activation, P-selectin expression, and aggregation. Immunofluorescence confocal microscopy of murine carotid thrombi from CD36– mice showed a significant decrement in endothelial antigen accumulation, which suggests that CD36 plays a role in MP recruitment into thrombi. These results provide what we believe to be a novel role for CD36 in thrombosis.
Alterations of cross-bridge kinetics in human atrial and ventricular myocardium
Authors: Thorsten Ruf, Heiner Schulte-Baukloh, Jens Lüdemann, Herbert Posival, Friedhelm Beyersdorf, Hanjörg Just, Christian Holubarsch
Journal: Cardiovascular Research (1998)

Condensed abstract: We analyzed actomyosin cross-bridge kinetics in human atrial and ventricular muscle strip preparations by using sinusoidal length changes from 0.1 to 60 Hz. The minimum stiffness frequency was higher in atrial than in ventricular human myocardium and lower in failing than in non-failing left ventricular human myocardium. β-Adrenergic stimulation increased the minimum stiffness frequency by 18±3% (p<0.05). Cross-bridge kinetics are temperature-dependent, with a Q10 of at least 2.7. Background: Dynamic stiffness measurements have revealed acute and chronic alterations of actomyosin cross-bridge kinetics in cardiac muscles of a variety of different animal species. We studied dynamic stiffness in right atrial and left ventricular preparations of non-failing and failing human hearts and tested the influence of the temperature and β-adrenergic stimulation on cross-bridge kinetics. Methods and Results: Muscle strips were prepared from right atria and left ventricles from human non-failing and failing hearts. After withdrawal of calcium, steady contracture tension was induced by the addition of 1.5 mM barium chloride. Sinusoidal length oscillations of 1% muscle length were applied, with a frequency spectrum of between 0.1 and 60 Hz. Dynamic stiffness was calculated from the length change and the corresponding force response amplitude. The specific minimum stiffness frequency, which indicates the interaction between cross-bridge recruitment and cross-bridge cycling dynamics, was analyzed for each condition: (1) The minimum stiffness frequency was 0.78±0.04 Hz in left ventricular myocardium and 2.80±0.31 Hz in right atrial myocardium (p<0.01) at 27°C. (2) The minimum stiffness frequency was 41% higher in non-failing compared to failing left ventricular human myocardium. (3) Over a wide range of experimental temperatures, the minimum stiffness frequency changed, with a Q10 of at least 2.7. (4) β-Adrenergic stimulation significantly (p<0.05) increased the minimum stiffness to 18±3% higher frequencies and significantly (p<0.05) lowered contracture tension by 7±1%. Conclusions: The contractility of human heart muscle is not only regulated by excitation–contraction coupling but also by modulation of intrinsic properties of the actomyosin system. Acute and chronic alterations of cross-bridge kinetics have been demonstrated, which play a significant role in the physiology and pathophysiology of the human heart.
The plasmin cascade and matrix metalloproteinases in non-small cell lung cancer
Authors: G Cox, W P Steward, K J O'Byrne
Journal: Thorax (1999)

There are several steps involved in the metastatic spread of cancer from the primary tumour to a secondary remote site. Firstly, the cancer cells have to escape from the primary site and then intravasate into the blood or lymphatic circulation. The cells must survive transportation in the circulation before extravasating at a distant site. These cells then need to establish themselves at the new site before growth and replication can occur to form a metastatic colony. During this time the malignant cell has to avoid destruction by the host immune system. Vital to the growth of both the primary and metastatic disease is the capacity of the tumour to induce breakdown of the extracellular matrix (ECM) and the formation of a blood supply through new blood vessel formation, a process known as angiogenesis. The ECM is a framework of proteins and proteoglycans secreted by and surrounding stromal fibroblasts. It gives structural support to cells and plays a central role in cell adhesion, diVerentiation, proliferation, and migration. The ECM is separated from epithelial cells by a basement membrane which is made up of type IV collagen and creates a scaVold upon which heparan sulphate, laminin, and other components are arranged. 1
Distribution of the retrotransposable element 412 in Drosophila species
Authors: G. Cizeron, F. Lemeunier, C. Loevenbruck, A. Brehm, C. Biemont
Journal: Molecular Biology and Evolution (1998)

Copy numbers of sequences homologous to the Drosophila melanogaster retrotransposable element 412, their distribution between the chromosome arms and the chromocenter, and whether they contain full-size copies were analyzed for 55 species of the Drosophila genus. Element 412 insertion sites were detected on the chromosome arms of D. melanogaster, Drosophila simulans, and a few species of the obscura group, but the chromocenter was labeled in almost all species. The presence of element 412 sequences in the majority of species shows that this element has a long evolutionary history in Drosophilidae, although it may have recently invaded the chromosomes in some species, such as D. simulans. Differences in copy number between species may be due to population size or specific endogenous or environmental factors and may follow the worldwide invasion of the species. Putative full-length copies were detected in the chromocenters of some species with no copies on the chromosome arms, suggesting that the chromocenter may be a shelter for such copies and not only for deleted ones.
The Persian Gulf Experience and Health
Authors: Gareth M. Green
Journal: JAMA (1994)

FOLLOWING the return of US and coalition forces from the complex environment of the Persian Gulf region during Operations Desert Shield and Desert Storm and the operational conditions of the military deployment, a variety of health effects have been reported. Many troops were exposed to potentially adverse substances and experiences present in this wartime environment, fumes and smoke from military operations, oil well fires, diesel exhaust, toxic paints, pesticides, sand, depleted uranium, infectious agents, chemoprophylactic agents, and multiple immunizations; some troops are convinced they were exposed to chemical or biological weapons. Few combat casualties occurred, but substantial transient gastrointestinal and respiratory symptoms were seen during the troop buildup and immediately after the short conflict. Since then, there have been increasing reports of illness from troops who were participants in these operations, and many attribute their health problems to these experiences. Many of the cases include combinations of nonspecific symptoms of
Measuring the accuracy of genome-size multiple alignments
Authors: Amol Prakash, Martin Tompa
Journal: Genome biology (2007)

Abstract Whole-genome alignments are invaluable for comparative genomics. Before doing any comparative analysis on a region of interest, one must have confidence in that region's alignment. We provide a methodology to measure the accuracy of arbitrary regions of these alignments, and apply it to the UCSC Genome Browser's 17-vertebrate alignment. We identify 9.7% (21 Mbp) of the human chromosome 1 alignment as suspiciously aligned. We present independent evidence that many of these suspicious regions represent misalignments.
Human Papillomavirus Type 18 DNA Load and 2-Year Cumulative Diagnoses of Cervical Intraepithelial Neoplasia Grades 2-3
Authors: L. F. Xi, L. A. Koutsky, P. E. Castle, C. M. Wheeler, D. A. Galloway, C. Mao, J. Ho, N. B. Kiviat
Journal: JNCI Journal of the National Cancer Institute (2009)

The clinical relevance of the amount of human papillomavirus type 18 (HPV18) DNA in cervical tissue (ie, HPV18 DNA load) is unknown. Study subjects were 303 women who were HPV18 positive at enrollment into the Atypical Squamous Cells of Undetermined Significance (ASC-US) and Low-Grade Squamous Intraepithelial Lesion (LSIL) Triage Study. HPV18 DNA load, expressed as copies of HPV18 per nanogram of cellular DNA, at enrollment was quantitatively measured. Subjects were followed up semiannually for a period of 2 years for detection of cervical intraepithelial neoplasia 2–3 (CIN2–3). A linear regression model was used to examine associations of CIN2–3 with HPV18 DNA load. All statistical tests were two-sided. CIN2–3 was confirmed in 92 of 303 (30.4%) HPV18-positive women. Among women without CIN2–3, HPV18 DNA load was positively associated with increasing severity of cervical cytology at enrollment ( Ptrend < .001). However, among those with CIN2–3, HPV18 DNA load was not associated with severity of cervical cytology at enrollment ( Ptrend = .33). The ratios of geometric means of HPV18 DNA load at enrollment among women with CIN2–3, relative to those without, were 6.06 (95% confidence interval [CI] = 0.31 to 117.92) for those with normal cytology at enrollment, 0.50 (95% CI = 0.10 to 2.44) for those with ASC-US, 0.11 (95% CI = 0.03 to 0.46) for those with LSIL, and 0.07 (95% CI = 0.01 to 0.80) for those with high-grade squamous intraepithelial lesion (HSIL). After adjusting for age and coinfection with other high-risk HPVs, a statistically significant association of lower HPV18 DNA load with CIN2–3 was observed among women with LSIL or HSIL at enrollment ( P = .02). Within the 2-year period, HPV18 DNA load was unrelated to the timing of CIN2–3 diagnosis. Overall results were similar when the outcome was CIN3. HPV18 DNA load was higher for women with LSIL or HSIL at enrollment with no evidence of CIN2–3 during the 2-year follow-up period than it was for women with CIN2–3. Thus, testing for high levels of HPV18 DNA does not appear to be clinically useful.
Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting.
Authors: T A Lister, D Crowther, S B Sutcliffe, E Glatstein, G P Canellos, R C Young, S A Rosenberg, C A Coltman, M Tubiana
Journal: Journal of Clinical Oncology (1989)

The Ann Arbor classification for describing the stage of Hodgkin's disease at initial presentation has formed the basis upon which treatment is selected and has allowed comparison of results achieved by different investigators for almost two decades. A meeting was convened to review the classification and modify it in the light of experience gained in its use and new techniques for evaluating disease. It was concluded that the structure of the classification be maintained. It was particularly recommended: (1) that computed tomography (CT) be included as a technique for evaluating intrathoracic and infradiaphragmatic lymph nodes; (2) that the criteria for clinical involvement of the spleen and liver be modified to include evidence of focal defects with two imaging techniques and that abnormalities of liver function be ignored; (3) that the suffix 'X' to designate bulky disease (greater than 10 cm maximum dimension) be introduced; and (4) that a new category of response to therapy, unconfirmed/uncertain complete remission (CR[u]), be introduced to accommodate the difficulty of persistent radiological abnormalities of uncertain significance.